Virtual Library

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    ES04 - Multimodality Management of Small Cell and Neuroendocrine Cancers (ID 7)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 6
    • Now Available
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      ES04.01 - Update in Systemic Treatment of SCLC (Now Available) (ID 3168)

      10:30 - 12:00  |  Presenting Author(s): Sumitra Thongprasert

      • Abstract
      • Presentation
      • Slides

      Abstract

      Chemotherapy combination of cisplatin plus etoposide is the standard option for extensive stage Small Cell Lung Cancer (SCLC); though the response rate was very high, however most cases of the extensive stage recurred within one year and there was no good regimen for second line. Several chemotherapeutic agents such as topotecan, irinotecan, amrubicin or combination of cyclophosphamide, doxorubicin and vincristine (CAV) had been used as second line treatment with minimal benefit.

      Within the past couple years there’re the new way of treating lung cancer especially the use of immunotherapy, which several agents had their roles in the treatment of Non-Small Cell Lung Cancer (NSCLC). The study of immunotherapy in SCLC was very slow. The use of T cell immune-checkpoint inhibitors (anti-PD1: nivolumab, pembrolizumab; anti-PD-L1: atezolizumab, durvalumab; anti-CTLA-4: ipilimumab, tremelimumab) have shown promising antitumor activity with the potential to prolong survival in SCLC patients.

      Nivolumab was the first immunotherapy agent that had approved by The US Food and Drug Administration (FDA) 2018 to be the third line drug according to the outcome in CheckMate-032, which’s a multicenter, open-label trial in patients with metastatic solid tumors. This subgroup comprised 109 patients with metastatic SCLC, with disease progression after platinum-based therapy and at least one other prior line of therapy, regardless of tumor PD-L1 status. All patients received nivolumab at3 mg/kg by intravenous infusion over 60 minutes every 2 weeks. The ORR was 12% (95% CI: 6.5, 19.5). Responses were durable for 6 months or longer in 77%, 12 months or longer in 62%, and 18 months or longer in 39% of the 13 responding patients. PD-L1 tumor status did not appear to be predictive of response.

      Pembrolizumab has been granted a priority review designation by the FDA for the treatment of patients with advanced small cell lung cancer (SCLC) whose disease has progressed following ≥2 prior lines of therapy. Data from the phase II KEYNOTE-158 and phase Ib KEYNOTE-028 studies, pembrolizumab at 200 mg intravenously (IV) every 3 weeks for 2 years or until disease progression, unacceptable toxicity, or study withdrawal elicited 19% and 33% overall response rates (ORRs) in patients with extensive-stage SCLC, respectively.

      Atezolizumab plus carboplatin and etoposide, was approved by FDA for the first-line treatment of adult patients with extensive-stage small cell lung cancer based on the data from IMpower133 which is a randomized treatment using atezolizumab 1200 mg and carboplatin AUC 5 mg/mL/min on day 1 and etoposide 100 mg/m2 intravenously on days 1, 2 and 3 of each 21-day cycle for a maximum of 4 cycles, followed by atezolizumab 1200 mg once every 3 weeks until disease progression or unacceptable toxicity, or placebo and carboplatin AUC 5 mg/mL/min on day 1 and etoposide 100 mg/m2 intravenously on days 1, 2, and 3 of each 21-day cycle for a maximum of 4 cycles, followed by placebo once every 3 weeks until disease progression or unacceptable toxicity. Overall survival (OS) was 12.3 months for patients receiving atezolizumab with chemotherapy and 10.3 months for those receiving placebo with chemotherapy (hazard ratio 0.70; 95% CI: 0.54, 0.91; p=0.0069). Median PFS was 5.2 months (4.4, 5.6) compared with 4.3 months (4.2, 4.5) in the atezolizumab and placebo arms, respectively (HR 0.77; 0.62, 0.96; p=0.0170).

      In conclusion, there are several new ways and also new agents that target the immune cell and should be able to improve the outcome and survival of SCLC.

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      ES04.02 - Pathology Overview for Carcinoid and NE Spectrum (Now Available) (ID 3169)

      10:30 - 12:00  |  Presenting Author(s): Elisabeth Brambilla

      • Abstract
      • Presentation
      • Slides

      Abstract

      Pathology Overview for carcinoid and Neuroendocrine Spectrum

      The spectrum of neuroendocrine (NE) tumors ranges from low grade typical carcinoid (TC) to intermediate grade Atypical carcinoids to high grade small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) Although very different from high grade tumors in their molecular genetics and expression profiling, carcinoid are included in the spectrum of NE tumors since WHO 2015 (1) on the basis of their common NE epithelial differentiation.Carcinoids display many clinical differences with high grade NE tumors being not strongly associated with smoking (only 20-40% smokers), their specific association with Multiple Endocrine Neoplasia type 1 (MEN1 ) not seen in High grade tumors and their occurrence on the background of NE cell hyperplasia and tumorlets in 60% of TC and AC, very rare in high grade tumors . Whereas carcinoid are never combined with conventional lung cancer , 20 to 25% of SCLC and LCNEC are combined. Since the NE markers are common in the full spectrum , morphology , mitoses and KI 67 (proliferations markers) are useful to differentiate carcinoids from SCLC and LCNEC . The accurate diagnosis of each is critical in view of their eminently different therapeutic management .

      Small cell lung carcinoma (SCLC

      SCLC is the most frequent NE lung tumor (15-20% of lung cancer) and has the worse prognosis in the spectrum. Most are proximal,70% perihilar forming peribronchial growth involving lymph nodes .Less than 5% are solitary primary nodules stage I. SCLC is a high grade malignant epithelial NE tumor with characteristic cytopathologic features recognizable in routine microscopy without use of immunohistochemistry (IHC) in optimal cell preservation. IHC may be used in suboptimal condition (crush artifact) to confirm the diagnosis.

      SCLC is made of sheets of small cells ,round/oval or spindle shaped forming whorls, with little cytoplasm , nuclei with unconspicuous nucleoli , finely granular dispersed chromatin , and nuclear molding . Mitotic rate is very high more than 50 reaching 100 for 2mm2 and KI67 exceeds 50% (50-100%).Extensive necrosis is frequent .Most SCLC express NE markers Chromogranine A, Synaptophysin and CD56 . 75% express TTF1 (recommended clone 8G7G3 1) . Less than 10% remain negative for all 3 NE markers and TTF1 . In these cases a P40 staining is mandatory to eliminate a basaloid carcinoma (P40 Positive) with which it may be confused in suboptimal preparations .

      SCLC can present as pure or combined. Any association of small cells with another NSCLC (Adenocarcinoma, Squamous cell carcinoma , large cell or large cell NE carcinoma , sarcomatoid giant and spindle cells ) is diagnosed as combined SCLC (20%) .

      Several studies of their molecular characteristics were recently published and compared with other tumors of the NE spectrum . Theses are specific , closer from a part of LCNEC but distinct from theses of carcinoids (Georges 2016 , Georges 2018 ) . Small cell carcinoma in non-smokers should be looked for EGFR mutation (acquired after TKI therapy of an Adenocarcinoma or spontaneous ).

      Large cell neuro endocrine carcinoma (LCNEC)

      LCNEC is a high grade NE lung tumor accounting for 3% of lung cancers .The diagnosis is based on the necessary association of NE morphology (organoid nesting ,rosettes ,palisading) and expression of NE markers (at least one) : chromogranine A, synaptophysin and CD56. Seventy-nine % develop in the lung periphery , 5% show endobronchial growth .They form circonscribed nodular mass intensely necrotic .They lack typical cytology in contrast with SCLC .The mitotic rate is more than 10 per 2mm2to distinguish them from atypical carcinoid (2 -10/2mm 2) ,ranging from 20 to 80-100 with KI67 very high exceeding 50% usually 80-100%. They are composed of large cells with low nuclear to cytoplasmic ratio , a conspicuous nucleoli and vesicular chromatin .A spectrum of morphologies range from SCLC (small cell –like) to non small cell-like or to a few atypical carcinoids-like , showing the need for an accurate diagnosis using objective criteria (proliferation). A constellation of multiple criteria should be used to distinguish them fro SCLC or AC .Combined LCNEC is the association of any LCNEC component with a conventional component ( 25% ). Due to spatial heterogeneity of NE morphology and NE expression the diagnostic may be difficult on small biopsies .However a NSCLC without NE morphology but 1 or 2 NE markers is diagnosed as a NSCLC (with unclear phenotype ) since 15 % of NSCLC also express 1 or 2 NE markers.TTF1 is expressed in 41 % of LCNEC specially when combined with adenocarcinoma.Molecular genomics and expression profiling classify in 2 categories one simiilar to SCLC with biallelic inactivation of P53 and RB genes and another with KEAP 1 or LKB1 mutations looking like NSCLC .LCNEC are very different from Carcinoids (Georges 2018 )

      Carcinoids tumors : Typical and Atypical Carcinoids

      Carcinoids account for 1-2 % of lung tumors of which 10% are Atypical carcinoid .Typical ( low grade) and atypical carcinoids(intermediate grade) are distinquished on objective criteria (mitoses index (table I) and necrosis, but KI67 has no defined cut- off to separate them.

      They develop centrally as endobronchial growth or in the lung periphery (16-40 %) Cytology allows accurate recognition . NE morphology is well achieved with organoid patterns( glandular, follicular ,trabecular , angiomatoid…) most often multiple .Spindle cell pattern is more frequent in the peripheral carcinoids.

      All express the 3 NE markers and TTF1 is usually negative (except in a few peripheral carcinoids )

      References

      Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of tumours of the lung, pleura, thymus and heart, 4th ed. Lyon: IARC; 2015. 


      Travis WD ,Nicholson AG ,Geisinger KR, Brambilla E.Tumors of the lower respiratory tract AFIP Atlas of Tumor pathology series 4 ed. AFIP Press Bethesda 2019

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      ES04.03 - Surgery for Early and Locally Advanced Small Cell Lung Cancer (Now Available) (ID 3170)

      10:30 - 12:00  |  Presenting Author(s): Eric Lim

      • Abstract
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      Abstract not provided

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      ES04.04 - Role of Stereotactic Body Radiation in Early and Advanced SCLC (Now Available) (ID 3171)

      10:30 - 12:00  |  Presenting Author(s): Roy Decker

      • Abstract
      • Presentation
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      Abstract

      Stereotactic Body Radiotherapy (SBRT) has been rapidly adopted as the standard of care for patients with early-stage Non-Small Cell Lung Cancer (NSCLC) who are medically inoperable, and more recently for selected patients with oligometastatic cancer. The utilization of SBRT in patients with Small Cell Lung Cancer (SCLC) is markedly lower, reflecting both the lower incidence and the lack of clinical data, but it has been increasing over the past several years. Given the aggressive nature and high metastatic potential of SCLC, the optimal integration of SBRT into the multimodality treatment of early-stage SCLC patients is critical, so that we don’t delay or otherwise compromise systemic therapy. In patients with advanced or recurrent SCLC, SBRT offers a valuable treatment option for well selected patients, a group that may be increasing as new therapeutic options emerge.

      Small Cell Lung Cancer (SCLC) represents less than 20% of all new lung cancer diagnoses. Compared to NSCLC, SCLC is less likely to present with localized disease, carries a higher risk of metastatic failure, and stage for stage is associated with worse overall survival. The majority of limited stage SCLC patients have locally advanced tumors, and the standard of care remains concurrent chemotherapy with fractionated thoracic radiation. Stage I SCLC is diagnosed in less than 5% of incident cases. Given the propensity for nodal metastasis, invasive staging of the mediastinum is indicated in all of these patients. For those who are node negative, there is a limited amount of data to guide decisions about optimal management. Surgery has emerged as a standard of care for operable patients, based on favorable outcomes in population-based studies. Following surgery, adjuvant chemotherapy is recommended regardless of tumor size, based on the high risk of subsequent metastatic failure.

      For those patients who won’t tolerate lobectomy, consensus guidelines now recognize that Stereotactic Body Radiotherapy (SBRT) is a treatment option, and a reasonable alternative to conventional chemoradiotherapy. This is largely justified by the observed increased efficacy of SBRT compared to fractionated radiation in stage I NSCLC, an observation which is now supported by a randomized trial. The published data to date suggests that the utilization of SBRT in stage I SCLC has been increasing. Single- and multi-institutional case series suggest, unsurprisingly, that this approach appears to be safe, and the efficacy in terms of local control appears to be similar to that seen in NSCLC patients. In the US, the use of SBRT in SCLC appears to be more common in elderly patients, and the utilization seems to be driven by large institutions.

      Chemotherapy is an essential part of multimodality care of SCLC in all stages of disease. The addition of adjuvant chemotherapy sequentially after SBRT in early stage patients is associated with improved survival in retrospective studies, similar to the better outcomes seen with surgery and chemotherapy in operable SCLC patients. Recent and ongoing prospective efforts are evaluating concurrent chemotherapy with SBRT, including both traditional short-course and more extended hypo-fractionated radiation schedules.

      Trends in stereotactic body radiation therapy for stage I small cell lung cancer. Stahl JM, Corso CD, Verma V, Park HS, Nath SK, Husain ZA, Simone CB 2nd, Kim AW, Decker RH. Lung Cancer. 2017 Jan;103:11-16.

      Multi-Institutional Experience of Stereotactic Ablative Radiation Therapy for Stage I Small Cell Lung Cancer. Verma V, Simone CB 2nd, Allen PK, Gajjar SR, Shah C, Zhen W, Harkenrider MM, Hallemeier CL, Jabbour SK, Matthiesen CL, Braunstein SE, Lee P, Dilling TJ, Allen BG, Nichols EM, Attia A, Zeng J, Biswas T, Paximadis P, Wang F, Walker JM, Stahl JM, Daly ME, Decker RH, Hales RK, Willers H, Videtic GM, Mehta MP, Lin SH. Int J Radiat Oncol Biol Phys. 2017 Feb 1;97(2):362-371.

      Clinical Outcomes of Stereotactic Body Radiotherapy for Patients With Stage I Small-Cell Lung Cancer: Analysis of a Subset of the Japanese Radiological Society Multi-Institutional SBRT Study Group Database. Shioyama Y, Onishi H, Takayama K, Matsuo Y, Takeda A, Yamashita H, Miyakawa A, Murakami N, Aoki M, Matsushita H, Matsumoto Y, Shibamoto Y; Japanese Radiological Society Multi-Institutional SBRT Study Group (JRS-SBRTSG). Technol Cancer Res Treat. 2018 Jan 1;17:1533033818783904.

      Stereotactic body radiotherapy with concurrent chemotherapy extends survival of patients with limited stage small cell lung cancer: a single-center prospective phase II study. Li C, Xiong Y, Zhou Z, Peng Y, Huang H, Xu M, Kang H, Peng B, Wang D, Yang X. Med Oncol. 2014 Dec;31(12):369.

      Outcomes of Stereotactic Body Radiotherapy for T1-T2N0 Small Cell Carcinoma According to Addition of Chemotherapy and Prophylactic Cranial Irradiation: A Multicenter Analysis. Verma V, Simone CB 2nd, Allen PK, Lin SH. Clin Lung Cancer. 2017 Nov;18(6):675-681.e1.

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      ES04.05 - Advances in Radionuclide Treatment for Neuroendocrine Tumours (Now Available) (ID 3172)

      10:30 - 12:00  |  Presenting Author(s): Angela Lamarca

      • Abstract
      • Presentation
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      Abstract

      Lung carcinoids (LC) are rare tumours, however incidence is increasing due to improvement in diagnostic techniques. They account for approximately 2% of all lung malignancies and around 20-30% of all neuroendocrine tumours (NETs). They characteristically have an indolent clinical behaviour with longer survival intervals compared to poorly differentiated lung neuroendocrine malignancies. LC are divided into typical or atypical carcinoid tumours according to pathological characteristics, such as amount of mitosis and necrosis.

      A significant proportion of LC expresses somatostatin receptors by immunohistochemistry. Nuclear medicine imaging, such as somatostatin receptor scintigraphy, has been employed for staging of LC for years. Development of new nuclear medicine imaging techniques, including Positron Emission Tomography (PET) combined with CT has improved diagnosis, staging and treatment of patients diagnosed with LC. 68-Gallium(68Ga)-radiolabelled PET (68Ga-DOTA-PET) tracers for functional NET imaging have emerged as potentially useful tools for diagnosis and staging.

      For localised stages of LCs, surgery is the treatment of choice, performed with curative intent. Locally advanced inoperable or metastatic tumours are treated with palliative approaches based on somatostatin analogues (SSAs), temozolomide-based chemotherapy combination and targeted therapies (everolimus). Recently, the use of Peptide Receptor Radionuclide Therapy (PRRT) has revolutionised the treatment of extra-pulmonary neuroendocrine tumours. Based on the results of the NETTER-1 study, PRRT has been approved for the management of small bowel and pancreatic NETs and it is considered a standard of care after progression to SSA for patients with uptake in 68Ga-DOTA-PET (theranostic approach).

      This lecture will summarise the state of the art of LC with a focus behind the rationale of PRRT and its potential role in the management of LCs.

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      ES04.06 - Systemic Treatment of Large Cell Neuroendocrine Cancer (Now Available) (ID 3173)

      10:30 - 12:00  |  Presenting Author(s): Fiona Blackhall

      • Abstract
      • Presentation
      • Slides

      Abstract

      Large cell neuroendocrine cancer (LCNEC) is a rare, aggressive cancer that accounts for approximately 3% of all lung cancer. It is characterised by high-grade features (>10 mitoses/2mm2) and the presence of neuroendocrine morphology and markers (1). The diagnosis of LCNEC is distinct from both non-small cell lung cancer (NSCLC) and other pulmonary neuroendocrine tumours such as carcinoids and small cell lung cancer (SCLC). Survival is poor with only 5% of patients alive at 5 years from diagnosis regardless of stage at presentation. Conventionally treatment has mirrored that of SCLC despite limited evidence for this approach. The recommended standard of care is a combination of platinum with etoposide based on the results of one single arm phase 2 study in which there were only 29 evaluable patients (2). The median progression free survival (PFS) and overall survival (OS) rates were 5 months and 8 months respectively. Of note the observed objective response rate was 34%, lower than reported ORRs in SCLC of ~70%. Similar worse outcomes in the LCNEC population are observed for treatment with irinotecan and cisplatin (3). The explanation for this disparity is provided by emerging evidence that LCNEC can be subcategorised into two major and clinically relevant subsets according to genomic characteristics (4). A ‘SCLC-like’ genomic profile is estimated to account for about 40% of LCNEC, characterised by RB1 and TP53 that hallmark SCLC and ‘SCLC-like’ LCNEC has clinical behaviour consistent with SCLC. The other subset is ‘NSCLC-like’ with wild-type RB1 as the main distinction alongside mutations that also occur recurrently, at various frequencies, in NSCLC such as STK11, KRAS, KEAP1 and NFE2L2. The latter were hypothesised to be relatively more sensitive to chemotherapy approved for NSCLC. Consistent with this, in a carefully conducted retrospective analysis patients with NSCLC-like LCNEC (RB1 wild type) who received platinum with gemcitabine or a taxane had a median OS of 9.6 months whereas those who received platinum and etoposide had a significantly shorter median OS of 5.8 months (p=0.026) (5). These results question the current standard of care for LCNEC and highlight the need for prospective examination of molecular subtyping to direct treatment decision making. The molecular heterogeneity underpinning LCNEC may also have implications for selection of immune checkpoint inhibitors (6) and other precision medicines targeting actionable mutations (7). The advent of specific KRAS inhibitors that appear promising in early phase development (8) generates further impetus to redesign our therapeutic algorithms for LCNEC according to genomic context if we are to improve outcomes for patients with this orphan disease.

      References

      1. Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JHM, Beasley MB, et al. The 2015 World Health Organization Classification of Lung Tumors. Journal of Thoracic Oncology.10(9):1243-60.

      2. Multicentre phase II study of cisplatin-etoposide chemotherapy for advanced large-cell neuroendocrine lung carcinoma: the GFPC 0302 study. Le Treut J et al. Ann Oncol. 2013: 24(6):1548-52.

      3. Combination chemotherapy with irinotecan and cisplatin for large-cell neuroendocrine carcinoma of the lung: a multicentre phase II study. Niho et al. J Thoracic Oncol 2013: 8:980-4

      4. Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma–like and Non–Small Cell Carcinoma–like Subsets. Rekhtman N et al. Clinical Cancer Research. 2016;22(14):3618.

      5. Molecular Subtypes of Pulmonary Large-cell Neuroendocrine Carcinoma Predict Chemotherapy Treatment Outcome. Derks JL et al. Clinical Cancer Research. 2018;24(1):33.

      6. Genomic Alterations (GA) and Tumor Mutational Burden (TMB) in Large Cell Neuroendocrine Carcinoma of Lung (L-LCNEC) as Compared to Small Cell Lung Carcinoma (SCLC) as Assessed Via Comprehensive Genomic Profiling (CGP). Chae et al. J Clin Oncol 2017; 35:15 suppl, 851

      7. Comparison of genomic landscapes of large cell neuroendocrine carcinoma, small cell lung carcinoma, and large cell carcinoma. Zhou Z et al. Thorac Cancer 2019 10(4):839-847

      8. Direct Ras G12C Inhibitors : Crossing the Rubicon. Lindsay C and Blackhall F. BJC. 2019 In press

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    ES10 - Oncology Drug Approval: Challenges and Opportunities (ID 13)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Advanced NSCLC
    • Presentations: 5
    • Now Available
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      ES10.01 - US Food and Drug Administration (Now Available) (ID 3205)

      13:30 - 15:00  |  Presenting Author(s): Gideon M Blumenthal

      • Abstract
      • Presentation
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      Abstract

      Dr Blumenthal will provide the US FDA Oncology Center of Excellence perspective on Oncology Drug Approval: Challenges and Opportunity. With the recent influx of novel targeted therapies, immunotherapy and chemotherapy to treat patients with lung cancers, there are increased challenges to ensuring that safe and effective therapies are available to patients as efficiently as possible while ensuring that the evidence generated is robust and reliable. This talk will discuss FDA's perspective on global drug development.

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      ES10.02 - Japan Pharmaceuticals and Medical Devices Agency  (Now Available) (ID 3206)

      13:30 - 15:00  |  Presenting Author(s): Sumimasa Nagai

      • Abstract
      • Presentation
      • Slides

      Abstract

      The Pharmaceuticals and Medical Devices Agency (PMDA) and the Ministry of Health, Labour and Welfare (MHLW) are responsible for reviewing applications and approving the marketing authorization of drugs, medical devices, and regenerative medicines in Japan. All applications for marketing authorization in Japan are submitted to the PMDA. The PMDA conducts scientific review. Review reports prepared by the PMDA are then submitted to MHLW. The MHLW approves the marketing authorization.

      Japanese regulation has two categories of regulatory review: standard review and priority review. Priority review is applied to orphan drugs and products designated by the MHLW. Other than orphan drugs, the MHLW designates medical products as priority review products based on the following criteria described: 1. Seriousness of the target disease and 2. Clinical usefulness of the drug: no standard therapy exists, and clinical usefulness is superior to the existing products in terms of efficacy, safety, or the patient’s quality of life. The target total review time for standard review products and priority review products is 12 months and 9 months, respectively.

      The conditional and term-limited approval system has been first introduced for regenerative medical products since November, 2014. Regenerative medical products may be granted conditional and term-limited approval if their efficacy can be assumed and safety is confirmed in early-phase (phase I and/or II) registration trials. In the approval system, sponsors of the products must confirm their efficacy and safety after marketing authorization in postmarketing clinical studies etc and by resubmitting applications for regular approval within a predetermined period (not more than 7 years). The conditional and term-limited approval for regenerative medical products is similar to the accelerated approval in the US.

      In addition, the conditional approval system for drugs has been newly instituted since October, 2017 in Japan. This may be granted if all of the following requirements are met: 1. seriousness of the target disease, 2. clinical usefulness of the drug: no standard therapy exists, and clinical usefulness is superior to the existing products in terms of efficacy, safety, or quality of life, 3. it is difficult or it takes too long time to conduct a confirmatory study, 4. exploratory clinical studies can show efficacy and safety, and 5. surveillance or clinical studies must be conducted as post-marketing requirement. Because these requirements include the requirements for priority review (seriousness of the target disease and clinical usefulness of the drug), drugs granted conditional approval can automatically enjoy priority review. Moreover, the requirement for conditional approval “it is difficult or it takes too long time to conduct a confirmatory study” in Japan is totally different from accelerated approval based on surrogate endpoint in the US. The requirement is similar to the requirement for marketing authorization under exceptional circumstances “companies cannot provide comprehensive clinical data because of the rarity of the disease” in the EU. Although the requirements for conditional approval for drugs in Japan include “surveillance or clinical studies must be conducted as post-marketing requirement”, the term of validity for conditional approval of drugs in Japan is not established, which is different from the conditional and term-limited approval for regenerative medical products in Japan. As of May 31, 2019, only lorlatinib for ALK fusion-positive non-small cell lung cancer and pembrolizumab for MSI-high solid cancer have been granted conditional approval for drugs in Japan. Conducting confirmatory comparative studies is not included in postmarketing requirements for the both drugs.

      The MHLW instituted in 2015 the SAKIGAKE (meaning pioneer or forerunner in Japanese) designation system for medical products for diseases in urgent medical need of innovative therapy and that may satisfying the following two conditions: 1. The medical product has been first developed in Japan, and a sponsor is planning to submit a marketing authorization application; and 2. Prominent effectiveness can be expected based on data from the mechanism of action, non-clinical studies, and early-phase clinical studies. Advantages of sponsors who have medical products granted SAKIGAKE designation are as follows: prioritized consultation (reduced waiting time), substantial pre-application consultation, prioritized review (target total review time of 6 months only for drugs, devices, and IVDs), assigning a PMDA manager as a concierge, and an extension of the reexamination period. Total review time for SAKIGAKE-designated regenerative medical products is not established. Although the SAKIGAKE designation is similar to a breakthrough therapy designation in the US and PRIME in the EU, the requirement “the medical product has been first developed in Japan” and the advantage of specific shortened total review time are unique to the SAKIGAKE.

      Companion diagnostics (CDx) are important for oncology drug development. Current regulatory considerations regarding CDx and tumor profiling test in Japan are similar to those in the US. As of May 31, 2019, three next generation sequencing-based oncology panel tests have been approved as CDx and/or tumor profiling test in Japan. However, more flexible regulations regarding CDx are necessary for efficient clinical practice and drug development.

      I will give an overview of regulatory frameworks and challenges regarding oncology drugs and companion diagnostics in Japan.

      References:

      Nagai S, Ozawa K. Regulatory approval pathways for anticancer drugs in Japan, the EU and the US. Int J Hematol. 2016;104:73-84.

      Nagai S, et al. Evolving Japanese regulations on companion diagnostics. Nat Biotechnol. 2016;34:141-144.

      Salgado R, Solit DB, Rimm DL, Bogaerts J, Canetta R, Lively T, Lyerly K, Span PN, Bateman-House A, Makady A, Bergmann L, Nagai S, et al.; IBCD-Faculty. Addressing the dichotomy between individual and societal approaches to personalised medicine in oncology. Eur J Cancer. 2019;114:128-136.

      Lyerly HK, Ren J, Canetta R, Kim GH, Nagai S, et al. Global Development of Anticancer Therapies for Rare Cancers, Pediatric Cancers, and Molecular Subtypes of Common Cancers. J Glob Oncol. 2018;4:1-11.

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      ES10.03 - China National Medical Products Administration (Formerly CFDA)  (Now Available) (ID 3207)

      13:30 - 15:00  |  Presenting Author(s): Tony Mok

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES10.04 - European Medicines Agency (Now Available) (ID 3208)

      13:30 - 15:00  |  Presenting Author(s): Jorge Camarero

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oncology Drugs Approval: Challenges and Opportunities

      In recent years, the development of new drugs in the oncology field has notably increased. This growth in oncology clinical trials appears to be mainly associated with the increasing knowledge in pathophysiology and molecular medicine in oncology. Targeted therapies have been approved, overall, on the basis of its ability to prolong progression free survival and/or life expectancy of patients. In addition, immunotherapy has arisen as a turning point in the treatment of cancer, opening a new era and setting up a milestone in the current armamentarium. However, the regulatory decision making process behind some of the approvals for these products have proven difficult and lead to important uncertainties still to be addressed. Such unanswered questions relate, among others, to the target population, subgroups of patients partially covered by authorized indications and limitations on important aspects such as duration and combination of treatments. Likewise, this increase in new molecules development poses a remarkable pressure on regulators, clinicians and payers, who albeit from different perspectives, face the very same problem of how to ensure (timely) access to patients of new authorized products. From a regulatory perspective, randomized clinical trials remain the gold standard for adequate assessment of both efficacy and safety. Nevertheless, conducting single arm studies is becoming a commonly approach for companies to speed up regulatory approval in those situations where there is an unmet medical need. The latter cast important doubts on when, where and how this strategy can be accepted.

      Last but not least, new clinical trials designs and the proposal of using Real Word Evidence/Real World Data to complement non-compelling clinical development, are creating a new parading when it comes to making a decision upon the benefit-risk balance

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      ES10.05 - Brazilian Health Regulatory Agency - Agência Nacional de Vigilância Sanitária (Now Available) (ID 3209)

      13:30 - 15:00  |  Presenting Author(s): Carlos Gil Ferreira

      • Abstract
      • Presentation
      • Slides

      Abstract

      Brazil, the largest country in South America, has become the second largest pharmaceutical market in the emerging world. The Brazilian Health Surveillance Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) was created in 1999 with the primary goal to protect and promote public health surveillance over products and services in Brazil. Its hallmarks are administrative independence, financial autonomy, and the stability of its directors. Within the federal public regulatory structure, the agency is linked to the Ministry of Health [1].

      Despite major advances in the regulatory process in Brazil, it is important to highlight that a major delay in cancer drugs approval over the last decade has had a negative impact on patient access to novel medications in Brazil. According to Barrios et al., [2] well-established and adequately functional drug approval legislation is indispensable to guarantee a country’s population health. Any malfunctions or delay in such a crucial process have serious consequences. As an example, the drug Crizotinib (Xalcori®Pfizer, NY, USA), which had its approval denied by ANVISA in June 2014 may be seen as a landmark. Assuming different premises, Barrios et al. [2] calculated 1.367 years of life lost over 34 months due to lack of access to Crizotinib between August 2011 (FDA approval) to June 2014 (refusal by ANVISA). Of note, Crizotinib was not approved in Brazil until Feb 2016, what may have added additional 804 years of life lost to final numbers due to this delay. Other example of unexplained delay in drug approval in lenalidomide. The gap between the drug approval in the US and Brazil was 12 years.

      Regarding drugs that do require a companion diagnostic, the situation may become more complicated since, unlike the US Food and Drug Administration, no clear mechanism is in place with ANVISA for the simultaneous linking of most companion diagnostic tests with their respective targeted therapeutic drug [3].

      In trying to understand the reasons behind this delayed drug approval process, methodological, cultural, political and ideologic reasons may account. At odds with other regulatory agencies such the FDA that allow conditioned approval based on non randomized data for drugs addressing unmet medical needs. For many years ANVISA authorities mandated randomized phase 3 data for a definitive approval, since no conditioned approval was allowed. In this context, having a specific oncology area or committee, such as the FDA Oncology Drug Advisory Committee [4], may be crucial. Fast track approval, breakthrough designation, companion diagnostics, different surrogate endpoints, integration of real world evidence (RWE) into the regulatory process are very specific topics from the oncology field and do require to be analyzed under the perspective of cancer specialists. From a political, cultural and ideologic perspective, althoughit is notorious that Brazil has invested substantially in expanding access to health care for all of its citizens, the country has, essentially, two clear distinct and dissimilar health systems [3]. The public system allows drugs to become commercially available through processes that are different from those in place in the private health-care system. Although difficult to measure those disparities and difficulties to reimburse expensive drugs in the public system, may have influenced the delayed process during the last decade.

      Over the last decade, delays at ANVISA’s approval process have been considered the only reason for the inequitable access to oncology care between the USA and Brazil. Yet, this may be a biased conclusion and a more comprehensive analysis in needed. By analyzinga basket of twenty-three oncology products approved by ANVISA after 2002 Bustamante et al. [5] identified that on average there was a difference of 8.6 months (449 X 186 days). However on average, a delay in the manufacturers’ submission for regulatory approval of 1.1 years (393 days between Brazil and the USA) was also identified.

      More recently, a trend toward improvements in the drug approval process has been identified (ex. Osimertinib and Durvalumab). Osimertinib was firstly approved by ANVISA in 2017 as a second line treatment in patients who did not respond well to the initial drug. With the new determination, in 2018 ANVISA approved its use as a first therapy to treat locally advanced non-small cell lung cancer. Durvalumab was approved by ANVISA in 2017. Nevertheless there is clear room for a continuous improvement. Increase in the number of ANVISA technicians, continuous training and collaboration with academic institutions and other regulatory agencies elsewhere are mandatory. Close scientific collaboration and open and transparent dialogue between ANVISA and pharmaceutical companies are required. In sum, if we are to have a continuous improvement in the oncology drug approval process, all the stakeholders (ANVISA, drug manufactures, patient advocacy, players at the private and public health systems) must act together.

      References

      1. Ba KH andSassi AB. ANVISA: an introduction to a new regulatory agency with many challenges. AAPS Open2018; 12 Dec 2018; 4:9.

      2. Barrios PM, Debiasi M, Lopes G, Barrios CH. P1.51: Impact of Regulatory Delays in Drug Approval: Mortality and Morbidity Due to With Lack of Access to Crizotinib in Brazil: Track: Supportive Care and Others. IASLC 7th Latin American Conference on Lung Cancer, 25-27 August 2016 • Panama City, Panama; Volume 11, Issue 10, Page S215.

      3. Ferreira CG, Achatz MI, Ashton-Prolla P, Begnami MD, Marchini FK, Stefani SD. Brazilian health-care policy for targeted oncology therapies and companion diagnostic testing. Lancet Oncol. 2016 Aug;17(8):e363-e370.

      4. Vaccari L.A. The Role of the Oncology Drug Advisory Committee in the FDA Review Process for Oncologic Products. In: Teicher B.A., Andrews P.A. (eds) Anticancer Drug Development Guide. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ, 2004.

      5. Martin de Bustamante M, Martin de Bustamante M, Duttagupta S, Beckerman R, Smith NJ, Roitberg F, Lopes G.
Regulatory approval for oncology products in brazil: a comparison between the FDA and Anvisa approval timelines.
 Value in Health 18 (2015) a805–a881. Abstract PCN60.

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    ES12 - Lung Cancer Pathology in the Age of Genomics (ID 15)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Pathology
    • Presentations: 5
    • Now Available
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      ES12.01 - Multiple Lung Nodules (Now Available) (ID 3218)

      15:15 - 16:45  |  Presenting Author(s): Sanja Dacic

      • Abstract
      • Presentation
      • Slides

      Abstract

      Advanced imaging techniques resulted in increased detection of multiple tumors of the lung. Distinguishing synchronous primary lung cancers from intrapulmonary metastases (separate nodules) is important because treatments are very different. In addition, patients with independent primary tumors are expected to have better prognosis. Staging of such tumors as independent primary tumors or intrapulmonary metastases is often challenging, particularly in squamous cell carcinomas. Martini and Melamed modified criteria were used as the main approach for many decades with the idea that morphology of metastases should match the primary tumor, while different morphology supports classification of tumors as unrelated separate primaries. The 8th edition of the AJCC staging of the lung cancer pretty much has replaced this classification by establishing a multidisciplinary approach to these tumors as a standard of care and by promoting the tools such as comprehensive histologic assessment, imaging studies and molecular characterization either by CGH or biomarker testing. Comprehensive histologic assessment is based on the 2015 WHO classification of lung cancers and includes determination of the main histologic tumor type, quantitative subtyping particularly of lung adenocarcinomas, and assessment of cytologic and stromal characteristics. This approach can be relatively easily applied in lung adenocarcinomas, while squamous cell carcinoma remains a great challenge. A recent study conducted by the IASLC Pathology committee showed a good agreement (κ score 0.60) among thoracic pathologists in the histologic assessment of independent primary tumors from intrapulmonary metastasis. Despite a good agreement, there were cases with split opinions supporting a need for ancillary studies.

      Over the past decade many studies reported different molecular approaches to analysis of multiple lung tumor nodules including DNA microsatellite analysis, CGH/aCHG and most recently next generation sequencing. The data from published reports indicate a highly variable percentage of multifocal tumors identified as clonally related (up to 70%). Discrepancy between clinical and molecular classification of originally presumed cases of multiple primary lung cancers ranged in different series from 18% to 30%. Recent recommendations for routine molecular profiling of lung adenocarcinoma resulted in a widespread use of targeted mutational profiling for oncogenic mutations (i.e. EGFR, KRAS, BRAF etc) and gene rearrangements (i.e.ALK, ROS1) which results can be used in staging of multiple lung cancers. A different mutation profile in oncogenic mutations strongly indicates two separate primary tumors. However, the presence of a common driver mutation does not necessarily indicate tumors of similar origin. Therefore, limited molecular panels may not be sufficient in some cases. The detection of shared identical breakpoints by whole genome sequencing has been recently proposed as potentially more accurate and specific for lineage determination than the analysis of driver mutations alone. Also whole exome and whole genome sequencing approaches have been reported, but these assays may be technically challenging and turnaround time may not be suitable for routine clinical use.

      References:

      Girard N, Deshpande C, Lau C, Finley D, Rusch V, Pao W, et al. Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. Am J Surg Pathol. 2009;33(12):1752-64.

      Detterbeck FC, Franklin WA, Nicholson AG, Girard N, Arenberg DA, Travis WD, et al. The IASLC Lung Cancer Staging Project: Background Data and Proposed Criteria to Distinguish Separate Primary Lung Cancers from Metastatic Foci in Patients with Two Lung Tumors in the Forthcoming Eighth Edition of the TNM Classification for Lung Cancer. J Thorac Oncol. 2016;11(5):651-65

      Nicholson AG, Torkko K, Viola P, Duhig E, Geisinger K, Borczuk AC, et al. Interobserver Variation among Pathologists ts and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung. J Thorac Oncol. 2018;13(2):205-17.

      Murphy SJ, Aubry MC, Harris FR, Halling GC, Johnson SH, Terra S, et al. Identification of independent primary tumors and intrapulmonary metastases using DNA rearrangements in non-small-cell lung cancer. J Clin Oncol. 2014;32(36):4050-8.

      Liu Y, Zhang J, Li L et al. Genomic heterogeneity of multiple synchronous lung cancer. Nat Commun 2016 Oct 21;7:13200.

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      ES12.02 - Invasive Mucinous Adenocarcinoma (Now Available) (ID 3219)

      15:15 - 16:45  |  Presenting Author(s): Yasushi YATABE

      • Abstract
      • Presentation
      • Slides

      Abstract

      Invasive mucinous adenocarcinoma (IMA) is a variant of adenocarcinoma defined by the current WHO classification of lung tumors.1 Although IMA used to be categorized into mucinous bronchioloalveolar carcinoma in most cases with the previous classification scheme,2 separation of this variant was based on unique clinical, radiological, pathological, and genetic characteristics as shown in the following table. Morphologically, IMAs consist of goblet and/or columnar tumor cells, which resemble normal intestinal and/or primitive gut epithelium. This subtype adenocarcinoma develops not only in the lung but also in every organ system, such as the ovary, pancreas, colorectum, and stomach, which are associated with the primitive gut tube in development. Interesting, all mucinous carcinomas have frequent KRAS mutations and quite similar immunohistochemical phenotype, including expression of CK20, CDX2, HNF4a, and villin. The strong correlation between KRAS mutations and heavy smokers is known, but IMA is not such a case. Indeed, TP53 mutations, which is also associated more with smokers, are quite rare in IMAs. IMA commonly develops in the peripheral lung parenchyma, but there are no normal counterpart cells. Recently, inactivating mutations of TTF1/NKX2.1 have been reported in IMA.3, 4 This alteration can repress TTF1 function, resulting in gastrointestinal differentiation. TTF1-depletion using KRASG12D-transgenic mice induced mucinous tumors, which shared a morphological and phenotypical resemblance to IMA, including columnar tumor cells with goblet cell features and HNF4a expression.5, 6 Because the other mechanisms of TTF1 impairment, the molecular pathway of IMA could be summarized in figure 1. However, it remains unclear why KRAS is selectively mutated in this subtype, and what induce TTF1 mutations.

      References
      1. Travis WD, Brambilla E, Burke A, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyon: International Agency for Research on Cancer; 2015.
      2. Travis WD, Brambilla E, Noguchi M, et al. International Association for the study of lung cancer/American thoracic society/European respiratory society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol 2011;6:244-285.
      3. Matsubara D, Soda M, Yoshimoto T, et al. Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas. Cancer science 2017;108:1888-1896.
      4. Hwang DH, Sholl LM, Rojas-Rudilla V, et al. KRAS and NKX2-1 Mutations in Invasive Mucinous Adenocarcinoma of the Lung. J Thorac Oncol 2016;11:496-503.
      5. Maeda Y, Tsuchiya T, Hao H, et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J Clin Invest 2012;122:4388-4400.
      6. Snyder EL, Watanabe H, Magendantz M, et al. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Mol Cell 2013;50:185-199.

      Table 1 Difference between IMA and AIS/MIA/LPA1

      Table 1 Difference between IMA and AIS/MIA/LPA

      Invasive Mucinous ADC

      AIS/MIA/LPA

      Female

      ~60%

      ~70%

      Smoker

      ~45%

      ~46%

      Clinical symptoms

      Mucinous sputa

      Mostly no symptom

      Radiographic appearance

      Majority consolidation; Air-bronchogram

      Majority ground-glass attenuation

      Frequent multifocal & multi-lobar presentation

      Cell type

      Mucin-filled, columnar and/or goblet

      Type II pneumocyte &/or Clara cell

      Phenotype

      CK7

      Mostly positive (90%)

      Positive (~95%)

      CK20

      Positive (~54%)

      Negative (<5%)

      TTF1

      Mostly negative (<10%)

      Positive (~65%)

      CDX2

      Possible to be positive

      Negative

      Genotype

      KRAS

      Frequent (~75%)

      Some (~15%)

      EGFR

      Almost none (<5%)

      Frequent (~45%)

      AIS, adenocarcinoma in situ; MIA, minimally invasive adenocarcinoma; LPA, lepidic predominant adenocarcinoma

      fig1.jpg

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      ES12.03 - Tumor Heterogeneity (Now Available) (ID 3220)

      15:15 - 16:45  |  Presenting Author(s): Wendy Cooper

      • Abstract
      • Presentation
      • Slides

      Abstract

      While intertumoral heterogeneity is well recognised in many solid tumours including NSCLC, intratumoral heterogeneity has only recently gained attention. Heterogeneity of tumor morphology, protein expression, gene expression, epigenetic or genetic alterations has the potential to impact optimal biopsy strategies, diagnostic assessment, treatment decisions and clinical outcome.

      Sequencing of NSCLC from multiple sites of disease shows frequent evidence of intratumoral heterogeneity in terms of genetic mutations, translocations and copy number alterations, although not to the same extent as seen in other tumor types, such as clear cell renal cell carcinoma. NSCLC studies have demonstrated a common pattern of intratumoral heterogeneity with main clonal driver mutations and branched evolutionary acquired mutations. Of clinical relevance, mutations in known lung cancer driver oncogenes (such as EGFR, BRAF and MET) are generally present in all tumor regions in keeping with early evolutionary events. This finding is consistent with the high response rates to tyrosine kinase inhibitors that target these genetic alterations, across multiple sites of disease.

      Later subclonal driver mutations are found commonly in NSCLC and include alterations in genes such as PIK3CA and NF1. Metastatic sites can exhibit mutational profiles closely related to specific spatial regions of the primary tumor demonstrating that subclones can determine the course of systemic disease resulting in subclonal diversification. Clonal evolution is driven by multiple factors including selective pressure from targeted therapies and adaptive mechanisms due to interaction with immune cells and the microenvironment. Treatment resistance can occur due to acquisition and/or selection of clones and contributes to temporal heterogeneity. The hierarchy of genetic alterations can be used to trace clonal intratumoral heterogeneity although adequate sequencing depth is required to accurately assess for subclonal mutations.

      Reassuringly, sequencing of a single region of a tumor should be sufficient to identify known targetable driver mutations as they generally occur early in the evolutionary course of the disease. The exact clinical significance of various subclonal mutations is less well understood. Intratumoral heterogeneity can potentially lead to sampling errors when single sites of disease are sampled for mutational events that may only exist in another metastatic site. For this reason, testing for genetic markers of treatment resistance may be more appropriately performed on circulating tumour DNA as the ctDNA may derive from multiple metastatic deposits, although lower sensitivity limits the effectiveness of this approach. Liquid biopsy approaches also have the advantage of providing a contemporaneous sample, more likely to reflect impact of most recent therapy.

      Further investigation of spatial and temporal tumoral heterogeneity by comprehensive deep sequencing of multiple spatially discrete sites of disease at different time points may assist in understanding the complexity of intratumoral heterogeneity and could potentially impact optimal biopsy and treatment strategies, particularly when assessing for drug resistance.

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      ES12.04 - Machine Learning and Integrative Multi-Omics Analysis Identify Novel Molecular Groups of Lung Neuroendocrine Tumors (Now Available) (ID 3221)

      15:15 - 16:45  |  Presenting Author(s): Lynnette Fernandez-Cuesta

      • Abstract
      • Presentation
      • Slides

      Abstract

      figure.jpgThis work is part of the lungNENomics project, a large multi-omic and multidisciplinary effort, built up on our previous published work (1-4). The lungNENomics project aims at the molecular characterization of rare lung neuroendocrine neoplasms through the integration of whole-genome sequencing, transcriptome sequencing and methylation data, as well as the correlation with epidemiological and clinical information, and taking advantage of unique biorepositories, advanced computational approaches, and state-of-the-art in vitro models. The talk would provide an overview of the global lungNENomics project, as well as presenting the identification of a novel molecular entity.

      The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compared and contrasted the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Integrative analyses on 257 lung neuroendocrine neoplasms stratified atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identified therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirmed the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveiled the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

      Funding: U.S. National Institutes of Health (NIH), French National Cancer Institute (INCa), French Ligue Nationale contre le Cancer (LNCC), and the Dutch Cancer Society (DCS)

      Website: rarecancersgenomics.com

      Twitter: @CancersRare

      References

      1. Peifer M*, Fernández-Cuesta L*, Sos ML, George J, Seidel D, Kasper LH, Plenker D, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012 PMID: 22941188

      2. Fernandez-Cuesta L, Peifer M, Lu X, Sun R, Ozretić L, Seidal D, Zander T, et al. Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun. 2014 PMID: 24670920

      3. George J*, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Müller C, Dahmen I, Delhomme TM, Ardin M, Leblay N, Byrnes G, Sun R, De Reynies A, McLeer-Florin A, Bosco G, Malchers F, Menon R, Altmüller J, Becker C, Nürnberg P, Achter V, Lang U, Schneider PM, Bogus M, Soloway MG, Wilkerson MD, Cun Y, McKay JD, Moro-Sibilot D, Brambilla CG, Lantuejoul S, Lemaitre N, Soltermann A, Weder W, Tischler V, Brustugun OT, Lund-Iversen M, Helland Å, Solberg S, Ansén S, Wright G, Solomon B, Roz L, Pastorino U, Petersen I, Clement JH, Sänger J, Wolf J, Vingron M, Zander T, Perner S, Travis WD, Haas SA, Olivier M, Foll M, Büttner R, Hayes DN, Brambilla E, Fernandez-Cuesta L*, Thomas RK. Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nat Commun. 2018 PMID: 29535388

      4. Derks JL, Leblay N, Lantuejoul S, Dingemans AC, Speel EM, Fernandez-Cuesta L. New Insights into the Molecular Characteristics of Pulmonary Carcinoids and Large Cell Neuroendocrine Carcinomas, and the Impact on Their Clinical Management. J Thorac Oncol. 2018 Review. PMID: 29454048

      5. Alcala N*, Leblay N*, Gabriel AAG*, Mangiante L, Hervas D, Giffon T, Sertier AS, Ferrari A, Derks J, Ghantous A, Delhomme TM, Chabrier A, Cuenin C, Abedi-Ardekani B, Boland A, Olaso R, Meyer V, Altmuller J, Le Calvez-Kelm F, Durand G, Voegele C, Boyault S, Moonen L, Lemaitre N, Lorimier P, Toffart AC, Soltermann A, Clement JH, Saenger J, Field JK, Brevet M, Blanc-Fournier C, Galateau-Salle F, Le Stang N, Russell PA, Wright G, Sozzi G, Pastorino U, Lacomme S, Vignaud JM, Hofman V, Hofman P, Brustugun OT, Lund-Iversen M, Thomas de Montpreville V, Muscarella LA, Graziano P, Popper H, Stojsic J, Deleuze JF, Herceg Z, Viari A, Nuernberg P, Pelosi G, Dingemans AMC, Milione M, Roz L, Brcic L, Volante M, Papotti MG, Caux C, Sandoval J, Hernandez-Vargas H, Brambilla E, Speel EJM, Girard N, Lantuejoul S, McKay JD, Foll M#, Fernandez-Cuesta L#. Integrative and comparative genomic analyses identify clinically relevant groups of pulmonary carcinoids and unveil the supra-carcinoids. Nat Commun. In Press

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      ES12.05 - Impact of STAS in Lung Cancer Staging (Now Available) (ID 3222)

      15:15 - 16:45  |  Presenting Author(s): William D. Travis  |  Author(s): Rania G. Aly, Takashi Eguchi, Natasha Rekhtman, Yukako Yagi, Prasad S Adusumilli

      • Abstract
      • Presentation
      • Slides

      Abstract

      Spread through air spaces (STAS) is an established histologic marker of poor prognosis found in 15-60% of lung cancers. The association with poor prognosis is supported by data from over 3500 patients from multiple multidisciplinary investigative groups worldwide. This prognostic significance has been demonstrated in all major types of lung cancer including adenocarcinoma,1 squamous cell carcinoma,2 small cell carcinoma,3 large cell neuroendocrine carcinoma,3, atypical carcinoid3 and pleomorphic carcinoma.4, 5

      As this large volume of clinical data has accumulated some important issues that have arisen. 1) Importance of processing, 2) Role in Staging? 3) Limited resection vs lobectomy and 4) Frozen section.

      Criteria for STAS

      The original definition of STAS by Kadota et al and the 2015 WHO consisted of tumor cells within the first alveolar air spaces in the lung parenchyma beyond the edge of the main tumor. In adenocarcinoma it can occur as one of three morphologic patterns including 1) micropapillary structures within air spaces; 2) solid nests or tumor islands and 3) scattered discohesive single cells.1, 6 In a recent paper we also proposed to require the presence of more than a single STAS cluster.3 The solid nest pattern is characteristic in other lung cancer histologies such as squamous cell carcinoma and neuroendocrine tumors. 3-dimensional studies with serial histologic sectioning and microCT whole block imaging suggest that there may be two mechanisms of spread into the adjacent lung: 1) detachment, migration through air spaces and reattachment with vessel co-option and 2) tumor islands of continuous tumor spread into adjacent air spaces.

      An important component of the diagnostic criteria is the distinction from artifacts: 1) mechanically induced tumor floaters that are randomly situated often at the edge of the tissue section or out of the plane of section; 2) jagged edges of tumor cell clusters suggesting fragmentation or edges of a knife cut during specimen processing; 3) isolated tumor clusters at a distance from the tumor rather than spreading in a continuous manner from the tumor edge and 4) linear strips of cells lifted off alveolar walls.

      Importance of Processing

      To assess for STAS histologic sections need to be taken in such a way to maximize the interface between the tumor and adjacent non-neoplastic lung parenchyma. For example, sections of subpleural tumors that maximize assessment of the visceral pleura or the interface with dense fibrotic scars or post-obstructive organizing are not well suited for assessment of STAS. This applies to both frozen and permanent sections.

      Role of STAS in Staging?

      Although the prognostic significance of STAS, has led some to suggest it might be included as a factor in staging,7, 8 there is insufficient data at this time to make such a recommendation. Tumor size should continue to be measured according to the gross and/or microscopically recognized edge of lung cancers rather than according to the maximum distance of furthest STAS. Although vascular (V) and lymphatic (L) invasion are recognized in TNM staging, only visceral pleural invasion (VPI) is officially incorporated as a T-factor in the 8th Edition. STAS is regarded as a sign of invasion similar to V, L and VPI, however, more data is needed before introducing this as a T-factor for staging.

      Limited resection vs lobectomy

      Evidence is accumulating that indicates an increased risk of recurrence and worse survival associated with STAS positive tumors treated by limited resection compared to lobectomy.5, 9

      Role of Frozen Sections in Assessing STAS

      There is limited data evaluating pathologist’s ability to recognize STAS in frozen section. Eguchi et al found the sensitivity and specificity of frozen section for prediction of STAS were 71% and 92%. respectively and interrater reliability across 5 pathologists was 0.67.9

      Walts AE et al studied frozen section for evaluation of STAS and recommended that current evidence did not warrant frozen section evaluation for STAS.10 However, frozen section sensitivity to detect STAS positivity was 50%, with a 100% positive predictive value and an 8% negative predictive value. These studies suggest if a pathologist sees STAS on a frozen section there is a 92-100% likelihood it will be present on permanent sections. Both studies were retrospective so attention was not always given to including the tumor edge and adjacent lung. More studies are needed to evaluate the potential role of frozen section in detecting STAS and guiding intraoperative decisions by surgeons.

      REFERENCES

      1. Kadota K, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      2. Lu S, et al. Spread through Air Spaces (STAS) Is an Independent Predictor of Recurrence and Lung Cancer-Specific Death in Squamous Cell Carcinoma. J Thorac Oncol 2017;12:223-34.

      3. Aly RG, et al. Spread Through Air Spaces (STAS) Is Prognostic in Atypical Carcinoid, Large Cell Neuroendocrine Carcinoma, and Small Cell Carcinoma of the Lung. J Thorac Oncol 2019.

      4. Yokoyama S, et al. Tumor Spread Through Air Spaces Identifies a Distinct Subgroup With Poor Prognosis in Surgically Resected Lung Pleomorphic Carcinoma. Chest 2018;154:838-47.

      5. Liu H, et al. Prognostic Impact of Tumor Spread Through Air Spaces in Non-small Cell Lung Cancers: a Meta-Analysis Including 3564 Patients. Pathol Oncol Res 2019.

      6. Travis WD, et al. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon: International Agency for Research on Cancer; 2015.

      7. Uruga H, et al. Will spread through air spaces be a staging parameter in lung cancer? Journal of thoracic disease 2018;10:593-6.

      8. Dai C, et al. Tumor Spread through Air Spaces Affects the Recurrence and Overall Survival in Patients with Lung Adenocarcinoma >2 to 3 cm. J Thorac Oncol 2017;12:1052-60.

      9. Eguchi T, et al. Lobectomy Is Associated with Better Outcomes than Sublobar Resection in Spread through Air Spaces (STAS)-Positive T1 Lung Adenocarcinoma: A Propensity Score-Matched Analysis. J Thorac Oncol 2019;14:87-98.

      10. Walts AE, et al. Current Evidence Does Not Warrant Frozen Section Evaluation for the Presence of Tumor Spread Through Alveolar Spaces. Arch Pathol Lab Med 2018;142:59-63.

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    GR03 - Problem Areas for the Next WHO Classification of Lung Cancers (ID 31)

    • Event: WCLC 2019
    • Type: Grand Rounds Session
    • Track: Pathology
    • Presentations: 5
    • Now Available
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      GR03.01 - High Grade Neuroendocrine Tumors (Now Available) (ID 3309)

      15:45 - 17:15  |  Presenting Author(s): MAURO GIULIO PAPOTTI

      • Abstract
      • Presentation
      • Slides

      Abstract

      The four-tier WHO 2015 classification scheme of lung neuroendocrine neoplasms (NEN) includes morphologically and clinically heterogeneous conditions (1). High grade tumors typically encompass large and small cell neuroendocrine carcinomas (LCNEC and SCLC, respectively). The survival of these two types of poorly differentiated NENs is similar and significantly different from that of the well differentiated carcinoid tumors. Thus their appropriate classification is a clinically relevant exercise. While the morphological features of classical SCLC and those of low grade carcinoids allow to easily take these two tumors apart, the correct classification of some atypical carcinoids and of LCNEC is less straightforward.

      In fact, morphology alone may not be sufficient to identify the various histotypes (that still represent the most relevant prognostic parameter in NENs), and to specifically classify aggressive forms into the group of high grade carcinomas. Even immunophenotype profiling may fail to some extent and only the more recent genetic data have been able to better stratify variations within each single histological type (as recognized by the current WHO criteria). According to such criteria (1), high grade neuroendocrine (NE) carcinomas are defined as malignant tumors made of large or small cells having a solid, diffuse (or more rarely irregularly organoid) growth patterns, with extensive necrosis and a mitotic index exceeding 10 per 10 high power fields. This definition fits for a relatively wide group of tumors, whose clinical behavior is not perfectly overlapping. In particular, while SCLC are invariably associated to a high mitotic rate and high grade cytological features including classical salt&pepper chromatin pattern, LCNEC belong to a grey area that merges with atypical carcinoids on the one side (having intermediate values of mitotic index), and with SCLC on the other (with the occurrence of combined small and large cell NE carcinoma variants).

      Immunophenotypic markers are not always useful for accurately stratifying NENs. In fact, chromogranin A, synaptophysin and CD56 are generally expressed by the majority of NENs, though with a different intensity and distribution (for example, SCLC may be negative or only focally reactive for chromogranin, but invariably expresses synaptophysin) (2,3). Some transcription factors such as TTF1 and hASH1 are usually intensely positive in high grade tumors, both LCNEC and SCLC, as opposed to carcinoid tumors, that are generally not reactive (with the possible exception of some peripherally located spindle cell carcinoids).

      The proliferation index, as defined by Ki-67 immunohistochemistry, was proposed as an effective complementary tool to identify different prognostic subgroups, although its use is not officially accepted by the WHO classification with the exception of a differential diagnostic role in small biopsy specimens (1). Indeed, high grade tumors have a much higher mean Ki67 index compared to carcinoids (mean values of 60-80% versus 2-8%). For this reason, the integration of Ki67 data with the two official morphological parameters (necrosis and mitoses) proved effective in a proposed grading system (4).

      The spectrum of aggressive NENs is unfortunately complicated by the existence of combined NENs, having areas of brisk proliferation admixed with a relatively quiescent tumor cell population. In addition, rare cases have been demonstrated to progress from well differentiated carcinoid to high grade NE carcinomas. The relationship between low and high grade NENs is further supported by the observed heterogeneous genetic profile of high grade tumors, namely LCNEC. Apart from the original detection of the carcinoid-specific MEN1 mutations in a small fraction of “morphological” LCNECs, and of two other different groups of LCNEC, one related to SCLC and the other associated to a genetic signature of non small cell lung carcinomas (5,6), recent comprehensive genomic and transcriptomic analyses of 75 LCNEC identified two molecular subgroups, labeled "type I LCNEC" (having bi-allelic TP53 and STK11/KEAP1 gene alterations, and a NE profile with ASCL1 high / DLL3 high / NOTCH low), and "type II LCNEC" (enriched for bi-allelic inactivation of TP53 and RB1 genes, reduced NE markers, ASCL1 low / DLL3 low / NOTCH high, upregulation of immune-related pathways) (7). In this latter study, some genomic alterations were shared with pulmonary adenocarcinomas and squamous cell carcinomas.

      In a more recent study (8), the reverse approach was used, starting from a series of carcinoid tumors. With the aim of a full molecular NEN characterization by integrative analyses of genomic, transcriptomic, and methylome data, three molecular groups were identified: clusters A through C were enriched by typical carcinoids (TC), atypical carcinoids (AC) and LCNEC, respectively. Interestingly, the latter cluster also included a subgroup of six “morphological” ACs, here designated “supra-AC” that were molecularly similar to LCNEC, thus supporting the postulated link between the low and high grade lung NENs. Therefore, misclassification is common between AC and LCNEC, due to the existence of “carcinoid-like” LCNEC (5,7), possibly resulting from the evolution of a well- into a poorly differentiated NEN (9), as also reported in thymic LCNEC (10).

      In conclusion, the correct classification of high grade lung NENs is in general easily obtained in conventional forms of oat cell SCLC and of highly atypical and proliferating LCNEC. Conversely, the separation is more subtle in the presence of the rare intermediate (grey zone) cases, standing between AC and LCNEC, that probably correspond to the recently proposed category of “G3 NE Tumor” in the pancreas (11) and the gastrointestinal tract (expected in the next WHO classification of digestive system NENs).

      References

      1 Travis et al. WHO classification of tumors of the lung. IARC press, Lyon, 2015

      2 Thunissen E et al. J Thorac Oncol 2017;12:334-346

      3 Yatabe et al. J Thorac Oncol 2019;14:377-407

      4 Rindi G et al. Endocr Rel Cancer 2013;21:1-16

      5 Rekthman N et al. Clin Cancer Res 2016; 22, 3618-3629

      6 Simbolo M et al. J Pathol 2017; 241: 488–500

      7 George J et al. Nat Commun 2018; 9: 1048 (1-13)

      8 Alcala N et al. Nat Commun 2019 (in press)

      9 Pelosi G et al. Virchows Arch 2018;472:567-577

      10 Fabbri A et al. Virchows Arch 471, 31-47

      11 Lloyd RV et al. WHO classification of endocrine tumors. IARC press, Lyon, 2017

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      GR03.02 - Adenocarcinoma (Now Available) (ID 3310)

      15:45 - 17:15  |  Presenting Author(s): Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Many of the limitations in the WHO 2004 classification for adenocarcinomas (confusion over the term bronchioalveolar adenocarcinoma, usage of the term “mixed pattern” and no classification for small biopsy/cytology specimens) were addressed in the 2011 IASLC/ATS/ERS multidisciplinary classification,1 and this proposal was adopted by the 2015 WHO classification with minor changes.2

      Adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma and invasive mucinous adenocarcinoma have now replaced the term “bronchioloalveolar adenocarcinoma”, with subsequent TNM staging changes to use invasive size for T factor size.3 However there remains significant interobserver variation between pathologists in relation to the point at which invasion starts, indicating that tighter definitions of distinguishing a lepidic pattern from other invasive patterns are needed, especially in areas where these disagreements have a clinical impact.

      Interobserver agreement between pathologists has been shown to be much better for distinction of invasive patterns (acinar, papillary, micropapillary, solid). Accumulating data supports the 2015 WHO proposal that the cribriform pattern be regarded as a pattern with adverse prognostic significance. It is also proposed that micropapillary be expanded to include a filigree, as well as classical, pattern. One of the most important needs is for pathologists to better recognize the morphologic spectrum of the micropapillary pattern which is often underestimated. Several publications suggest prognostic groupings as lepidic, acinar/papillary and solid/micropapillary as a stratification, and these have been shown to predict response to adjuvant therapy.4 This leads into the issue of grading of resected adenocarcinomas and the presence of more aggressive histological patterns as a minor component.

      The histological feature termed “spread through airspaces” or STAS has been shown to be a poor prognostic factor for all major histologic types of lung cancer, including adenocarcinoma where it is frequently seen. There is considerable evidence that the presence of STAS carries prognostic significance,5,6 in particular in relation to non-anatomic resections, but there remains a need to identify where STAS begins and artefactual dissemination of tumour due to handling and processing of specimens ends.7 A tighter definition and evidence of international reproducibility is needed.

      While subtyping of histological patterns is well established in non-mucinous adenocarcinomas, mucinous adenocarcinomas are less well characterised. Various patterns of mucinous differentiation have been proposed, as well as assignment of histologic patterns in similar fashion to non-mucinous ADCs although only invasive mucinous adenocarcinomas (IMA) and colloid adenocarcinomas currently have specific subgroupings.2 This proposal has proved to be well founded given the specific molecular features and behaviour pattern of IMAs,8 although again work is required to refine prognostication. More data is also required tumours with mixed mucinous and non-mucinous areas.

      Resections are increasingly occurring after neoadjuvant therapy, with there is already a need to assess these in a structured fashion.9,10 Work is ongoing within the IASLC Pathology Committee to propose a method for classification in this clinical scenario.

      The 2015 WHO classification saw a seminal change in its structure, in that a classification system was proposed for biopsies and cytology specimens, rather than solely resections. In addition, a major theme utilized in the 2015 WHO classification was a multidisciplinary approach incorporating surgery, imaging, oncologic respiratory medicine, molecular biology as well as pathology. which needs to be maintained into the discussions of future classifications.1 This approach must remain and will likely need to be enhanced, given the revolution in molecular and immunologic characterisation of tumours, especially adenocarcinomas, and all these new clinically relevant findings will need to be part of pathologic reporting for the ensuing decades. The relative importance and structure of morphologic, immunohistochemical, molecular and immunologic data will need to be incorporated into a system that is appropriate not just for the most advanced cancer centres where all data are available but for laboratories and diagnostic services in underserved countries where morphologic features may be the only ones available.

      REFERENCES

      1. Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society: international multidisciplinary classification of lung adenocarcinoma: executive summary. Proc Am Thorac Soc 2011;8:381-5.

      2. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. Lyons, France.: International Agency for Research on Cancer (IARC); 2015.

      3. Travis WD, Asamura H, Bankier AA, et al. The IASLC Lung Cancer Staging Project: Proposals for Coding T Categories for Subsolid Nodules and Assessment of Tumor Size in Part-Solid Tumors in the Forthcoming Eighth Edition of the TNM Classification of Lung Cancer. J Thorac Oncol 2016;11:1204-23.

      4. Tsao MS, Marguet S, Le Teuff G, et al. Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection. J Clin Oncol 2015;33:3439-46.

      5. Chen D, Mao Y, Wen J, et al. Tumor Spread Through Air Spaces in Non-Small Cell Lung Cancer: a systematic review and meta-analysis. Ann Thorac Surg 2019.

      6. Kadota K, Nitadori J, Sima CS, et al. Tumor Spread through Air Spaces is an Important Pattern of Invasion and Impacts the Frequency and Location of Recurrences after Limited Resection for Small Stage I Lung Adenocarcinomas. J Thorac Oncol 2015;10:806-14.

      7. Blaauwgeers H, Flieder D, Warth A, et al. A Prospective Study of Loose Tissue Fragments in Non-Small Cell Lung Cancer Resection Specimens: An Alternative View to "Spread Through Air Spaces". Am J Surg Pathol 2017;41:1226-30.

      8. Fernandez-Cuesta L, Plenker D, Osada H, et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov 2014;4:415-22.

      9. Qu Y, Emoto K, Eguchi T, et al. Pathologic Assessment After Neoadjuvant Chemotherapy for NSCLC: Importance and Implications of Distinguishing Adenocarcinoma From Squamous Cell Carcinoma. J Thorac Oncol 2019;14:482-93.

      10. Blumenthal GM, Bunn PA, Jr., Chaft JE, et al. Current Status and Future Perspectives on Neoadjuvant Therapy in Lung Cancer. J Thorac Oncol 2018;13:1818-31.

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      GR03.03 - Pleomorphic Carcinomas (Now Available) (ID 3311)

      15:45 - 17:15  |  Presenting Author(s): Alain Borczuk

      • Abstract
      • Presentation
      • Slides

      Abstract

      The category of sarcomatoid carcinoma in lung cancer classification is composed of five tumor types - pleomorphic, spindle, giant cell, carcinosarcoma and blastoma. While these are all relatively rare tumors, the pleomorphic carcinoma category is the most common of this group. Pleomorphic carcinomas are defined as combinations of adenocarcinoma, squamous carcinoma or large cell carcinoma with a spindle or giant cell element. It may be that spindle or giant cell examples, while diagnostically more challenging, represent variants of similar histogenesis but with complete mesenchymal transformation. Small cell carcinoma in a pleomorphic carcinoma is exceedingly rare. These tumors are often bulky tumors at presentation, with a propensity for central necrosis. Historically, this tumor is highly aggressive and treatment refractory.

      The histology of this tumor type includes correct identification of a malignant spindle component morphologically, or a giant cell component. While nuclear pleomorphism is an aspect of the tumor, the degree of nuclear enlargement, multinucleation and the presence of emperipolesis all distinguish giant cells of pleomorphic carcinoma from nuclear enlargement in high grade tumors. Immunohistochemistry has be helpful in identifiable a cytokeratin positive spindle or giant cell component. The use of zinc finger E-box binding homeobox1 (ZEB1), a protein involved in epithelial-mesenchymal transition to identify spindle or giant cell component of these tumors, both in small samples and resections, is emerging.

      Molecular alterations have also been linked to pleomorphic carcinomas. The tumors harbor mutations in KRAS as well as a higher rate of MET exon 14 skipping mutations. This is generally confined to cases with an adenocarcinoma component. TP53 mutations are also frequent. The molecular mechanisms of pleomorphic carcinoma with a squamous only epithelial component remain to be characterized.

      It has been proposed that MET exon 14 mutations may be targetable using agents such as crizotinib. In addition, these tumors show an elevated rate of high positive PDL1 immunoreactivity which may offer immunotherapy option in these patients.

      The relationship between large cell carcinoma and new entities such as SMARCA4 deficient carcinoma/sarcoma and the category of sarcomatoid carcinoma remains unclear. Greater elucidation of the molecular underpinning of sarcomatoid carcinoma categories may help clarify the place for these entities within the classification of lung cancer.

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      GR03.04 - Molecularly-Defined Thoracic Malignancies (NUT, SMARCA4 and Others Sarcomas) (Now Available) (ID 3312)

      15:45 - 17:15  |  Presenting Author(s): Akihiko Yoshida

      • Abstract
      • Presentation
      • Slides

      Abstract

      Classification of tumors has been traditionally based on clinical and histological findings, with each entity often being characterized by molecular genetic changes. However, a few recently described tumor entities are defined by specific genetic abnormalities, and three such tumors are discussed here with a particular emphasis on their nosologic controversy. [NUT carcinoma] NUT carcinoma is a poorly-differentiated aggressive carcinoma with frequent squamous differentiation. NUT carcinoma harbors NUTM1 rearrangement by definition, with the most common fusion partner being BRD4 (~70%) and uncommon partners including NSD3 and BRD3. NUT carcinomas typically involve organs along the midline, such as the head, neck, and upper aerodigestive tract in young patients; however, a broader range of patient age and tumor sites exist. Recently, NUTM1 rearrangement has been reported in a small number of malignant tumors that lack epithelial differentiation, some of which show an undisputable phenotype of sarcoma. Tumors with CIC-NUTM1 fusion are the best known and their histological and transcriptomic similarities to CIC-DUX4 sarcomas suggest their relatedness with CIC sarcomas. Other NUTM1-rearranged sarcomas are highly heterogeneous, both histologically and genetically, including fusion partners such as BCORL1, MXD1, MXD4, and MGA. Interestingly, MGA-NUTM1 sarcomas have been repeatedly documented in the thoracic cavity of adults. More recently, NUTM1 rearrangement has been discovered in benign and malignant skin adnexal tumors. NUTM1 rearrangement is therefore no longer a signature of a single entity NUT carcinoma, and phenotypic correlation is critical for diagnosis. [SMARCA4-deficient thoracic sarcoma (DTS)] SMARCA4 is a core catalytic subunit of the SWI/SNF chromatin remodeling complex. SMARCA4 deficiency in thoracic tumors primarily occurs in association with carcinomas, accounting for 5–15% of lung adenocarcinomas and up to 30% of large cell and pleomorphic carcinomas. These carcinomas typically affect smoking men and are more common in poorly differentiated TTF1-negative tumors that are wild-type for EGFR and ALK. SMARCA4- DTS is a recently recognized sarcoma type with fewer than 60 cases reported to date. SMARCA4-DTS most commonly occurs in young to middle-aged adult men (median, 40 years old) with heavy smoking exposure and presents as large tumors in the thoracic cavity. SMARCA4-DTSs are aggressive, and the median survival is 4–7 months. Histologically, the tumors consist of diffusely infiltrating large dyscohesive epithelioid cells with relatively monotonous nuclei and prominent nucleoli, similar to proximal-type epithelioid sarcoma. Rhabdoid cells are seen in a subset of cases. By definition, all cases are deficient in SMARCA4 immunohistochemically because of inactivating SMARCA4 mutation. SMARCA4-DTS is different from SMARCA4-deficient lung carcinoma with respect to demographics (younger), clinical outcome (worse), histological features (more dyscohesive), immunophenotype (frequent positivity for CD34, SOX2, and/or SALL4, and negativity for claudin-4), and gene expression profiles. Interestingly, some SMARCA4-DTS tumors tested have frequent C:G/A:T transversion mutations and mutations in TP53, KRAS, KEAP1, and/or NF1, a shared profile with smoking-associated lung adenocarcinomas. The question has thus been raised whether these sarcomas might represent a dedifferentiated form of lung carcinoma. Nonetheless, an epithelial component has not been reported in any of the documented SMARCA4-DTS cases. Furthermore, most examples are not centered in the lung, and some entirely lack lung parenchymal involvement. [Primary pulmonary myxoid sarcoma (PPMS) with EWSR1-CREB1] PPMS is a rare low-grade lung sarcoma of young adults often presenting as an endobronchial mass. The tumor consists of multinodular myxoid growth that is populated by corded or reticular proliferation of spindle and/or epithelioid cells. These tumors often coexpress vimentin and epithelial membrane antigen and harbor EWSR1-CREB1 fusion. Tumors with a similar histological appearance have recently been reported in various soft tissue and visceral sites, including the brain, by the names of myxoid variant of angiomatoid fibrous histiocytoma (AFH) and intracranial myxoid mesenchymal tumors, which harbor EWSR1 fusions with genes encoding one of the CREB family transcription factors (ATF1, CREB1, or CREM). Primary pulmonary AFHs have been reported, with some showing myxoid features. Although PPMS is recognized in the WHO classification of the lung as a distinctive tumor, a significant overlap in histology and genetics, albeit several differences, may suggest a close relationship between PPMS and myxoid AFH.

      References:

      1. French CA. NUT Carcinoma: Clinicopathologic features, pathogenesis, and treatment. Pathol Int. 2018 Nov;68(11):583-595.

      2. Dickson BC, et al. NUTM1 Gene Fusions Characterize a Subset of Undifferentiated Soft Tissue and Visceral Tumors. Am J Surg Pathol. 2018 May;42(5):636-645.

      3. Le Loarer F, et al. Clinicopathologic Features of CIC-NUTM1 Sarcomas, a New Molecular Variant of the Family of CIC-Fused Sarcomas. Am J Surg Pathol. 2019 Feb;43(2):268-276.

      4. Stevens TM, et al. NUTM1-rearranged neoplasia: a multi-institution experienceyields novel fusion partners and expands the histologic spectrum. Mod Pathol.2019 Feb 5. [Epub]

      5. Sekine S, et al. Recurrent YAP1-MAML2 and YAP1-NUTM1 fusions in poroma and porocarcinoma. J Clin Invest. 2019 May 30;130. [Epub]

      6. Le Loarer F, et al. SMARCA4 inactivation defines a group of undifferentiated thoracic malignancies transcriptionally related to BAF-deficient sarcomas. Nat Genet. 2015 Oct;47(10):1200-5.

      7. Yoshida A, et al. Clinicopathological and molecular characterization of SMARCA4-deficient thoracic sarcomas with comparison to potentially related entities. Mod Pathol. 2017 Jun;30(6):797-809.

      8. Thway K, et al. Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion: a new tumor entity. Am J Surg Pathol. 2011 Nov;35(11):1722-32.

      9. Smith SC, et al. At the intersection of primary pulmonary myxoid sarcoma and pulmonary angiomatoid fibrous histiocytoma: observations from three new cases. Histopathology. 2014 Jul;65(1):144-6.

      10. Schaefer IM, et al. Myxoid variant of so-called angiomatoid "malignant fibrous histiocytoma": clinicopathologic characterization in a series of 21 cases. Am J Surg Pathol. 2014 Jun;38(6):816-23.

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      GR03.05 - Grading of NSCLCs - Problems and Solutions (Now Available) (ID 3313)

      15:45 - 17:15  |  Presenting Author(s): Andre Luis Moreira

      • Abstract
      • Presentation
      • Slides

      Abstract

      Background

      Tumor grading has been a traditional component of the pathologic evaluation and in many organ systems, tumor grading offers guideline to therapy and patient management. The latter has not been applied to NSCLC. However, considering the new advances in therapy modalities for NSCLC and advances in adenocarcinoma classification, it is now clear that there are different types of adenocarcinomas and these tumors should not be treated the same way. The 2015 WHO classification of pulmonary adenocarcinoma based on the predominant histological pattern has consistently been found to correlate with prognosis. There is broad agreement that the five histological patterns (lepidic, acinar, papillary, solid and micropapillary) are important prognostic indicators. Recent studies have proposed the inclusion of a number of additional pathologic features (the role of secondary patterns, non-traditional pattern such as cribriform and complex glandular patterns, nuclear grade, mitotic counts, presence of spread through alveolar space (STAS), and necrosis.) that also have prognostic value. The addition of these histological features to the predominant pattern could offer greater refinement of a grading scheme. Supplementing the classification of lung adenocarcinomas with an objective grading system will help define prognostic groups that could benefit from the changing landscape of emerging management and treatment options.

      Contrary to adenocarcinoma, there has been little advancements in the histological prognostic indicators in squamous cell carcinoma of the lung. Isolated reports have suggested that the presence of tumor budding into the stroma is the sole indicator of poor prognosis. Keratinization, which has been traditionally used to grade these tumors, does not appear to have prognostic value. However, a systematic evaluation of prognostic markers in these tumors have not been carried out. A summary of the current efforts in squamous cell carcinoma will be discussed.

      The IASLC pathology panel has proposed a systematic study to evaluate a set of histological criteria that have been described as prognostic indicators in adenocarcinoma aimed at establishing an objective grading system of invasive lung adenocarcinoma.

      Design

      A multi-institutional study involving well-annotated multiple cohorts of stage 1 adenocarcinomas with at least five years of follow up were evaluated. Annotation included an estimate of the percentage for each histological pattern present for each case; nuclear grade, cytology grade; and mitotic counts with pattern hot-spot association, presence of STAS, and necrosis. A cohort of 284 cases was used as a training set. Univariate analysis was performed to identify significant associations of histological features with recurrence-free survival and overall survival. ROC curve analysis was used to select the best model based on combinations of several features and its association with disease recurrence or death of disease. The results were validate on independent cohorts of 212 cases.

      Results

      Review of the literature showed that there are many variation in the classification and definitions on non-traditional patterns. In our cohorts, cribriform and complex glandular patterns followed similar curve as traditional high grade patterns (solid and micropapillary), therefore these non-traditional pattern were defined as patterns of high grade in the model. Another are of variation is the percentage of high grade pattern that can influence outcome. Therefore, the cut-off for a high grade pattern associated with recurrence or death of disease was also established in the training cohort and correspond to 20%. Therefore, amounts smaller than 20% of high grade pattern did not influence outcome.

      In the training cohort (n=284) all parameters tested, predominant patterns, mitotic count, nuclear grade, cytological grade, and STAS (but not necrosis) were found to have significant prognostic value on a univariate analysis. A Baseline Model composed of Age + Gender + Race + Type of surgery + Pathological Stage; showed an AUC of 0.673. In an attempt to improve this curve, histological parameters were added to the model.

      The addition of only the predominant pattern to the baseline increases the AUC to 0.698.

      A model based on the combination of predominant pattern paired with the second predominant pattern was found to have the highest AUC (0.765), followed by a combination of predominant pattern plus worse pattern (AUC=0.74). Addition of other histological features (nuclear grade, mitotic count, STAS etc.) did not significantly improve the model.

      Similar results were found in the validation set (N=212). The combination of the two most predominant patterns showed an AUC = 0.763, followed by a combination of predominant + worse pattern with AUC = 0.766. Addition of other histological features did not show improvement of the model.

      There was no statistical difference between the models using the two most predominant patterns and the predominant plus worse. There was good reproducibility scores for the 2 models

      Conclusion

      Our results suggest that an objective grading system for pulmonary adenocarcinoma is possible. Considering that there is no significant differences between a model that accounts for the 2 most predominant pattern and another composed of the predominant plus worse pattern. The IASLC pathology panel proposes the later to be used, because pathologists traditionally grade tumors by the worse component. Therefore, histologic assessment of the predominant pattern and worse pattern, would represent the most parsimonious and prognostic grading system for stage I lung adenocarcinomas.

      The use of the model in two other independent cohorts of adenocarcinomas (stages 1-3), as well as a reproducibility study will be discussed.

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    IBS02 - Making Sense of Treatment with so Many Options: My Algoritm (Ticketed Session) (ID 33)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Advanced NSCLC
    • Presentations: 3
    • Now Available
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      IBS02.01 - Making Sense of Treatment with so Many Options: My Algoritm - A European View (Now Available) (ID 3318)

      07:00 - 08:00  |  Presenting Author(s): Noemi Reguart

      • Abstract
      • Presentation
      • Slides

      Abstract

      The treatment paradigm for metastatic non-small cell lung cancer (NSCLC) continues to evolve quickly due to the introduction of immunotherapy and new targeted therapies as well as our increasing knowledge of molecular signaling pathways. As a result of treatments becoming more efficacious and more personalized, outcomes for selected patients with NSCLC are increasing. Algorithms change rapidly and those published one year ago are already outdated today. In this interactive session, we will discuss current treatment algorithm / recommendations for advanced NSCLC patients, those whose tumors have driver oncogenes as well as wild-type lung tumors. We will describe the decision-making process to arrive at a treatment recommendation for a particular patient from the perspective of three different areas of the world: Europe, North-America and Australia. Recommendations for the best standards of care, based on evidence-based medicine and local clinical practice guidelines will be covered and applied in this case to the European local-practice context.

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      IBS02.02 - Making Sense of Treatment with so Many Options: My Algoritm - A North American View (Now Available) (ID 3319)

      07:00 - 08:00  |  Presenting Author(s): Rogerio Lilenbaum

      • Abstract
      • Presentation
      • Slides

      Abstract

      The Treatment of Lung Cancer: Can it be logical?

      The treatment of lung cancer has evolved dramatically in the past decade. Targeted therapy, and more recently immunotherapy have provided not only new and better treatment options, but have radically transformed the understanding of the biology of the disease.

      For the individual practitioner, and even for the thoracic oncologist expert, it can be challenging to keep up with the new advances and apply the data to clinical practice.

      Consensus guidelines have become a popular vehicle to educate and support decision making at the individual level. Oncologists often rely on recommendations from professional societies, such as ASCO, IASLC, ESMO, and NCCN, to refresh their knowledge and to identify a treatment algorithm that is appropriate for a specific patient. There is however significant heterogeneity among the guidelines in terms of methodology and strength of recommendations.

      Guidelines are based on systematic reviews of the literature, and interpreted by a recognized panel of experts. The recommendations should be rated based on the quality of the evidence. Translating the recommendation into a treatment decision requires consideration of additional factors, clinical and non-clinical, that balance the weight of the evidence with the uniqueness of the patient’s circumstances.

      In general, when the evidence is strong, and the patient falls into the subset for whom the recommendation is intended, the intervention should be offered. Conversely, if the recommendation is weak, or the patient has factors that cofound the clinical context, clinicians need to be more discretionary and consider alternative options. Just as important, guidelines can discourage the use of ineffective, unproven, or even harmful therapies. They also serve as a platform for discussions among clinicians, or between clinicians and patients when controversies about treatment arise.

      Another level of decision tool is a clinical pathway, which provides an evidence-based, step by step protocol for delivering care to patients with specific diseases and stages. Studies have documented that use of pathways is associated with improved outcomes and often lower costs. Several health care systems across the US have implemented pathways for cancer care, with varying degrees of adherence.

      One type of pathway often used in oncology focuses on chemotherapy regimens. Committees of national experts provide recommendations as to the most appropriate regimens for a specific stage and disease, such as advanced non-small cell lung cancer, with and without a molecular target. The options are ranked based on efficacy; toxicity; and costs, usually in this order. Institutions may acquire the pathway from a vendor, or decide to rely on their own experts to develop recommendations. These guidelines should be updated frequently.

      Financial aspects become more relevant in chemotherapy pathways. In cases where efficacy and toxicity do not differ significantly among the regimens, differences in cost ultimately determine the order of prioritization. Because drug costs account for a large component of the financial well being of a cancer hospital, Pharmacy Committees are often asked to develop guidelines for selection of the more cost-effective therapies, and pathways can assist in this process.

      Other potential benefits of clinical pathways include the ability to collect information on providers’ practices; identify outliers with respect to priority regimens; and flag regimens that have limited efficacy data in a particular setting. Above all, pathways promote standardization of care within institutions, particularly when oncologists are spread across multiple sites.

      Guidelines and pathways are designed primarily to improve quality and consistency of care, and are not meant to replace clinical judgement. At a time when advances in cancer treatment outpace any one individual’s ability to keep up with the new information, they serve as a valuable resource for physicians and patients alike.

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      IBS02.03 - Making Sense of Treatment with so Many Options: My Algoritm - An Australian View (Now Available) (ID 3321)

      07:00 - 08:00  |  Presenting Author(s): Michael Boyer

      • Abstract
      • Presentation
      • Slides

      Abstract

      Section not applicable

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    IBS12 - Case-Based Management of Brain Metastasis (Bm) in Advanced Lung Cancer Patients: Changing the Standards (Ticketed Session) (ID 43)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
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      IBS12.01 - Questions to Be Addressed (Now Available) (ID 3351)

      07:00 - 08:00  |  Presenting Author(s): Matthias Guckenberger

      • Abstract
      • Presentation
      • Slides

      Abstract

      Brain metastases develop in relevant numbers of patients through their courses of metastatic non-small cell lung cancer (NSCLC) and are associated with worsening of quality-of-live and survival. Traditionally, outcome was very poor due to the lack of effective treatment options, for the brain metastases but also for extracranial metastatic disease. Recent advances in imaging, local and systemic treatment options have changed the prognosis of patients with NSCLC brain metastases and have challenged traditional treatment strategies. Management of patients with brain metastases today needs a more individualized approach due to the multiple factors influencing the decision making process: patient performance status; number, location and size of brain metastases; presence of symptoms and neurological deficits; presence and extend of extracranial disease; histology and presence of activating driver mutations; available systematic treatment options and their CNS activity; patient preference.

      From a local treatment perspective, radiosurgery and neurosurgical resection are treatment options, which have shown to improve survival in patients with limited brain metastases. Whole brain radiotherapy is not recommended after radiosurgery and neurosurgical resection; however stereotactic radiotherapy should be added to the resection cavity to improve local metastasis control. The value of radiosurgery without whole brain irradiation for multiple brain metastases is currently under investigation. Whole brain irradiation is today still recommended for patients with multiple and in particular symptomatic brain metastases; whether hippocampal avoidance can reduce the risk of damage to the neurocognitive system is not finally answered. The landscape is currently changing rapidly and fundamentally due to identification of activating driver mutations and the existence of effective targeted drugs. Additionally, treatment with immune checkpoint inhibition has also shown intracranial activity. Consequently, there is in particular a need to identify optimal combined modality strategies of local radiotherapy and systemic targeted drugs and immunotherapy.

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      IBS12.02 - Questions to Be Addressed (Now Available) (ID 3352)

      07:00 - 08:00  |  Presenting Author(s): Egbert F Smit

      • Abstract
      • Presentation
      • Slides

      Abstract

      Case-Based Management of Brain Metastasis (Bm) in Advanced Lung Cancer Patients: Changing the Standards. Questions to Be Addressed

      M. Guckenberger, E.F. Smit

      Dept. of Radiation Oncology, USZ, Switserland, Dept. of Thoracic Oncology, NCI, The Netherlands.

      Brain metastases develop in relevant numbers of patients through their courses of metastatic non-small cell lung cancer (NSCLC) and are associated with worsening of quality-of-live and survival. Traditionally, outcome was very poor due to the lack of effective treatment options, for the brain metastases but also for extracranial metastatic disease. Recent advances in imaging, local and systemic treatment options have changed the prognosis of patients with NSCLC brain metastases and have challenged traditional treatment strategies. Management of patients with brain metastases today needs a more individualized approach due to the multiple factors influencing the decision making process: patient performance status; number, location and size of brain metastases; presence of symptoms and neurological deficits; presence and extend of extracranial disease; histology and presence of activating driver mutations; available systematic treatment options and their CNS activity; patient preference.

      From a local treatment perspective, radiosurgery and neurosurgical resection are treatment options, which have shown to improve survival in patients with limited brain metastases. Whole brain radiotherapy is not recommended after radiosurgery and neurosurgical resection; however stereotactic radiotherapy should be added to the resection cavity to improve local metastasis control. The value of radiosurgery without whole brain irradiation for multiple brain metastases is currently under investigation. Whole brain irradiation is today still recommended for patients with multiple and in particular symptomatic brain metastases; whether hippocampal avoidance can reduce the risk of damage to the neurocognitive system is not finally answered. The landscape is currently changing rapidly and fundamentally due to identification of activating driver mutations and the existence of effective targeted drugs. Additionally, treatment with immune checkpoint inhibition has also shown intracranial activity. Consequently, there is in particular a need to identify optimal combined modality strategies of local radiotherapy and systemic targeted drugs and immunotherapy.

      From a systemic treatment perspective, it has become apparent that brain metastases may also be sensitive to tyrosine kinase inhibitors against a variety of targets and emerging data suggest that immune checkpoint inhibitors display activity as well. Therefore, in case of asymptomatic brain metastases at diagnosis when the primary lung cancer is characterized by an oncogenic driver, nowadays many would favour initial treatment with tyrosine kinase inhibitors in an effort to delay radiotherapy to the brain as long as possible. Whether symptomatic brain metastases at diagnosis may be managed in a similar manner, especially when refractory to high dose steroids, is less clear. The third generation EGFR TKI (osimertinib) and second/third generation Alk inhibitors (ceritinib, alectinib, brigatinib and lorlatinib) are associated with response rates in the brain in the relapse setting on treatment of first/second generation EGFR TKi’s or first generation Alk inhibitor that are not different from extracranial response rates. Thus, also in this clinical situation, systemic treatment plays an important role in delaying radiotherapy – in particular whole brain radiotherapy- as long as possible. It should be noted however, that there are no formal randomized comparisons available of these treatment modalities.

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    IBS23 - Treatment of NSCLC OMD in Clinical Practice (Ticketed Session) (ID 54)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Oligometastatic NSCLC
    • Presentations: 3
    • Now Available
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      IBS23.01 - Radiotherapy of OMD in Daily Clinical Practice (Now Available) (ID 3385)

      07:00 - 08:00  |  Presenting Author(s): Ritsuko Komaki-Cox

      • Abstract
      • Presentation
      • Slides

      Abstract

      Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer related death in the world.1 Analysis of patterns of failure after first-line systemic therapy for metastatic NSCLC suggest that most progression events, either within or outside the central nervous system (CNS), occur only at sites of disease known to exist at baseline, rather than in new sites.2 Once systemic treatment becomes more efficacious, for patients with limited numbers of metastases, ablation of those metastases may be advantageous in terms of cytoreduction or removal of dominant disease sites that may seed other sites in the future. Stage IV disease that is limited to only a small number of sites (“oligometastatic” disease (OMD)) may reflect a more indolent phenotype that could benefit from local ablative therapy (e.g. surgery or radiation) for consolidation, as suggested by some preclinical and translational analyses.3,4 Several retrospective and small prospective trials have suggested that local therapy may be beneficial for patients with stage IV NSCLC presenting with limited metastases .5-8

      At MDACC, we have performed a randomized, phase II study (NCT01725165) to evaluate progression-free survival (PFS) after aggressive local consolidative therapy (LCT) versus maintenance therapy or observation for patients with stage IV NSCLC with ≤3 metastases remaining after front line systemic therapy. As secondary aims, we explored: (1) the safety and incidence of high-grade toxicity, (2) overall survival (OS), (3) patterns of failure and the effect of salvage therapy among patients who crossed over to the local consolidation group, (4) time to development of disease at new metastatic sites, and (5) predictors of PFS.

      Findings of our randomized trial of aggressive LCT followed by standard maintenance therapy versus maintenance therapy alone for patients with oligometastatic NSCLC that did not progress after initial systemic therapy were as follows.10 We found that the PFS time for the standard (maintenance therapy) group was almost exactly as had been hypothesized from prior studies (3.9 months observed vs. 4 months hypothesized), whereas that of the experimental (LCT) group was substantially longer than predicted (11.9 months observed vs. 7 months hypothesized). Notably, our hypothesis was based on retrospective data in which sites of new disease versus sites of known disease could be followed more thoroughly for progression. In addition, time to the appearance of a new lesion was longer for patients in the LCT arm than for in the no-LCT arm (11.9 months vs. 5.7 months, p=0.0497), suggesting that the LCT could be altering the natural history of the disease2, either by limiting the potential for later spread or possibly by altering systemic anticancer immune responses to facilitate longer control of subclinical disease. Our trial used SBRT or surgery for local treatment for the oligometastasis. However more recent trial was done by consolidative radiotherapy for the limited oligometastatic NSCLC showing SBRT(SABR)

      Prior to the maintenance chemotherapy improved PFG compared to maintenance chemotherapy alone.10

      Common oligometastatic lesions we usually treat by radiotherapy are brain, bone, adrenal gland, lung, liver lymph node, mediastinum, pleura and muscle. Daily clinical practice, we need to use image guided radiotherapy with 4 D simulation. We should use SBRT or SABR to eliminate oligometasis without overlapping previously irradiated area and avoid critical organs.

      Take home message: 1) We have enough evidence that treating oligometastasis by aggressive local treatment improved PFS and less appearance of new lesions.

      2) Patients are able to tolerate local aggressive RT by SBRT (SABR).

      3) Need to consider patients with oligometastases to be treated agressibly by SBRT (SABR).

      4) Efficacy to improve OS by additional immunotherapy to the SBRT or SABR to the oligometastasis requires a prospective randomized studies in future.

      References

      1.Siegel RL, Miller KD, Jemal A, CA, Cancer J for Clinicians: Cancer Statistics 2019 Volume 69 (1): 1-84.

      2.Rusthoven KE, Hammerman SF, Kavanagh BD, Birtwhistle MJ, Stares M, Camidge DR. Is there a role for consolidative stereotactic body radiation therapy following first-line systemic therapy for metastatic lung cancer? A patterns-of-failure analysis. Acta Oncol 2009; 48(4): 578-83.

      3.Wong AC, Watson SP, Pitroda SP, et al. Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT). Cancer 2016.

      4.Lussier YA, Xing HR, Salama JK, et al. MicroRNA expression characterizes oligometastasis(es). PLoS One 2011; 6(12): e28650.

      5. Salama JK, Chmura SJ, Mehta N, et al. An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease. Clin Cancer Res 2008; 14(16): 5255-9.

      6.Inoue T, Katoh N, Aoyama H, et al. Clinical outcomes of stereotactic brain and/or body radiotherapy for patients with oligometastatic lesions. Jpn J Clin Oncol 2010; 40(8): 788-94.

      7.Pfannschmidt J, Dienemann H. Surgical treatment of oligometastatic non-small cell lung cancer. Lung Cancer 2010; 69(3): 251-8.

      8. De Ruysscher D, Wanders R, van Baardwijk A, Dingermans AC, et al, Radiacal Treatment of Non Small Cell Lung cancer Patients with Synchronous Oligometastases: Long Term Results of a prospective Phase II trial (Nct01282450) Journal of Thoracic Oncology 2012 ;7(10) 1547-1555

      9. Gomez DR, Blumenschein GR, Lee JJ, Hernandez M, Ye R, Camidge DR, Doebele RC, Skoulidis F, Gaspar LE, Gibbons DL, Karam JA, Kavanagh BD, Tang C, Komaki R, Louie AV, Palma DA, Tsao AS, Sepesi B, William WN, Zhang J, Shi Q, Wang XS, Swisher SG, Heymach JV. Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study. Lancet Oncol. e-Pub Vol 17,1672-1682, 10/2016. PMID: 27789196

      10. Iyengar P, Wardak Z, Gerbrer D, et al :Consolidative Radiotherapy for Limited Metastatic Non-Small Cell Lung Cancer: A Phase 2 Randomized Clinical Trial.JAMA Oncology 4(1) 2018 ,1-8

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      IBS23.02 - Oncological Treatment of Omd in Daily Clinical Practice (Now Available) (ID 3386)

      07:00 - 08:00  |  Presenting Author(s): Sanjay Popat

      • Abstract
      • Presentation
      • Slides

      Abstract

      The front line systemic treatment of metastatic non-small cell lung cancer (NSCLC) has changed rapidly over the past 10 years, from the establishment of histology-specific chemotherapy, the introduction of molecular targeted therapies for specific somatic sensitizing gene mutations/fusions, and now the routine use of immune checkpoint inhibitors either as monotherapy or in combination with chemotherapy. Current data suggests that oncogene addicted tumours have little benefit from checkpoint inhibitor monotherapy, and so advanced NSCLC can be functionally categorized into those that are oncogene addicted and ideally treated with molecular targeted therapy – either as monotherapy or in combination with other therapies- or immune sensitive, ideally treated with immune checkpoint inhibitors again as monotherapy or in combination with chemotherapy. At the same time, advances in radiotherapy delivery have meant that small volume metastatic disease can be treated at ablative doses of radiotherapy. How these two modalities should be integrated in patients with oligometastatic disease for optimal survival and minimal toxicities has been debated over recent months.

      In parallel our understanding of the natural history of different types of NSCLC has become better understood, alongside the phenotypic and genotypic selection pressures put on them by systemic therapy. Thus, recognizing that patients with oncogene addicted disease such as ALK and ROS1 fusions or EGFR mutations have a high propensity to CNS metastases, and that next generation CNS-penetrant kinase inhibitors are optimally used up front, SRS to brain metastases may be deferred and used on demand in case of late progression, effectively withholding whole brain radiotherapy until much later in the patient care timeline. However, trial data to support this decision making is currently lacking and awaited. Understanding that patients with oncogene addicted disease now have a median survival quadrupled to that previously (now in excess of 4 years) with optimal sequencing of kinase inhibitors, allows a more thoughtful way to integrate a more radical approach into those with small volume oligometastatic disease.

      We therefore now recognize several states of oligometastatic disease, with much of our information and treatment paradigms evolving from the treatment of patients with oncogene addicted disease. Patients may have the now well-known synchronous or metachronous oligometastatic disease state. Moreover, the integration of kinase inhibitors has identified an oligoprogressive disease occurring in around 30% of cases, and the ability to treat such cases with radical radiotherapy or a surgical approach. In such cases, tissue sampling may be required not only to plan the next steps of systemic therapy by tissue genotyping for acquired resistance mechanisms and new molecular target identification, but also for fiducial placement. Another less well defined disease entity is that of oligopersistent disease- defined as small volume radically treatable disease present after the bulk of oligo- or poly-metastatic disease has responded well to initial therapy, with patient series data suggesting a survival benefit for radically consolidating (oligo-consolidation) or optimally debulking in this approach.

      The integration of immune checkpoint inhibitors has again changed patterns of disease response and progression. Certainly, major durable responders are observed with checkpoint inhibitors alone, and the role of radically consolidating such patients may be debatable given that around 30% of patients with 50%+ PDL1 expression treated with front-line pembrolizumab monotherapy survive 5 years. However, acquired checkpoint inhibitor resistance is common and single centre series have suggested a rate of 30% of patients progressing with oligoprogression, suitable for ablative therapy or resection.

      In this presentation, I will discuss all these issues, including concerns about toxicities, and duration of therapy, arguing for a consensus on oligo-definitions, and molecular stratification within trials, encouraging enrolment into ongoing clinical trials to quantify the magnitude of benefit afforded by radically treating the oligometastatic state.

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      IBS23.03 - Surgical Treatment of OMD in Daily Clinical Practice (Now Available) (ID 3387)

      07:00 - 08:00  |  Presenting Author(s): Paul De Leyn  |  Author(s): Herbert Decaluwe

      • Abstract
      • Presentation
      • Slides

      Abstract

      Patients with metastatic non-small cell lung cancer (stage IV) are usually deemed to be incurable and no local aggressive treatment is generally indicated. However, stage IV NSCLC cancer is a heterogeneous group. This is confirmed by the 8 thh TNM NSCLC staging system. Stage M1a are patients with separate tumor nodules (s) in a contralateral lobe, tumor metastatic pleural or pericardial nodule, or malignant pleural pericardial effusion. M1b is single extra thoracic metastatic disease in one organ and M1c are patients with multiple extra thoracic metastasis in one or several organs.

      Oligometastatic disease is widely recognized as patients with a limited number of controllable secondary lesions. The exact number of metastasis and definition is still debate.

      Over the last years remarkable advances in chemotherapy strategy and immunotherapy have resulted in substantial survival benefits in patients with stage IV NSCLC. This questions in some patients the need of aggressive treatment of residual or recurrent disease.

      In literature, there are several studies on the role of surgery in patients with lung cancer and single metastasis in the brain, adrenal or contralateral lung. Most of the evidence is based on small retrospective series that were collected over an extended period of time.

      More recently, there is some experience with multimodal treatment including surgery in patients with oligometastatic disease and more metastasis also in different organs. There are several prognostic factors. Mediastinal nodal involvement and tumor size are important. In all patients, FDG- PET could be performed. Since prognosis is very small in N2 patients, invasive mediastinal staging (endoscopically or surgically) should be performed before embarking on an aggressive multimodal surgical treatment of oligometastatic disease. Over the last years, robotic surgery or uniportal VATS is becoming less invasive with less postoperative complications and better tolerance of neoadjuvant or adjuvant therapy. When surgery is part of multimodal treatment of patients with oligometastatic disease pneumonectomy should be avoided.

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    JCSE01 - Joint IASLC-CSCO-CAALC Session (ID 63)

    • Event: WCLC 2019
    • Type: Joint IASLC-CSCO-CAALC Session
    • Track:
    • Presentations: 24
    • Now Available
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      JCSE01.02 - The Opportunity of Drugs Development on Immunotherapy in China (Now Available) (ID 3416)

      07:00 - 11:15  |  Presenting Author(s): Qing Zhou

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immunotherapy gets the breakthrough after almost 100 years of silence. PD1/PD-L1 inhibitors as the representative have been extensively studied in various human malignant tumors and get promising long term response with relatively fewer adverse events. The first PD1 inhibitor indication was approved for melanoma in Japan on July 2014. Up to now, the US Food and Drug Administration had approved several PD-1 pathway blockade treatments including nivolumab, pembrolizumab and atezolizumab using in first line and second line of NSCLC. In China, nivolumab was approved for second line setting for advanced NSCLC and pembrolizumab combined with chemotherapy were approved for first line setting of advanced NSCLC. Two novel PD-1 inhibitors from Chinese pharmaceutical companies were approved for melanoma and lymphoma by National Medical Products Administration (NMPA) of China. And, a lot of clinical trials about domestic novel PD-1 and PD-L1 inhibitors from Chinese pharmaceutical companies are now ongoing.

      IO arena faces intense in-class competition from both MNC (Multi-National Corporation) and domestic pharmaceutical company in China. Now there are more than 20 IO antibodies from 10 MNCs and 16 pharmaceutical companies in China. Besides PD1/PD-L1 and CTLA4, other hot IO drugs such as IDO or Lag3 et al are also under investigation. Clinical trials about some novel combination, for example, CMET inhibitor plus IO, anti-angiogenesis drugs plus IO, et al, are also ongoing.

      There are special questions which need to be settled in China. Chinese population has relatively high rates of hepatitis B virus infection and much higher proportion of EGFR mutation. The delightful changing recently is some studies emerging to consider the characteristics of the Chinese or Asian populations. Some clinical trials are trying to answer these questions. Besides clinical trials for advanced NSCLC, Clinical trials focus on local advanced NSCLC, early stage NSCLC and SCLC are also ongoing. New adjuvant and adjuvant IO trials have started in China. Most importantly, some novel combinations overcoming previous IO resistance are now on the way, which will give more interesting results in the near future.

      Research about Chinese IO treatment remains in their early stage and further efforts are needed to improve the design of future clinical trials and translational research. Meanwhile, the other hot IO drugs and phase I studies need to speed up in China.

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      JCSE01.03 - Any Difference on Efficacy and Toxicity Between East and West? (Now Available) (ID 3417)

      07:00 - 11:15  |  Presenting Author(s): Jie Hu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Any difference on efficacy and toxicity between east and west?

      Jie Hu

      Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

      Abstract

      Lung cancer is now the most commonly diagnosed cancer and the leading cause of cancer related mortality, taking about 1.6 million lives each year. There has been long evidenced that different population display differential sensitivity and safety profiles on different treatment. in addition, many other factors can also influence therapeutic response of patients, such as lifestyle, metabolism, dietary etc. Here we try to explore the impact and underlying mechanism of ethnic difference on response and tolerance of various therapeutic regimens such as cytotoxic chemotherapy, TKIs, antiangiogenic drugs and ICIs.

      Treatment patterns of lung cancer has been transformed over the years, leading to the better outcomes of patients. The 5-year overall survival (OS) rate of advanced NSCLC is less than 5% in the standard chemotherapy era. Although widely used of tyrosine kinase inhibitors (TKIs) prolonged progression-free survival (PFS) and OS in patients harboring driver gene mutations, the long-time survival rate was still low due to acquired drug resistance. Over the last five years, emergence of immune checkpoint inhibitors(ICIs)has greatly improved outcomes of NSCLC with objective response rate (ORR) about 20% and 5-year OS rate nearly 16% in previous treated patients based on multiple clinical trials data. A retrospective review of the SEER database found that Asian population presented with higher percentage of metastatic lung cancer but significantly greater overall survival rate among nine different ethnic groups. Furthermore, among the total Asian population, Chinese has the highest percentage of adenocarcinomas (69.4%). The latest data show mutation rate of epidermal growth factor receptor (EGFR) in Adenocarcinoma is 40.3~64.5% and 75% in certain clinically enriched population such as non-smoking adenocarcinoma. These data can fully explain the better outcomes of TKIs in Asia population.

      There has evidence that different population has different sensitivity and toxicity to different anti-tumor regiments. Studies showed that hematological toxicities of docetaxel were more frequently observed in Japanese compared to US/European patients. In addition, it is reported that docetaxel-induced grade 3/4 neutropenia is higher in Asian clinical trials than non-Asian trials. On the other hand, the discrepancy of dosage regimen between Japanese (60 mg/m2) and western population implies ethnic difference in PK. Similar data of carbo-platin/paclitaxel and irinotecan-based regimens have been reported in many phase 3 or phase 2 trials.

      Meanwhile, there are many studies compared the adverse events of TKIs in different ethnics and data suggested that incidence of ILD caused by gefitinib and erlotinib is higher in Japan (1.2~5.4%) than in the rest of the world.

      Despite promising outcomes of ICIs, the clinical trials for Asia population is still rare now. Checkmate 078 was the first trial to predominantly recruit Chinese NSCLC patients, the ORR of Chinese population was 17%, which is in accordance with Caucasian population. However, according to PMS study of Japan and several published meta-analysis results, Asian patients were more likely to develop pneumonitis with the incidence rate 5.7~9.6% in ICIs mono-therapy and these rate would be increased significantly when combined with other drugs. Many genetic studies have revealed the prevalence of genetic polymorphisms (i.e. mutation of SFTPC, ABCA3; telomere-associated genes like TERT, TERC, RTELI, PARN; SNP of MUC5B etc.) was associated with susceptibility to ILD in Japanese. Understanding characteristics of genomic profile will be of no doubt to facilitate the selection of targeted population of ICIs.

      Except for the toxicity of ICIs, we should pay attention to the drug response of particular groups of population, which were excluded from clinical trials according to the entry criteria of RCT. Among these HBV-infected NSCLC patients seemed to be more emergency as HBV infected population of Asia is accounted for 62% of global HBV burden, therefore, efficacy and toxicity of ICIs on HBV infected NSCLC patients will be discussed based on many clinical trials or real world data.

      In a word, ethnic difference can influence efficacy and toxicity of different treatment options. More genomic mapping and preclinical research should be implemented to explore the relationship between ethnic diversity and varying degrees of response.

      Key word: ethnic, efficacy, toxicity, TKIs, ICIs

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      JCSE01.04 - Neo-Adjuvant Immunotherapy in Lung Cancer (Now Available) (ID 3419)

      07:00 - 11:15  |  Presenting Author(s): Nan Wu

      • Abstract
      • Presentation
      • Slides

      Abstract

      Immune checkpoint inhibitors (ICIs) therapy have been recommended as the standard of care in the first-line treatment strategy of selected advanced non-small cell lung cancer (NSCLC) patients. Effective therapies also needed for NSCLC patients in early-stage, whose failure arises both local relapse and remote metastasis after surgery. Lavin et al revealed that an immunosuppressive microenvironment had developed even in stage I disease, which promoted the investigation of immunotherapeutic regimens in early stage population1. The success of ICIs in the metastatic disease has also generated enthusiasm to initiate clinical trials to evaluate the utility of ICIs as neoadjuvant therapy in the setting of resectable NSCLC2. Theoretically, immunotherapy in patients with early-stage NSCLC may have more favorable antitumor effects due to lack of T cell function depletion and less tumor clonal heterogeneity. However, there are lots of details need to be discussed, and this necessitates a review regarding neoadjuvant immunotherapy topic.

      The fundamental premise on the application of neoadjuvant immunotherapy is the safety and feasibility. In a cohort of 21 patients, Forde et al revealed neoadjuvant nivolumab was associated with well tolerance and few side effects, did not delay surgery and induce a major pathological response (MPR) in 45% of resected tumors2. MPR rate is associated with long term survival outcomes, thus it is considered as a surrogate endpoint for recurrence and survival3.Radiologic assessment of treatment cannot predict pathological response accurately after ICIs therapy. Chest CT might underestimate response rate accurate after neoadjuvant ICIs therapy compared with pathological assessment (10% vs. 45%)2. This phenomenon was postulated to be related with T-cell infiltration and peritumoral inflammation during the early stage of treatment, which was defined as “pseudo-progression” by some experts4. Bott et al analyzed operative details and postoperative outcomes in this cohort. Unexpected perioperative morbidity and mortality was not observed. The rate of conversion was moderately high because of hilar inflammation and fibrosis, which might develop as a result of response to treatment5. The surgical outcomes proved the feasibility and safety of pulmonary resection after neoadjuvant nivolumab monotherapy and encouraged the execution of following neoadjuvant immunotherapy trials relevant to surgical practice.

      In the setting of resectable NSCLC, what is optimal sequence of immunotherapy and surgery? There is no straight evidence available to clear the issue right now. However, differing from perioperative chemotherapy, the administration of ICIs in the preoperative phase while the tumor is in situ might provide greater therapeutic efficacy in terms of elevated and sustained peripheral tumor-specific immune responses compared with adjuvant immunotherapy6. Liu et al proved it through utilizing a murine model of triple-negative breast cancer (TNBC). Therefore, the utilization of ICIs prior to surgery has been presumed to be capable of potentially eliminating micrometastatic disease and thus decrease the risk of recurrence in resectable NSCLC. It was also interesting that mice given neoadjuvant chemotherapy displayed no significant anti-tumor benefit over adjuvant chemotherapy in the same murine model, which was consistent with the results of clinical trials7.

      The optimization of neoadjuvant schemes is underway in resectable NSCLC patients. Since the combination of nivolumab plus ipilimumab showed encouraging clinical activity characterized by a high response rate and durable response in setting of advanced NSCLC8-9, the combination of double ICIs has been incorporated into the neoadjuvant care of resectable NSCLC patients. The NEOSTAR trial randomized patients to receive nivolumab or nivolumab plus ipilimumab before surgery10. The combination therapy was associated with an increased number of tumor-infiltrating lymphocytes compared to monotherapy, suggesting superior therapeutic efficacy in doublet ICIs group. However, higher proportion of patients did not receive scheduled surgery (doublet 23.8% vs monotherapy 8.7%) was a problem need attention.

      ICIs in combination with chemotherapy (ICI-CT) was another direction of neoadjuvant immunotherapeutic schemes. Safety and tolerability of neoadjuvant ICIs combined with platinum-based doublet chemotherapy has been proved in the KEYNOTE-189 trial11and KEYNOTE 407 trial12. NADIM trial is an ongoing phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC patients with ICI-CT as a neoadjuvant treatment13. In NADIM trial, pathological response rate was also higher than that assessed by RECIST. Neoadjuvant ICI-CT yields an unprecedented response rate prompting the regimen as the most promising neoadjuvant scenario. All the oncologists are eager to observe the long-term outcomes of NADIM, which would finally revise the standard pathway of curing early stage NSCLC.

      In this new era of immunotherapy for NSCLC, multiple questions remain regarding the integration of immunotherapy and traditional therapy protocol. For instance, whether concurrent chemoradiotherapy combined with ICIs could be a neoadjuvant regimen for resectable stage IIIA (N2) NSCLC? Accrued evidence indicates that radiation could stimulate the immune system via upregulating tumor-associated antigens, augmenting MHC class I surface expression, increasing T-cell tumor-specific CD 8+ T cells, et al14. PACIFIC trial has delineated ICI significantly prolonged overall survival among patients with stage III, unresectable NSCLC following concurrent chemoradiotherapy15. If irradiation could produce systemic effects under ICI and contribute to the development of a broader range of cancer treatments16, surgery would be asked to perform a better local tumor control. Surgery for advanced NSCLC are increasingly expanding in setting of partial or complete treatment response after immunotherapy17. It will indeed take years before we exactly know how to most effectively incorporate ICI into other traditional therapies, including surgery.

      It is always attractive to predict which individuals will have a long-lasting response. Fortunately, neoadjuvant therapy allows for an assessment of treatment effect, as well as pathological response due to the convenience of specimencollection after surgery. Optimal biomarkers should be capable to improve patient selection for ICI treatment. Therapeutic selection based on actionable genomic alterations can clearly delineate patients who will receive survival benefit from a given therapy. However, the same scenario cannot certainly happen for immune-based biomarkers. Some experts deem deescalating therapy of single agent checkpoint blockade should be approached with caution regarding the lack of transformative immune-based biomarker18. Except PD-L1 express and TMB, dynamics of the immune system need to be standardized to ensure the accuracy of results and uniformity across clinical trials19. To capture a perfect biomarker to predict clinical responses to ICIs is an unrealistic goal in the short-term. Further studies are desiderated to identify biomarkers associated with improved survival.

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      JCSE01.05 - Biomarker in Immunotherapy: Myth or Reality? (Now Available) (ID 3418)

      07:00 - 11:15  |  Presenting Author(s): Alfredo Addeo

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background: NSCLC treatment landscape has rapidly evolved with several immune checkpoint inhibitors (ICIs) approved initially in second line as monotherapy and subsequently in first line as either monotherapy or in combination with chemotherapy. The recent presentation at the ASCO 2019 of the 5 years overall survival (OS) of the Keynote 001 has further strengthened the importance and impact of ICIs on patients with NSCLC, showing unprecedented 5 years overall OS. However up to 50-60% of NSCLC patient does not benefit from such a treatment. The need to validate and find out new effective biomarker (BM) remains crucial.

      Discussion: PD-L1 expression is the only approved BM in NSCLC that proved to be predictive of better OS for anti-PD1 (Pembrolizumab). Despite several advantages such as short turnaround time (TAT), relatively simple IHC assay (gone through an harmonized process in the blueprint2) there are several limitations: PD-L1 non expresser could still be responders and benefit form ICIs or in driven mutated NSCLC the PD-L1 level might be very high, generally mediates by the JAK3 pathway, but not being responsive to ICIs for the rarity of T cell infiltrations.

      A new promising BM is the tumour mutation burden (TMB). The prevalence of somatic mutation varies between 0.01 mut/Mb to 400 mutations/Mb. Some of these mutations led to the translation of novel peptide epitopes or neoantigens that should enhance the immunogenicity of the tumour by eliciting T cell repertoire. The hypothesis then is that in case of high TMB ICIs should work better than chemo. So far this has been partially seen in some studies in term of response rate (RR) an progression free survival (PFS) but no study has been designed yet as having primary endpoint better OS in High TMB patients. Furthermore there are several aspects to consider about TMB: TAT is at least 2 week (it the first studies were conducted by using whole exome sequencing), high cost, no clear cut-off, unclear if it should be performed on cancer tissue or circulating tumour DNA (ctDNA) and the most important one the prospective trial has ever validated TMB as predictive of better OS compared to chemotherapy.

      There are several new BM in embryonic phase: role and importance of TILs, immune gene signature, INFgamma relatedmRNAbased signatures, myeloid-derived suppressor cells(MDSCs) or the neutrophil-to-lymphocyte ratio (NLR) at baseline. None of them is ready for prime time but there are ongoing studies that hopefully will validate useful BM to adopt in clinical practice

      Conclusion: are BMs reality? Yes we already have a reliable predictive BM which remains PD-L1 expression. TMB might represent a possible alternative to identify a different subgroup of NSCLC patients. PD-L1 high and high TMB might partially overlap but they highly likely correspond to 2 different patients populations. There is indeed room for improvement and more BMs are needed: possibly simple to adopt in clinical practice, with short TAT and most important showing OS benefit, to definitively move from the myth to the reality.

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      JCSE01.06 - New Era Beyond PD-1/PD-L1 (Now Available) (ID 3420)

      07:00 - 11:15  |  Presenting Author(s): Luis Paz-Ares

      • Abstract
      • Presentation
      • Slides

      Abstract

      Over the past few years, targeting immune checkpoints such as PD-1/PD-L1 (and in some extend CTLA-4) has changed the landscape of lung cancer therapy and largely impacted patients with notable therapeutic benefits. However, not all lung cancer patients respond to immune checkpoint inhibitors and actually only some 15-20% of those with metastatic disease achieve long term survival, reflecting to the complexity of immune checkpoints and daunting tumor resistance. In order to broaden the possibilities of lung cancer immunotherapy, we need to seek alternative immune checkpoints beyond PD-1/ PD-L1, test novel combination strategies of immune checkpoint inhibitors and more conventional treatments, and increase the predictive potential of biomarkers to optimally guide clinical practice. Meanwhile, there are a number of unsolved questions that may require our attention for future better clinical performance.

      The wide range of immune-related adverse effects (irAEs) that accompany immune checkpoint inhibitors can complicate this efficacious immunotherapy and restrict its use in cancer patients. The precise pathophysiology underlying irAEs is frequently unknown, but may be related to breaking the balance of immunologic homeostasis. Although any organ system is possibly influenced, irAEs most commonly involve the gastrointestinal tract, endocrine glands, and skin. Most of the toxic effects are reversible, but deaths due to severe irAEs such as myocarditis and pneumonitis can occur. The serious problem of irAEs particularly requires to define optimal strategies for multidisciplinary and collaborative management, and ad-hoc education programs. Of note, recent data suggest that prophylactic TNF blockade uncouples efficacy and toxicity in dual CTLA-4 and PD-1 immunotherapy.

      The clinical therapeutic efficacy of immune checkpoint inhibitors remains controversial. Tumor resistance, primary and acquired, is a daunting challenge that limits the responsiveness to immunotherapy, and deserves intensive investigation. Hyperprogressive disease (HPD) following immunotherapy also deserve adequate attention. Evidence suggests that MDM2 family amplification or EGFR, KEAP and LKB1 aberrations may lead to poor clinical outcomes on IO treatment and may account for the risk of HPD.

      Preclinical and clinical testing of alternative immune checkpoints is mandatory, particularly in programs that coupled a biomarker driven strategy. It is noteworthy that tumor infiltrating T cells can simultaneously express PD-1/PD-L1 along with other immune checkpoints. Also, evidence has delineated that upregulation of compensatory inhibitory molecules such as LAG-3, VISTA, and TIM-3 may mediate tumor resistance to immune checkpoint inhibitors. Understanding the precise molecular mechanisms of different immune checkpoints will benefit the design of effective combination therapies and overcome potential resistance.

      More well-designed combination strategies (antiangiogenics, targeted therapies, chemotherapeutics,...) that can yield remarkable and synergistic clinical benefits are critical for immune checkpoint therapy. To optimize the combination therapies, we should carefully explore effective and safe doses of treatments, sequencing of the agents, appropriate timing, and so on. There is a pressing need to study the indepth mechanisms of the interaction between chemo-radiotherapy or targeted therapy and the immune system. In addition, identifying more combinations of immune checkpoint inhibitors and new treatment approaches such as by-specific antibodies, chimeric antigen receptor T cell (CAR-T) immunotherapy, TILs, modulating the microbioma and tumor vaccines is a tantalizing option.

      Finally, due to the complexity of the immune system, developping and validating a multiparametic model of predictive biomarkers is much required. As mentioned earlier, PD-L1 expression can inform treatment decisions, but its clinical value still needs confirmation in different patient cohorts. Meanwhile, certain genomic tumor aberrations, TMB and TME are future directions for routine clinical practice. Different TIL phenotypes, diverse TCRs, immune gene signatures, and genetic features derived from blood monitoring or TME hold high potential, but are ready for clinical use as yet.

      References

      Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after Immunotherapy: Analysis of Genomic Alterations Associated with Accelerated Growth Rate. Clin Cancer Res. 2017; 23: 4242-4250.

      Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med. 2018;378(2):158–68.

      Kato S, Goodman A, Walavalkar V, Barkauskas DA, Sharabi A, Kurzrock R. Hyperprogressors after immunotherapy: analysis of genomic alterations associated with accelerated growth rate. Clin Cancer Res. 2017;23(15):4242–50.

      Teixeira VH, Pipinikas CP, Pennycuick A, Lee-Six H, Chandrasekharan D, Beane J, et al. Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions. Nat Med. 2019; 25: 517-525.

      Turajlic S, Sottoriva A, Graham T, Swanton C. Resolving genetic heterogeneity in cancer. Nat Rev Genet. 2019; 20:404-416.

      Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, et al. Neoantigen-directed immune escape in lung cancerevolution. Nature. 2019; 567:479-485.

      Wrangle JM, Patterson A, Johnson CB, Neitzke DJ, Mehrotra S, Denlinger CE, et al. IL-2 and Beyond in Cancer Immunotherapy. J Interferon Cytokine Res. 2018; 38:45-68.

      Naing A HJ, Papadopoulos KP et al. Responses and durability of clinical benefit in renal cell carcinoma treated with pegilodecakin in combination with anti-PD-1 inhibitors (oral presentation). Presented at: European Society of Medical Oncology.2018.

      Naing A, Papadopoulos KP, Autio KA, et al. Safety, antitumor activity, and immune activation of pegylated recombinant human interleukin-10 (AM0010) in patients with advanced solid tumors. J Clin Oncol. 2016;34(29):3562–9.

      Paz-Ares L, Kim TM, Vincente D, Felip E, Lee DH, LeeKH,. Et al. Updated results of M7824 (MSB0011359C), a bifunctional fusion protein targeting TGF-B and PD-L1, in second-line (2L) NSCLC. Annals of Oncology 2018; 29 (suppl_8): viii493-viii547.

      Ben-Avi R, Farhi R, Ben-Nun A, Gorodner M, Greenberg E, Markel G, et al. Establishment of adoptive cell therapy with tumor infiltrating lymphocytes for non-small cell lung cancer patients. Cancer Immunol Immunother. 2018; 67:1221-1230.

      Lan Y, Zhang D, Xu C, Hance KW, Marelli B, Qi J, et al. Enhanced preclinical antitumor activity of M7824, a bifunctional fusion protein simultaneously targeting PD-L1 and TGF-β. Sci Transl Med. 2018; 17;10(424).

      Strauss J, Heery CR, Schlom J, Madan RA, Cao L, Kang Z, Lamping E, et al. Phase I Trial of M7824 (MSB0011359C), a Bifunctional Fusion Protein Targeting PD-L1 and TGFβ, in Advanced Solid Tumors. Clin Cancer Res; 24(6):1287-1295.

      Zitvogel L, Ma Y, Raoult D, Kroemer G, Gajewski TF. The microbiome in cance immunotherapy: Diagnostic tools and therapeutic strategies. Science. 2018; 23; 359: 1366-1370.

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      JCSE01.09 - A Phase II Umbrella Study of Camrelizumab in Different PD-L1 Expression Cohorts in Pre-Treated Advanced/Metastatic Non-Small Cell Lung Cancer (Now Available) (ID 3423)

      07:00 - 11:15  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Cheng Huang, Yun Fan, Jifeng Feng, Hong-ming Pan, Liyan Jiang, Jin-Ji Yang, Xing-Ya Li, Xiao-Qing Liu, Jiang-Ping Xiong, Yan-Qiu Zhao, Ying Cheng, rui Ma, Jie Wang, Yi-Na Wang, Yan-Hui Liu, Dong-Mei Lin, Wei Shi, Xiang Lin

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background
      The role of PD-L1 expression in 2nd line and beyond non-small cell lung cancer (NSCLC) remains controversial. Camrelizumab (SHR-1210) is a potent anti-PD-1 monoclonal antibody and has shown promising activity in NSCLC in Phase I studies. We report results from the SHR-1210-201 study (NCT03085069), a phase II umbrella study of camrelizumab monotherapy in different PD-L1 expression cohorts in Chinese patients with previously treated advanced or metastatic NSCLC.

      Methods
      Patients who progressed during or following platinum-based doublet chemotherapy were enrolled and assigned to one of 4 cohorts based on PD-L1 expression. Patients with EGFR or ALK genomic alterations were eligible provided they had disease progression with at least one approved tyrosine kinase inhibitor and with ≥50% PD-L1 expression in tumor. All enrolled patients received camrelizumab at 200 mg IV Q2W until loss of clinical benefit. The primary endpoint was objective response rate (ORR), other endpoints included progression-free survival (PFS) and overall survival (OS).

      Results
      As of Aug 1st 2018, of all the 259 patients who underwent screen, 229 cases could be pathologically evaluated. PD-L1 expression were 47.6% (109/229) in PD-L1 < 1%, 27.1% (62/229) in PD-L1 1-<25%, 8.7% (20/229) in 25-<50% and 16.6% (38/229) in 50%. A total of 63.8% (146/229) patients were enrolled. 89.0% of patients had stage IV NSCLC and 54.8% had non-squamous tumor histology. ORR was 18.5% (95%CI: 12.6%–25.8%) in ITT population. Subgroup analysis showed increased PD-L1 expression was associated with better response rate (Table 1). No response was observed in patients with EGFR mutation. The responders had durable response (median: 15.1 months; 95%CI: 5.5–not reached). Median PFS was 3.2 months (95%CI: 2.0–3.4) and median OS was 19.4 months (95%CI: 11.6–not reached) (Table 1). Treatment-related adverse events (AEs) occurred in 87.7% of patients (all Grade); 20.5% had ≥G3 related AE; and 15.8% had related SAE. 21.2% of AEs led to dose interruption and 7.5% led to treatment discontinuation.

      Table 1 - Efficacy data in subgroups
      Population No of pts ORR, % (95%CI)

      PFS (month),

      median (95%CI)

      1YOS, % (95%CI)

      OS (month),

      median (95%CI)

      PD-L1<1% 74

      12.2% (5.7%, 21.8%)

      2.1 (1.9, 3.2) 47.1% (33.8%, 59.2%) 11.6 (7.8, NR)
      PD-L1 ≥1% and < 25% 31 19.4% (7.5%, 37.5%) 3.1 (1.8, 4.9) 76.7% (57.2%, 88.2%) NR (NR, NR)
      PD-L1 ≥25% and < 50% 11 45.5% (16.7%, 76.6%) 6.0 (1.9, NR) 81.8% (44.7%, 95.1%) NR (2.9, NR)
      PD-L1 ≥50% (without EGFR mutation) 25 28.0% (12.1%, 49.4%) 7.6 (3.3, 11.4) 55.2% (32.3%, 73.2%) NR (8.6, NR)
      PD-L1 ≥50% (with EGFR mutation) 5 0 1.7 (1.2, NR) 40.0% (5.2%, 75.3%) 10.3 (1.2, NR)
      ITT 146 18.5% (12.6%, 25.8%) 3.2 (2.0, 3.4) 56.6% (47.3%, 64.9%) 19.4 (11.6, NR)

      Abbreviation: NR, Not Reached.

      Conclusion
      In Chinese patients with previously treated advanced/metastatic NSCLC, camrelizumab demonstrated improved ORR, PFS, and OS compared with historical data of the 2nd line chemotherapy. The efficacy in patients with PD-L1 <1% is similar as the 2nd line mono-chemotherapy, while patients with higher PD-L1 expression derived greater benefit from camrelizumab, the ORR, PFS and OS in patients with PD-L1 ≥25% was comparable to the 1st line doublet chemotherapy in advanced NSCLC. Camrelizumab was well tolerated. This phase 2 data warrant further clinical studies of camrelizumab in NSCLC.

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      JCSE01.10 - Efficacy and Safety of Neoadjuvant PD-1 Blockade with Sintilimab in Resectable Non-Small Cell Lung Cancer (Now Available) (ID 3424)

      07:00 - 11:15  |  Presenting Author(s): Shuhang Wang  |  Author(s): Ning Li, Jianming Ying, Xiuli Tao, Fan Zhang, Ziran Zhao, Yun Ling, Yushun Gao, Jun Zhao, Qi Xue, Yousheng Mao, Wendong Lei, Ning Wu, Jianchun Duan, Yibo Gao, Zhijie Wang, Nan Sun, Jie Wang, Shugeng Gao, Jie He, Hui Zhou, Shuyan Wang

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background
      NSCLC patients who have potentially resectable disease often subsequently relapse after surgery. New therapy that prevents relapse after surgery is desperately needed. In this study, we tested the efficacy and safety of neoadjuvant sintilimab, an anti-PD-1 antibody, for patients with resectable sqNSCLC in China.

      Methods
      All patients had treatment-naïve resectable sqNSCLC (stage IB-IIIA) that was confirmed by histopathology. Patients received two cycles of sintilimab (200 mg IV) on Day 1 and 22. Surgery was performed between Day 29-43. An enhanced PET/CT was obtained at baseline and seven days prior to surgery. Preliminary analysis of safety profile and efficacy was planned after at least 20 patients had received operation.

      Results
      As of Jan. 28, 2019, 22 patients (20 males and 2 females) with sqNSCLC received two doses of sintilimab followed by radical resection. The median age was 61.5 yr (range, 48 to 70). Six (27.3%) and four (18.2%) patients experienced neoadjuvant treatment emergent adverse events (TEAEs) and neoadjuvant treatment-related AEs (TRAEs), respectively. Most of the TEAEs and TRAEs were grade 1 or 2. Three patients achieved radiological partial response: an ORR of 13.6% based on RECIST 1.1. Ten patients (45.5%) achieved a major pathologic response (MPR, ≤10% viable tumor cells), including four (18.2%) had complete pathologic response (no viable tumor cell). There was a direct correlation between pathological response and decrease in the standardized uptake values (SUV) in the primary tumor. Among nine patients with > 30% decrease of SUV, eight had MPR, compared with no MRP response in the 11 patients with ≤30% decrease of SUV.

      Conclusion
      Neoadjuvant sintilimab for sqNSCLC patients was tolerable and the 45.5% MRP rate is encouraging. A decrease in SUV may be predictive of pathologic response after PD-1 therapy in sqNSCLC.

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      JCSE01.11 - Efficacy and Safety of Sintilimab with Anlotinib as First-Line Therapy for Advanced Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 3425)

      07:00 - 11:15  |  Presenting Author(s): Baohui Han  |  Author(s): Tianqing Chu, Runbo Zhong, Hua Zhong, Bo Zhang, Wei Zhang, Chunlei Shi, jialin Qian, Yuchen Han

      • Abstract
      • Presentation
      • Slides

      Abstract
      Background
      Given the synergy effect of immunotherapy and anti-angiogenic therapy in advanced NSCLC, FDA approved atezolizumab plus bevacizumab and chemotherapy as first-line treatment. However, chemo-free first-line strategy of PD-1/PD-L1 inhibitor combining angiogenesis modulator remains to be explored. This is the first trial evaluating sintilimab (anti-PD-1) plus anlotinib (multi-target TKI against tumor angiogenesis and proliferation) in treatment-naive advanced NSCLC patients and is one arm of Phase I anlotinib-based trial (NCT03628521).

      Methods
      Treatment-naive, stage IIIB/IV NSCLC patients aged 18-75 with ECOG PS 0-1 were eligible. Patients with EGFR, ALK or ROS1 mutations were excluded. Participants were given intravenous sintilimab (200mg q3w) and oral anlotinib (12mg/d 2 weeks on/1 week off) until progression or unacceptable toxicity. The primary endpoints were ORR and safety. The secondary endpoints included DCR, PFS and OS. AEs were graded according to CTCAE v4.0.

      Results
      From September-2018 to February-2019, 22 patients were enrolled. Most were male (95.5%), former/current smokers (63.6%) and squamous cell histology (54.5%). 4 had baseline brain metastases. All patients have received at least once tumor assessment as of Jul-3th-2019. Among all, 16 achieved confirmed PR, 6 achieved SD, ORR was 72.7% (49.8%, 89.3%) and DCR was 100% (84.6%, 100%). 6 month PFS rate is 93.8% (95%CI: 63.23%, 99.10%). Overall, sintilimab and anlotinib was well tolerated. 6 (27.3%) had grade 3 and above treatment related adverse event (TRAE). The most common TRAE included fecal occult blood, hyperuricemia, hyponatremia, foot-hand syndrome, etc. 21 patients had baseline PD-L1-evaluated and 18 patients got TMB status (details in table). Notably, 5 of 6 SD patients developed cavities inside, suggesting a synergetic anti-tumor effect from combination regimen.

      Conclusion

      In this interim analysis, sintilimab plus anlotinib showed high ORR (72.7%) and DCR (100%) with tolerable safety profile, supporting worthy of further development from this convenient chemo-free regimen in first line setting.

      table 1.jpg

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      JCSE01.12 - Discussant Oral Abstracts (Now Available) (ID 3426)

      07:00 - 11:15  |  Presenting Author(s): Bob T Li

      • Abstract
      • Presentation
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      Abstract not provided

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      JCSE01.13 - Discussant Poster Abstracts (Now Available) (ID 3427)

      07:00 - 11:15  |  Presenting Author(s): Shun Lu

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      JCSE01.14 - Higher Prevalence of EGFR Mutations Significantly Correlates with Lower PD-L1 Expression in Chinese Lung Adenocarcinoma (ID 3428)

      07:00 - 11:15  |  Presenting Author(s): Shiyue Zhang  |  Author(s): Shiwang Wen, Yuanzhu Jiang, Jun Guo, Xinglong Fan, Xuedong Pan, Yi Dai, Donglin Chen, Kai Wang, Xiaowei Dong

      • Abstract
      • Slides

      Abstract
      Background
      EGFR mutations are more prevalent in lung adenocarcinoma compared with other non-small cell lung cancer and are more prevalent in East Asians compared with the other populations. At the same time, we observed lower PD-L1 Tumor Proportion Score (TPS) in Chinese lung adenocarcinoma patients (pts) compared with that in Chinese lung squamous cell carcinoma pts and we also observed the proportion of PD-L1 positive (TPS >= 1%) in Chinese lung adenocarcinoma pts was lower than that in other multicenter cohorts. Then we hypothesize that the higher prevalence of EGFR mutations in Chinese lung adenocarcinoma pts correlates with lower PD-L1 expression.

      Methods
      The Origimed-based lung adenocarcinoma cohort was a retrospective cohort consisted of more than one thousand Chinese lung adenocarcinoma pts who underwent both NGS panel sequencing and PD-L1 immunohistochemistry (IHC) in a College of American Pathologists (CAP) certified and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory during the year 2017 and 2018. Antibodies used in the PD-L1 IHC assay included 28-8 (sample size = 883) and 22C3 (sample size = 158). Tumor Proportion Score (TPS) was applied. All the slides were reviewed by the same senior pathologist. All the EGFR mutations were manually reviewed in Integrated Genomics Viewer for confirmation. After confirmation, each pts was assigned to EGFR positive group or EGFR negative group. Fisher' s exact test and Student' s t-test were applied.

      Results
      For antibody 28-8, PD-L1 IHC was positive (TPS >= 1%) in 18% (66/370) EGFR positive pts and was positive in 35% (180/513) EGFR negative pts (fisher exact test p value = 1.6e-5). For antibody 22C3, PD-L1 IHC was positive (TPS >= 1%) in 14% (9/64) EGFR positive pts and was positive in 45% (42/94) EGFR negative pts (fisher exact test p value = 3.8e-3). And we observed a significantly lower PD-L1 TPS in EGFR positive pts for both antibodies (t-test p value = 3.5e-11 for PD-L1 antibody 28-8; t-test p value = 6.0e-5 for PD-L1 antibody 22C3).

      Conclusion
      The observation demonstrated that lower PD-L1 TPS in Chinese Lung Adenocarcinoma pts was significantly correlated with East-Asian-specific high prevalence of EGFR mutations. The observation reassured that EGFR mutation status should be examined simultaneously with PD-L1 IHC in lung adenocarcinoma pts because it was a confounding factor for predicting immunotherapy outcome using PD-L1 TPS. The observation partly explained the generally higher PD-L1 TPS in Chinese lung squamous carcinoma pts compared with that in Chinese lung adenocarcinoma pts.

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      JCSE01.15 - Liver Metastases Predicts Poorer Prognosis in Advanced NSCLC Patients Who Receiving Nivolumab Monotherapy (ID 3429)

      07:00 - 11:15  |  Presenting Author(s): Guowei Zhang  |  Author(s): Ruirui Cheng, Huijuan Wang, Zhiyong Ma

      • Abstract
      • Slides

      Abstract
      Background
      Nivolumab is a fully human IgG4 monoclonal antibody targeting the programmed death-1 (PD-1). It's a standard second-line treatment for advanced NSCLC. Liver metastases(LM) is one of the worst prognostic NSCLC metastatic sites, but the attention to LM is far lower than brain metastases and bone metastases.

      Methods
      Patients with stage IIIB-IV NSCLC treated with second-line or later nivolumab monotherapy were retrospectively collected from January 2016 to July 2018. The patients were divided into two cohorts based on the presence or absence of LM at the time of first dose. Study endpoints included OS and PFS.

      Results
      65 patients were included, including 10 patients with and 55 patients without LM. Baseline characteristics of the two cohorts were comparable, as shown in the below table.

      The median OS of the patients with and without LM was 7.5 and 20.7 months, respectively(HR =4.81;95%CI, 1.28-18.00;p=0.020). Their median PFS was 1.9 and 5.6 months, respectively(HR =4.47;95%CI, 1.61-12.35;p=0.004). COX multivariate regression analysis suggested LM was an independent prognostic factor. Kaplan-Meier curves of OS and PFS were shown in the below figure.



      Conclusion
      The outcome of advanced NSCLC patients with LM treated with Nivolumab monotherapy is relatively poor compared with those without LM.

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      JCSE01.16 - Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC (ID 3430)

      07:00 - 11:15  |  Presenting Author(s): Chao Zhang  |  Author(s): Si-yang Liu, Jian Su, Xuan Gao, Lian-peng Chang, Yan-Fang Guan, Hai-yan Tu, Jin-Ji Yang, Xu-Chao Zhang, Wen-Zhao Zhong

      • Abstract
      • Slides

      Abstract
      Background
      Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC).

      Methods
      We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs).

      Results
      290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs.



      Conclusion
      Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.

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      JCSE01.17 - Modelling the Immunosuppressive Difference of SBRT and CRT by Simulating the Dose to Circulating Lymphocytes in Non-Small Cell Lung Cancer (ID 3431)

      07:00 - 11:15  |  Presenting Author(s): Haihua Yang  |  Author(s): Yichao Shen, Yinnan Meng, Xingni Tang, Pinjun Gu, Changhui Yu, Wei Wang, Feng-Ming Spring Kong

      • Abstract
      • Slides

      Abstract
      Background
      Radiation-dose delivered to circulating lymphocyte (CL) has detrimental effect on immune system for cancer patients. Our study established a model to compare the cumulative dose on CL of patients with conventional fractionation radiotherapy (CRT) and stereotactic body radiation therapy (SBRT) in lung cancer with different target volume.

      Methods
      The improved model is based on convolution algorithm suggested by Yovino(Cancer Investigation, 2013). The current blood DVHs of each organ were multiplied with treatment field DVH to generate original DVHs. During one second, 0.6% of whole-body blood circulates through each organ and rest body according to blood circulating pattern and then new DVHs of organ were generated. The new DVHs would be used for next second’s calculation with treatment field DVH. Conventional fractionated non-small cell lung cancer plan 60Gy (30 fractions*2.0Gy) and SBRT plan 50Gy (5fractions*10Gy) are constructed for three patients with different target volumes. The primary endpoint is peak cumulative blood dose (PCBC).

      Results
      PCBC of three patients with CRT and SBRT were calculated as Figure 1. PCBC with CRT to circulating lymphocyte (CL) were 2.5Gy, 5.6Gy, 9.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. And PCBC with SBRT to circulating lymphocyte (CL) were 2.1Gy, 2.9Gy, 6.0Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively. PCBC gap of SBRT to circulating lymphocyte (CL) was decreased 0.4Gy, 2.7Gy, 3.5Gy in PTV-volume 17cm3, 33cm3, 120cm3, respectively.



      Conclusion
      An improved simulation-model was established, SBRT, compared to CRT, will lead to decreased cumulative dose on CL, which may cause less impact on immune system with the enlargement of PTV-volume.

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      JCSE01.18 - A CT-Based Radiomics Approach to Predict PD1 Inhibitor Response in Non-Small-Cell Lung Cancer (ID 3432)

      07:00 - 11:15  |  Presenting Author(s): Jialei Wang  |  Author(s): Shengping Wang, Hui Yu, Chang Liu, Xinmin Zhao, Si Sun, Jianhua Chang, Jie Qiao, Xianghua Wu

      • Abstract
      • Slides

      Abstract
      Background
      The purpose of this study was to investigate the use of radiomics features as predictive parameters of clinical outcomes of non-small-cell lung cancer (NSCLC) patients treated with PD1 inhibitor.

      Methods
      Forty-three stage IIIB/IV NSCLC patients without EGFR mutation or ALK rearrangement who received nivolumab were enrolled between Apr 2016 and Jan 2019. High-dimensional quantitative feature analysis via Pyradiomics was applied to extract 852 radiomics features of pre-anti-PD1 treatment CT. A radiomic score model was constructed from these features with the use of least absolute shrinkage and selection operator (LASSO) Cox regression. The radiomic score for each patient was computed using an equation in which the coefficients were derived from the LASSO Cox model to subgroup patients by progression-free survival (PFS). The median value of radiomic score was used as the cut-off value to cluster patients into high or low score groups.

      Results
      We developed a radiomic signature for PFS that included seven variables. The median value of radiomic score was 0.23. The objective response rate (ORR) was 16.3% (7/43), the median PFS was 2 months and median overall survival (OS) was 3.2 months of all 43 patients. A low radiomic score was associated with a higher ORR (33.7% vs 0%, p= 0.0036), improved PFS (median: 3 months vs 2 months; HR 0.14, 95% CI   0.053-0.39, P < 0.0001) and longer OS (median: 11.2 months vs 7.0 months; HR 0.12, 95%CI 0.04-0.31, p < 0.0001). Multivariate analysis also showed that a low radiomic score was related to better PFS (HR 0.12, 95% CI   0.041-0.32, P < 0.0001) and OS (HR 0.11, 95%CI 0.03-0.28, p < 0.0001).



      Conclusion
      The radiomic signature as an imaging predictor provided a promising way to predict clinical outcomes for NSCLC patients treated with PD-1 inhibitor.

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      JCSE01.19 - Tumor Mutation Score Is More Powerful Than Tumor Mutation Burden in Predicting Response to Immunotherapy in Non-Small Cell Lung Cancer (ID 3433)

      07:00 - 11:15  |  Presenting Author(s): Yuan Li  |  Author(s): Zuhua Chen, Long Wu, Weiping Tao

      • Abstract

      Abstract
      Background
      Tumor mutation burden (TMB) and PD-L1 expression are the two important biomarkers for immune checkpoint inhibitors (ICIs) in lung cancer. However, growing evidences are showing that not all mutations, such as EGFR mutation, are favorable factors in predicting clinical outcome of ICIs and the power of TMB, which is unselective, might be attenuated. Therefore, we developed tumor mutation score (TMS) as better biomarker for response of ICIs in non-small cell lung cancer (NSCLC).

      Methods
      TMS was defined as the number of genes with nonsynonymous somatic mutations. Mutations were detected by targeted next-generation sequencing (NGS) in 240 NSCLC patients treated with anti-PD-(L)1 monotherapy or in combination with anti-CTLA4. Durable clinical benefit (DCB) was defined as complete response (CR)/partial response (PR)/stable disease (SD) that lasted 6 months. TMS, TMB and PD-L1 expression were compared among DCB and no durable benefit (NDB) NSCLC patients.

      Results
      The total TMS was significantly correlated with TMB (R=0.98, P<0.001) and performed almost equally to TMB in the analysis. 12 genes and 11 genes (5 sharing genes) were significantly associated with longer progression-free survival (PFS) and response (DCB vs NDB), respectively. The number of mutated genes within these 18 genes were defined as TMS18. In the survival analysis of PFS, the HRs of the high group were TMS19 (HR=0.307, P<0.001), TMB (HR=0.455, P<0.001), and PD-L1 expression (HR= 0.403, P=0.02), separately. Moreover, patients with DCB had significantly higher TMS18 (P<0.001), TMB (P=0.006), and PD-L1 expression (P=0.032). High TMS18 group had highest proportion of CR/PR/SD patients, which was 74.1% (CR/PR/SD: 3/17/20), especially in distinguishing CR patients. Taken together, TMS18 was more powerful than TMB and PD-L1 in predicting response of ICIs in NSCLC.

      Conclusion
      Simple transformation from unselective TMB to selective TMS greatly enhanced the power of mutations-based biomarkers. TMS in combination with PD-L1 expression might yield better efficiency in predicting response of ICIs in NSCLC with future validation in larger cohorts.

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      JCSE01.20 - Pilot Study on the Tumor Immune Microenvironment Between Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancer (SCLC) (ID 3434)

      07:00 - 11:15  |  Presenting Author(s): Qian Chu  |  Author(s): Wei Zhang, Xun Yuan, Xue Wang, Shanshan Huang, Jingyao Tu, Fangfang Liu, Jin Li, Jing Li, Yuan Chen

      • Abstract

      Abstract
      Background
      Tumor immune microenvironment plays an important role in immunotherapy and prognosis. However, the differences and the clinical significance between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) is still largely unknown.

      Methods
      Resected lung cancer FFPE specimens and matched peripheral blood mononuclear cells (PBMC) from six patients with NSCLC (three adenocarcinoma, three squamous cell carcinoma) and three patients with SCLC were collected. All of the nine patients underwent stage III disease. Tumor mutation burden (TMB) was evaluated by hybridization capture based next-generation sequencing with 1021 cancer associated genes. Tumor infiltrating lymphocytes (TILs) were assessed by immunohistochemistry using multiple immune markers and meanwhile the intratumoral T-cell repertoires were analyzed via high-throughput sequencing of TCR β-chain.

      Results
      Typical EGFR mutations in adenocarcinoma (2 in 3), NSCLC and RB1 mutations in SCLC (3 in 3) were observed. SCLC patients showed significantly higher TMB than NSCLC. Regarding to the tumor immune microenviroment, SCLC tumors exhibited lower infiltration of CD3+ and CD8+ TILs (P< 0.05). Furthermore, we found that SCLC patients tended to have lower TCR Shannon index (P= 0.167) and higher Clonality index (P= 0.095). Interestingly, patients with higher Shannon index exhibited better Overall Survival (OS) while Clonality was potentially associated with decreased OS. However, further study with more patients is needed to confirm the results.

      Conclusion
      Tumor immune microenvironment varies between NSCLC and SCLC patients. Specifically, less prevalent and lower diversity of TILs were observed in SCLCs. This might potentially influence survival outcomes.

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      JCSE01.21 - Changes of Peripheral Blood sPD-L1 in Patients with Small Cell Lung Cancer During Chemotherapy and Its Clinical Significance (ID 3435)

      07:00 - 11:15  |  Presenting Author(s): Hao Tian  |  Author(s): Xiaoyan Kang, Lin Yang, Haibo Zhu, Wei Guo, Xia Song

      • Abstract

      Abstract
      Background
      As a new immunotherapeutic target, the inhibitors of programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1) pathway have been used to treat a variety of tumors including small cell lung cancer (SCLC). However, the biomarkers now used to predict the efficacy of SCLC immunological checkpoint inhibitors are still in the exploratory phase. The aim of this prospective study was to investigate the prevalence and prognostic roles of soluble PD-L1(sPD-L1 ) protein in the blood of patients with lung cancer.

      Methods
      A total of 94 patients with SCLC who were diagnosed by histopathology or cytopathology between March 2018 to November 2018 were enrolled. Blood samples plasma were collected at the time of diagnosis. 17 samples of healthy subjects matching in sex and age from the Health care Center of the hospital were also studied as control. The level of sPD-L1 protein in the blood was measured using an enzyme-linked immunosorbent assay (ELISA). And the correlation of sPD-L1 expression with tumor stage, distant metastasis, and pro gastrin releasing peptide (ProGRP) was analyzed.

      Results
      Expression of sPD-L1 in SCLC patients was significantly higher than healthy people(P<0.05).A cut-off value of 1.362ng/ml was distinguished in patients according to Receiver operating characteristic curve (ROC). Dynamic changes of sPD-L1 are associated with progressive disease(PD)a, partial response(PR)a and stable disease(SD)b in SCLC patients(a P<0.01,b P>0.05).The expression of sPD-L1 in serum was positively correlated with ProGRP.



      Conclusion
      Our results indicated that changes of plasma SPD-L1 levels in SCLC patients are associated with prognosis. Plasma sPD-L1 protein is a great biomarker in SCLC and may play an important role in sifting the beneficiaries of immunotherapy.

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      JCSE01.22 - Tumor Microenvironment Is Associated with Efficacy of PD-1/PD-L1 Inhibitors in Patients with Primary Pulmonary Lymphoepithelioma-Like Cancer (ID 3436)

      07:00 - 11:15  |  Presenting Author(s): Xu-Chao Zhang  |  Author(s): Kai Yin, Zhi Xie, Zhi Yi Lv, Jin-Ji Yang, Xue-Ning Yang, Qing Zhou, Wen-Zhao Zhong, Lin-Lin Li, Hui-Bo Feng, Wei-Bang Guo, Dan-Xia Lu, Yu Chen, Wen-Qing Yan, Yi-Long Wu

      • Abstract
      • Slides

      Abstract
      Background
      Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.Primary pulmonary lymphoepithelioma-like carcinoma (LELC) is Epstein-Barr (EB) virus related subtype of non-small-cell lung cancer. Evidence of immunotherapy in LELC is scarce. The role of immune markers in tumor microenvironment and their relation with the efficacy of PD-1/PD-L1 inhibitors in LELC remain poorly explored.

      Methods
      A total of seventeen patients treated with PD-1/PD-L1 inhibitors in Guangdong Lung Cancer Institute were enrolled. We detected multiple immune markers including PD-L1, IDO1, TIM3, LAG3, CD4 and CD8 by immunohistochemistry in eleven of these patients. Dynamic changes of the checkpoint biomarkers in two patients (#10 and #11) treated with PD-1 inhibitors were analyzed. Tumors with 1% TPS (tumor proportion staining) were defined as PD-L1 positive. H-score of PD-L1, IDO1, TIM3 and LAG3 was calculated by multiplying percentage of positively stained cells and intensity score (0, absent; 1, weak; 2, moderate; 3, strong). For CD4 and CD8, the H-score equals the percentage of staining positive lymphocytes among all nucleated cells.

      Results
      In the 17 patients, most of them suffered from lines of chemotherapy (only two patients (2/17, 11.8%) received PD-1/PD-L1 inhibitors as the first line therapy). There are eight males and nine females. The median age was 47 years (range from 13 to 63). All of them were stage IIIB and IV. Thirteen of seventeen patients received single agent PD-1/PD-L1 inhibitor. PD-1/PD-L1 inhibitor showed an 82.4% disease control rate and 17.6% objective response rate. The median progression free survival was 7.4 months. The overall survival was not reached. Biomarkers of IDO1, LAG3, and TIM3 were not mutually exclusive with PD-L1, and could be highly expressed in responder patients to PD1/PD-L1 inhibitors. Notably, TIM3 expression was up-regulated at disease progression in two patients treated with PD-1 inhibitor.



      Conclusion
      PD-1/PD-L1 inhibitors had preliminary good activity, and TIM3 up-regulation might be a mechanism of resistance to PD-1 inhibitors in advanced pulmonary LELC.

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      JCSE01.23 - Specific TP53 Mutation Subtypes as Biomarker for Response to PD-1/L1 Blockade Immunotherapy in NSCLC (ID 3437)

      07:00 - 11:15  |  Presenting Author(s): Hao Sun  |  Author(s): Si-yang Liu, Jia Ying Zhou, Meimei Zheng, Jiao Jiao Huan, Yan Fang Guan, Rui Gao, Xin Yi, Yi-Long Wu

      • Abstract
      • Slides

      Abstract
      Background
      Although TP53 co-mutation with KRAS have been proved to have predictive value for response to PD-1/L1 blockades, not all TP53 mutations are equal in this context. TP53 subtypes as independent factors to predict the response to PD-1/L1 blockade have not yet reported.

      Methods
      We performed an integrated analysis on the multiple-dimensional data types including genomic and clinical data from cohorts of NSCLC public (240 from MSK database) and local databases (224 patient with PD-L1 IHC score, 1986 NSCLC with TMB data). Durable clinical benefit (DCB) was defined as partial response/stable disease that lasted more than 6 months.

      Results
      The presence of mutant TP53 was associated with longer median progression free survival (mPFS) in NSCLC taking PD-1/L1 blockade therapy compared with TP53 wild-type group in the MSK-cohort (4.3 vs2.6 months, P=0.0027, HR=0.6409, 95%CI, 0.49 to 0.88). TP53 frameshift seemed to predict longer mPFS (6.6 months, P=0.0159, HR= 0.41, 95%CI, 0.26 to 0.65) than TP53 wild-type, TP53 missense (mPFS=4.27 months, P=0.17) and TP53 nonsense status (mPFS=2.7 months, P=0.002).NSCLC with TP53 frameshift mutation had a 52.9% rate of DCB, which was higher than TP53 missense (34.4%) and nonsense (21.1%) group. Besides, in the MSK cohort, five of six patients with TP53 truncated mutation in proline-rich (PR) domain (residues 58--101) achieved DCB, and one patient achieved 5.5 months of PFS and did not progress. Fractions of PD-L1 low-positive (1% - 49%) and PD-L1 high-positive (≥50%) tumors between each TP53 mutation subtype and wild-type groups are analyzed based on local data. The TP53 mutation rate was significantly higher in NSCLC with PD-L1 score >50% (P=0.004). But NSCLC with TP53 frameshift showed lower fractions of PD-L1 high-positive (12.5%, 2/16) compared with TP53 missense group (27.5%, 33/120) and TP53 nonsense group (25.8%, 8/31). PD-L1 low-positive rate is also lower in TP53 frameshift group (25.0%, 4/16) than TP53 missense (30.8%, 37/120) and nonsense group (29.0%, 9/31). Among 1986 NSCLC patients with TMB data, each TP53 mutation subtype is associated with significantly higher TMB than TP53 wildtype, especially among NSCLC with TP53 truncated mutation in PR domain (median TMB= 9 mut/Mbs). But no significant difference was found between TP53 mutation subtypes in TMB.



      Conclusion
      ​​​​​​Our study demonstrated heterogeneity among TP53 mutations in predicting the response to PD-1/L1 blockade therapy. TP53 frameshift mutation may contribute to better PD-1/L1 blockade therapy response beyond PD-1/L1 IHC status. And the truncated TP53 mutation in PR domain may contribute to DCB.

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      JCSE01.24 - Dynamic Changes of Plasma PD-L1 mRNA Expression Predict Response to Anti-PD-1/Anti-PD-L1 Treatment in Malignancies (ID 3438)

      07:00 - 11:15  |  Presenting Author(s): Jianguo Sun  |  Author(s): Qiao Yang, Mingjing Chen, Jiaoyang Gu, Linpeng Zheng, Yongxin Yu, Feng Li, Luping Zhang, Kai Niu

      • Abstract
      • Slides

      Abstract
      Background
      PD-L1 expression in malignant tumor tissues is a rational biomarker to predict the efficacy and prognosis of anti-PD-1/anti-PD-L1 treatment, but few studies focus on the role of blood PD-L1 expression.

      Methods
      Fifty-one paired tissue samples and blood samples, as well as clinicopathologic features, were collected from patients with diverse malignancies to investigate the correlation among tissue PD-L1 (tPD-L1) expression, plasma PD-L1 mRNA expression, soluble PD-L1 (sPD-L1) expression and clinicopathologic features. Tissue PD-L1 were measured by immunohistochemistry. PD-L1 mRNA and self-designed plasma inner reference PLACON were measured by quantitative real-time PCR. Soluble PD-L1 were detected by ELISA kit. Then, dynamic changes of blood PD-L1 expression (at baseline and within 2 months) were measured to evaluate the efficacy of patients with malignancies (n=24) who received anti-PD-1/anti-PD-L1 treatment.

      Results
      Moderate correlation between tPD-L1 and PD-L1 mRNA (r=0.62, P<0.001), weak correlation between tPD-L1 and sPD-L1 (r=0.37, P=0.007) and weak correlation between PD-L1 mRNA and sPD-L1 (r=0.32, P=0.02) were found. Most clinicopathologic features had no significant correlation with PD-L1 mRNA and sPD-L1 expression. Interestingly, patients without metastasis had higher PD-L1 mRNA and sPD-L1 expression than counterparts. Further, patients with over 2.03-fold PD-L1 mRNA increase (n=11) during treatment experienced improved progression-free survival (PFS) than those with less than 2.03-fold increase (n=13), these patients also had higher best overall response (bOR) rate (45.45% vs. 7.69%). By comparison, the dynamic changes of sPD-L1 expression had no significant correlation with PFS and bOR.



      Conclusion
      Our study demonstrates that plasma PD-L1 mRNA expression was significantly correlated with tissue PD-L1 expression, and provides proof for the application of plasma PD-L1 mRNA as a predictor for anti-PD-1/anti-PD-L1 treatment.

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      JCSE01.25 - TP53/KMT2C Co-Mutation as a Novel Biomarker for Immunotherapy in Non-Small Cell Lung Cancer Patients (ID 3862)

      07:00 - 11:15  |  Presenting Author(s): Qing Zhou  |  Author(s): Xiaoxiao Peng, Wenjing Wang, Weifeng Wang, Lin Zhang, Kai Wang, Shiyue Zhang

      • Abstract
      • Slides

      Abstract
      Background
      Immune checkpoint inhibitors (ICIs) have shown remarkable antitumor effects in non-small cell lung cancer (NSCLC), however only a subset of patients respond. Genomic alterations (GAs) detected by targeted next-generation sequencing (NGS) is increasingly used in clinical practice, but its correlation with recognized immune biomarkers and predictive value for ICIs response in NSCLC is unclear.

      Methods
      FFPE tumor and matched blood samples of 637 NSCLC patients (84 squamous cell and 553 non-squamous cell) were collected for targeted NGS panel sequencing from December 2017 to January 2019. GAs including single nucleotide variations, short and long insertions/deletions, copy number variations and gene rearrangements were assessed. TMB high (TMB-H) was defined as ≥10 muts/Mb. Positive PD-L1 expression was defined as ≥1% of tumor cells with membranous staining (22C3/28-8, DAKO). Genomic data and ICIs treatment outcome from a 240 NSCLC patient cohort was derived from cBioPortal (MSKCC, J Clin Oncol 2018).

      Results
      In 637 NSCLC patients, the prevalence of PD-L1≥1% was 26.5% and the median TMB was 4.6 muts/Mb (IQR, 2.3-10). Recurrent TP53, KRAS, LRP1B and KEAP1 mutations were significantly correlated with higher TMB (p value). TP53, KRAS and KEAP1 mutations were significantly enriched in the TMB-H/PD-L1+ subset while STK11 mutations were enriched in TMB-H/PD-L1- subset (p value). KMT2C, also known as MLL3, belongs to the mixed‐lineage leukemia (MLL) family of histone methyltransferases and its GAs was found in 5% of our cohort. Tumors with KMT2C and TP53 co-mutations (co-MUT) had a significantly higher TMB (15.1 muts/Mb) than TP53/KMT2C single-MUT (8.7 muts/Mb) and TP53/KMT2C co-WT (3.1 muts/Mb) tumors. Moreover, TMB-H/PD-L1+ subset was enriched in KMT2C and TP53 co-MUT (25%) comparing to TP53/KMT2C single-MUT (14.7%) and TP53/KMT2C co-WT (3.3%) tumors. Survival analysis from public clinical trials confirmed that patients with TP53/KMT2C co-MUT had remarkable clinical benefit to ICIs in both progression free survival (PFS) and durable clinical benefit (DCB). The median PFS was 7.3, 4.2 and 2.5 months for TP53/KMT2C co-MUT, TP53/KMT2C single-MUT and TP53/KMT2C co-WT patients, respectively (p=0.0032). TP53/KMT2C co-MUT was an independent variable of PFS (TP53/KMT2C co-MUT vs. TP53/KMT2C co-WT, HR: 0.47, 95%CI: 0.25-0.89, p=0.0199). Furthermore, TP53 with KMT2C or KRAS co-MUT expanded the patient population benefiting from ICIs (mPFS = 7.2 months, p=0.00042; DCB = 51.2%, p= 0.0195).

      Conclusion
      This study provides evidence that TP53/KMT2C co-MUT may serve as a predictive biomarker for ICIs in NSCLC. GAs detected by targeted NGS could illuminate insight for immunotherapy.

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      JCSE01.26 - PD-1 Inhibitor Plus Chemotherapy as 2nd/Subsequent Line Setting Demonstrate Superior Efficacy over PD-1 Inhibitor Alone in Pts of Advanced NSCLC (ID 3863)

      07:00 - 11:15  |  Presenting Author(s): Shengxiang Ren  |  Author(s): Yiwei Liu, Fei Zhou, Tao Jiang, Chunxia Su, Xiaoxia Chen, Caicun Zhou

      • Abstract
      • Slides

      Abstract
      Background
      PD-1/PD-L1 inhibitors have become standard of care as the 2nd-line setting and also approved as 1st line setting when combined with doublet chemotherapy in patients with advanced NSCLC. This study aims to compare the efficacy of PD-1 inhibitor plus chemotherapy with PD-1 inhibitor alone as 2nd/subsequent lines setting in patients with advanced NSCLC

      Methods
      Patients who received PD-1 inhibitor monotherapy or PD-1 inhibitor plus chemotherapy as 2nd/subsequent lines setting in Shanghai Pulmonary Hospital, Tongji University were retrospectively collected. Detailed clinicopathologic characteristics and therapeutic outcomes were analysis.

      Results
      From January 2016 to February 2019, 148 patients who meet the criteria were included. Among them, 116 were in PD-1 inhibitor monotherapy group and 32 were in PD-1 inhibitor plus chemotherapy group. Chemotherapy regimens were pemetrexed(n=9), docetaxel(n=2), nab-paclitaxel(n=18) and gemcitabine(n=3). The baseline characteristics such as age, gender, smoking status, histology, PD-1 mono-antibodies, line of therapy were similar in the 2 groups. Combination group showed a favorable ORR (28.1% vs. 13.8%, p=0.055) and a significantly longer PFS(median 4.9 vs 2.5 months, p=0.005) compared with ICI monotherapy. Overall survial (OS) data was immature in the cutoff date of follow up. In the subgroup of 96 patients (monotherapy group n=69/ Combination group n=27) who were included as 2nd line setting, PD-1 inhibitor plus chemotherapy had significantly higher ORR(ORR:33.3% vs 18.8%, p=0.129) and longer PFS(median PFS: 4.9 vs 2.9 months, p=0.041).



      Conclusion
      PD-1 inhibitor plus chemotherapy as 2nd/subsequent lines setting demonstrated superior efficacy over PD-1 inhibitor alone in patients with advanced NSCLC.

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      JCSE01.28 - Changes of Brain Structure in Advanced NSCLC Patients Receiving EGFR-TKIs: Dynamic Analysis Based on Series MRI Images (ID 3865)

      07:00 - 11:15  |  Presenting Author(s): Chunli Luo  |  Author(s): Beisheng Yang, Xiaojuan Zhou, Lin Zhou, Ying Zhou, Jiang Zhu, Meijuan Huang, Feng Peng, Yongmei Liu, Yongsheng Wang, Zhiping Li, You Lu, Su Lui, Youling Gong

      • Abstract
      • Slides

      Abstract
      Background
      EGFR-TKI was the standard care for metastatic NSCLC patients harboring positive EGFR mutation, which might inhibit EGF signaling pathway and consequently have effect on differentiation, maturation and rehabilitation of neural cells. For the first time, we evaluated the dynamic changes of white matter lesion (WML) and gray matter volume (GMV) among such patients based on series of MRI images.

      Methods
      We retrospectively identified 778 patients with pathologically diagnosed advanced NSCLC receiving first-generation EGFR-TKIs in our hospital from 2010 to 2017, and 75 patients without brain metastasis and else comorbidity (hypertension, etc.) were analyzed. The modified Scheltens visual scale were performed to evaluate the changes of WML based on the series (baseline, 12 months' point and 24 months' point) of MRI images, and CBM (cluster-based morphometry) method based on SPM12 were adopted to identify GMV loss. The statistical methods were performed using SPSS software 22.0.

      Results
      During the 24-month EGFR-TKI treatment, the patient's WML visual scores showed a progressive worsen. Comparing to the baseline (6.680±3.636), the scores were significantly changed at the 12 months' point (8.650±3.857; Mean scores increasing 1.973, 95% CI 1.595-2.352, p<0.001) and changed more obviously at the 24 months' point (10.110±3.854; Mean scores increasing 3.427, 95% CI 2.979-3.874, p<0.001), respectively. Also, the significant GMV loss were found in subregions of the right occipital lobe (mean decrease 76.714, 95% CI 40.739-112.690), left occipital lobe (mean decrease 93.476, 95% CI 37.483-149.469) and left basal ganglia (mean decrease 37.571, 95% CI 21.576-53.567), respectively (all p<0.005, the cluster level FDR<0.05).

      Conclusion
      Dynamic structural analysis of series brain MRI images showed the significant worsen of the WML and GMV loss in patients with advanced NSCLC receiving EGFR-TKIs chronically. Perspective studies are warranted to verify its impact on the cognitive deficiency and hypomnesis among these patients in future.

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    MS06 - An Interdisciplinary Approach to Optimal Nodal Staging (ID 69)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Staging
    • Presentations: 6
    • Now Available
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      MS06.01 - Radiologic Staging (Now Available) (ID 3467)

      11:00 - 12:30  |  Presenting Author(s): Jin Mo Goo

      • Abstract
      • Presentation
      • Slides

      Abstract

      Current definitions of borders for lymph node stations based on a few anatomic landmarks have limitations to explain the three-dimensional location of lymph nodes. Variability in the classification of lymph node stations (especially N1 vs N2 and N2 vs N3 categories) inevitably results in different management and also has an impact on database for the future revision of staging. Several articles have dealt with the ambiguity of the IASLC map and proposed recommendations. The Japan Lung Cancer Society and the Japanese Society for Radiation Oncology map provided more detailed description about the borders of lymph node stations (1).

      N2 vs N3

      1. Station 1 and 2

      - Proposal: Changing the lower border of #1 station (upper border of #2 station) to the thoracic inlet: upper border of the 1st ribs (anterior border of the 1st ribs on axial CT) (2) and manubrium

      2. Station 3a

      - Potential problem: Absence of sideness

      - Proposal: Split 3a to 3aR and 3aL with a left lateral border of the SVC (3) OR No change (like subcarinal lymph node)

      3. Station 3p

      Current border

      - Potential problem: Absence of sideness

      - Proposal: Right-sided lymph node OR No change (like subcarinal lymph node)

      4. Precarianl area (below the lower border of the azygos vein in the right side and upper rim of the left main pulmonary artery in the left side)

      - Current border: Lymph nodes located in the precarinal area is currently #10, hilar lymph nodes, but there is no description for the border between the right and left.

      - Proposal: Midline of the trachea

      N1 vs N2

      In the current IASLC lymph node map, the pleural reflection no longer serves as the border between nodal stations. However, still many physicians regard N2 lymph nodes as mediastinal lymph nodes, and a survey also support this trend (3). Therefore, if the IASLC abandons the notion that N2 lymph nodes are mediastinal lymph nodes, the current map needs only a minor modification. Instead, a clear announcement should be provided to avoid confusion from other researchers (2). If the IASLC regards N2 lymph nodes as mediastinal lymph nodes, major modifications are required.

      5. Station 4 and 10

      - Problematic area: Anterior aspect of the lower trachea and carina below the lower border of #4 lymph nodes are located in the mediastinum.

      6. Station 5 and 10

      - Problem: Pulmonary arteries are curved structures craniocaudally, and different interpretation of this border results in differeces among altases. The intersection of the left superior pumonary vein branch and left main pulmonary artery may serve as a clear border. If # 10 lymph nodes are classified as non-mediastinal lymph nodes, the border definition should also be modified.

      References

      1. Itazawa T, Tamaki Y, Komiyama T, et al. The Japan Lung Cancer Society-Japanese Society for Radiation Oncology consensus-based computed tomographic atlas for defining regional lymph node stations in radiotherapy for lung cancer. J Radiat Res 2017; 58:86-105.

      2. El-Sherief AH, Lau CT, Wu CC, Drake RL, Abbott GF, Rice TW. International association for the study of lung cancer (IASLC) lymph node map: radiologic review with CT illustration. Radiographics 2014; 34:1680-1691.

      3. El-Sherief AH, Lau CT, Obuchowski NA, Mehta AC, Rice TW, Blackstone EH. Cross-Disciplinary Analysis of Lymph Node Classification in Lung Cancer on CT Scanning. Chest 2017; 151:776-785.

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      MS06.02 - Endoscopic Nodal Staging (Now Available) (ID 3468)

      11:00 - 12:30  |  Presenting Author(s): Jose Sanz Santos

      • Abstract
      • Presentation
      • Slides

      Abstract

      1. INTRODUCTION.

      Endoscopic ultrasound (EUS) and endobronchial ultrasound (EBUS) were first described in the early 1980’s and 1990’s respectively. However, their incorporation into clinical practice began some years later, after the development of echoendoscopes and echobronchoscopes.

      2. PROCEDURE.

      EBUS-TBNA allows the sampling of retrotracheal (3P), upper paratracheal (2L,2R), lower paratracheal (4L/4R) and subcarinal (7) nodal stations. Moreover, EBUS-TBNA can access hilar (10L/10R) and interlobar nodal stations (11L/11R). EUS-FNA can access stations 2 and 4, subaortic (5), 7, paraesophageal (8L/8R) and pulmonary ligament (9L/9R).

      EBUS-TBNA/EUS-FNA is usually performed under conscious sedation or general anaesthesia in an outpatient setting. The reported complications rate for EBUS and EUS is < 1%.

      The current international guidelines for preoperative mediastinal staging of lung cancer1 recommends, for an endoscopy-based mediastinal staging procedure, as a minimum requirement, sampling the largest LN in 4R, 4L and 7 stations, as well as positron emission tomography (PET) positive LNs within each of these stations. Thus, 3 nodes is the minimum sampling requirement for an endoscopy-based staging procedure.

      3. MEDIASTINAL STAGING OF LUNG CANCER THROUGH ENDOSONOGRAPHY.

      3.1 EUS-FNA

      Overall, the reported pooled sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of EUS-FNA for lung cancer staging is 0.83, 0.97, 0.78 and 0.98 respectively2.

      3.2 EBUS-TBNA

      Two meta-analysis focussed on EBUS-TBNA in lung cancer staging were published ten years ago3,4. Most of the studies included patients with abnormal mediastinum on CT and/or PET/CT and thereby a high prevalence of disease. The reported pooled sensitivity was 0.9 and 0.93, respectively, ranging from 0.69 to 0.99.

      More recently, two meta-analysis5,6 have analysed the usefulness of EBUS-TBNA in lung cancer staging in patients with radiologically normal mediastinum. Both have shown similar pooled results for sensitivity (0.49, 0.495) and NPV (0.99, 0.93) with a similar median prevalence of N2/N3 disease (15.2%, 12.8%).

      3.3 Combined EUS/EBUS

      EBUS and EUS are complementary techniques that can access to different nodal stations. Thus, combination of both techniques may result in an increase of the sensitivity. A meta-analysis that included 2395 patients7 reported a mean sensitivity of the combined approach of 0.86 with a mean NPV of 0.92. Depending on the order of both techniques, the addition of EUS(B) to EBUS increased sensitivity by 0.12, and addition of EBUS to EUS(B) increased sensitivity by 0.22. However, no differences in sensitivity and NPV were shown between studies that performed EBUS first and studies that performed EUS first.

      3.4 Combined EUS-B/EBUS

      Combining EBUS with EUS has several limitations: usually needs to be performed by two different operators (pulmonologist/thoracic surgeon or gastroenterologist), in different settings, increasing the cost and waiting time of the procedure. These problems can be solved using a single scope (EBUS), in the same setting, by the same operator, by introducing the EBUS scope into the esophagus (EUS(B)). Several studies have demonstrated that EUS(B) combined with EBUS-TBNA results in an increase of the sensitivity compared with EBUS-TBNA alone8.

      4. THE N1 ELEMENT

      On the last years, several lung-sparing treatments for lung cancer have been developed. To select candidates for these techniques, accurate staging not only of the mediastinal nodes but also of the hilar nodes is crucial. One of the advantages of EBUS-TBNA is the ability to access N1 nodes.

      A study conducted by Yasufuku et al.9 that included patients with clinically N0/N1 disease eligible for surgical resection demonstrated that EBUS-TBNA can accurately access the hilar and interlobar LNs with a reported sensitivity, specificity, diagnostic accuracy and NPV of 0.76, 1, 0.96, and 0.96 respectively.

      5. HOT TOPICS

      Currently there are two questions that have to be answered:

      5.1 Must the combination EBUS/EUS (B) be performed routinely? In which order?

      As mentioned before7, EUS (B) needs to be added to EBUS in 25 patients and EBUS to EUS (B) in 14 patients to detect one additional patient with mediastinal nodal disease that would not have been detected if only one test had been performed.

      5.2 After an EBUS-TBNA procedure showing no mediastinal involvement, must patients undergo confirmatory mediastinoscopy?

      One recent meta-analysis10 studied the rate of unforeseen N2 disease in patients with lung cancer with or without mediastinoscopy after negative endosonography. In patients with EBUS and or EUS alone, the rate of unforeseen N2 was 9.3% for EBUS, and 13.4% for EUS. In patients with confirmatory mediastinoscopy the rate of unforeseen N2 disease after negative findings of EBUS (plus mediastinoscopy) was 11.2%, and after negative EUS (plus mediastinoscopy) was 14.9%.

      REFERENCES:

      1.De Leyn, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg. 2014 May;45(5):787-98.

      2.Micanes CG, et al. Endoscopic ultrasound-guided fine-needel aspiration for non-small cell lung cancer staging. A systematic review and metaanalysis. Chest 2007;131:539-548.

      3.Gu P, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur J Cancer. 2009 May;45(8):1389-9.

      4.Dong X, et al. Endobronchial ultrasound-guided transbronchial needle aspiration in the mediastinal staging of non-small cell lung cancer: a meta-analysis. Ann Thorac Surg 2013;96:1502-07.

      5.Leong TL, et al. Preoperative staging by EBUS in cN0/N1 lung cancer systematic review and meta-analysis. J Bronchol Intervent Pulmonol [Epub ahead of print]

      6.El-Osta H, et al. Endobronchial ultrasound for nodal staging of patients with non-small-cell lung cáncer with radiologically normal mediastinum a meta-analyisis. Ann Am Thorac Soc 2018;15:864-874.

      7.Korevaar DA, et al. Added value of combined endobronchial and oesophagueal endosonography for mediastinal nodal staging in lung cancer: a systematic review and meta-analysis. Lancet Respir Med 2016;4:960-68.

      8.Dhooria S, et al. Utility and safety of endoscopic ultrasound with bronchoscope-guided fine-needle aspiration in mediastinal lymph node sampling: systematic review and meta-analysis. Respir Care 2015;60(7):1040-1050.

      9.Yasufuku K, et al. Endobronchial ultrasound-guided transbronchial needle aspiration for differentiating N0 versus N1 lung cancer. Ann Thorac Surg 2013;96:1756-60.

      10.Bousema JE, et al. Unforeseen N2 disease after negative endosonography findings with or without confirmatory mediastinoscopy in resectable non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Oncol. 2019 Jun;14(6):979-992

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      MS06.03 - Pathologic Staging: Operative Events (Now Available) (ID 3469)

      11:00 - 12:30  |  Presenting Author(s): Thomas A. D'Amico

      • Abstract
      • Presentation
      • Slides

      Abstract

      Accurate pathologic nodal staging, a powerful prognostic factor after resection of lung cancer, requires thorough examination of the mediastinal lymph nodes. Accurate pathologic staging of lung cancer requires effective collaboration between the surgery and pathology teams. There is a quality gap in pathologic nodal staging from three sources: poor surgical lymph node examination practice (failure to collect nodes), problems in the pathologic transfer of specimens (loss in transit or improper communication of the source of specimens), and poor pathology examination practice (incomplete examination or inaccurate and inconsistent reporting).

      Adequacy of mediastinal lymph node dissection (MLND) during resection for lung is an important quality measure that is not universally met in the US. For most patients with lung cancer, mediastinal lymph node dissection or systematic sampling is recommended at the time of resection, but it is only infrequently performed. For example, 62% of pathologic N0 and N1 non-small cell lung cancer resections in the US SEER database have no mediastinal lymph nodes examined.

      There is also significant discordance between surgeon claims of the extent of mediastinal lymphadenectomy and verifiable lymph node examination from pathology reports. Review of pathology reports in one study suggested that only 8% of all resections meet systematic sampling criteria, 50% have random sampling, and 42% have no mediastinal lymph nodes examined. However, a blinded independent audit of the surgeons’ operation notes suggested that 29% of cases had described a mediastinal lymph node dissection procedure.

      Some surgeons utilize a strategy of using several pathologic variables to determine the need for MLND during resection for non-small cell lung cancer. The premise is that it is an important goal to “minimize surgical trauma”. However, most surgeons would agree that there is not significant trauma related to the dissection of clinically negative lymph nodes, and that the incremental trauma related to MLND is itself minimal.

      Other strategies to obviate MLND have been suggested. Sentinel lymph node identification has been proved unsuccessful for lung cancer; sentinel technologies do not reliably identify a single lymph node, and N2 disease may still be present even when the sentinel node is negative. In any case, that strategy was tested in an era when only N2 patients could receive adjuvant chemothererapy, and the strategy was based on finding micromestastic disease, not limiting surgical trauma. In an era where N1 disease and tumor size both direct adjuvant therapy, the effort to limit lymphadenectomy is even less useful and this practice should be scrutinized. Even in major cancer centers, the targets of ten lymph nodes and three N2 stations is not universally met.

      In summary, patients with cT2 or > N0 lung cancer should undergo pre-resectional staging with either endobronchial ultrasound or mediastinoscopy. At the time of anatomic resection, adequate management of mediastinal lymph nodes should also be performed, either complete mediastinal lymph node dissection (favored) or rigorous systematic mediastinal lymph node sampling, with the goal of at least 3 N2 stations, and at least 10 lymph nodes.

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      MS06.04 - Approaches to Overcoming the Nodal Staging Quality Gap (Now Available) (ID 3470)

      11:00 - 12:30  |  Presenting Author(s): Ray Osarogiagbon

      • Abstract
      • Presentation
      • Slides

      Abstract

      MS 06 04: Approaches to Overcoming the Nodal Staging Quality Gap: Extended Abstract.

      The importance of pathologic nodal staging. Surgical resection remains the most important curative-intent treatment modality for non-small cell lung cancer (NSCLC), with 75-85% of 5 year survivors having undergone resection. For such patients, the status of nodal involvement is the most important prognostic factor, which also has implications for subsequent management, since patients with any nodal involvement (pN1-3) benefit from adjuvant chemotherapy and those with mediastinal nodal involvement (pN2-3) may benefit from adjuvant radiation therapy. Nodal staging also influences risk-stratification for clinical trials eligibility.

      Defining nodal staging quality. There are no universally accepted criteria for defining nodal staging quality, but various professional organizations, including the American College of Surgeons Oncology Group (ACOSOG), the American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC), the American College of Surgeons Commission on Cancer (CoC), the European Society for Thoracic Surgery (ESTS), the International Association for the Study of Lung Cancer (IASLC) and the National Comprehensive Cancer Network (NCCN) have all proposed slightly different measures of the quality of pathologic staging, including nodal staging parameters.1

      The nodal staging quality gap. Despite the importance of pathologic nodal stage, the quality of application of nodal staging is highly variable. Three examples are: non-examination of lymph nodes in resection specimens (pNX) which exists in 12-18% of resections; non-examination of mediastinal lymph nodes, which is reported in up to 50% of resections; failure to achieve aggregate nodal staging quality requirements, such as the NCCN definition of quality, which is achieved in as few as 4% of surgical resections in population-based cohorts in the United States.2

      Survival implications. pNX resections have significantly inferior survival to pN0 resections, and are more similar to resections for pN1 NSCLC; pN0 and pN1 resections without examination of mediastinal nodes have 14% lower adjusted 5-year survival than those with at least one examined mediastinal lymph node; and achievement of all 4 elements of the NCCN definition of resection quality (anatomic resection, negative margins, examination of at least 1 hilar/intrapulmonary lymph node and at least 3 mediastinal nodal stations) is associated with 30% lower hazard of death within 5 years.3

      Causes of the gap, corrective interventions. The nodal staging quality gap can be localized to events during the surgical operation, the transfer of resection specimens and the pathology examination. Effective interventions must correct the problem at all its potential sites of origin. In the ‘chain of responsibility’ conceptual model, any breakdown in the surgical retrieval of lymph nodes, labeling of specimens, transfer of specimens, gross retrieval of lymph nodes from submitted material and pathologic examination of the retrieved material can break down the quality and accuracy of the final pathology report which is used for all subsequent oncologic care decision-making. Devices such as pre-labeled specimen collection kits are able to prevent breakdown at all links of this chain: they significantly increase the thoroughness of lymph node evaluation; rates of attainment of nodal staging quality measures; and survival. However, their impact on retrieval of intrapulmonary lymph nodes is limited.

      Specific interventions are also required to improve pathologic retrieval of intrapulmonary lymph nodes, given evidence that up to 90% of pulmonary resection specimens have lymph nodes discarded without examination, approximately 30% of which have metastasis, including in 12% of patients reported as having pN0. Patients with discarded intrapulmonary lymph node metastasis have worse survival than those without, irrespective of their pathologic nodal stage. Even in the mediastinal nodal dissection arm of the ACOSOG Z0030 trial, in which there was extensive evaluation of hilar and mediastinal lymph nodes, poor examination of intrapulmonary lymph nodes was common and had significant negative survival impact.4 Novel, anatomically sound gross dissection methods designed to focus on retrieval of lymph nodes in the peri-bronchial tree with particular emphasis on sites of bronchial bifurcation, significantly improve the yield of lymph nodes and decrease the incidence of discarded lymph nodes. Therefore, combining surgery with lymph node specimen collection kits and improved gross dissection methods is necessary to comprehensively overcome the nodal staging quality gap.

      What are the putative pathways for survival impact? Correct prognostication by more accurate risk-stratification, although beneficial in itself, would only impact on stage-stratified survival, without changing survival in aggregate populations. The finding of aggregate survival differences suggests benefit beyond mere stage re-categorization. One likely mechanism is improvement in identification of candidates for adjuvant therapy, which then provides an indirect means of risk-mitigation. However, given the larger reduction in hazard for death when surgical specimen collection kits are used, than would be expected from adjuvant therapy benefits alone, another plausible hypothesis is an inherent benefit of resecting oligo-metastatic lymph node disease. This hypothesis requires further testing. Interestingly, it fits the emerging understanding of suboptimal nodal staging as a type of incomplete resection (R-uncertain) and the IASLC’s proposal for creating a new category of ‘R-uncertain’ resections, the overwhelming majority of which are caused by poor nodal staging.5

      The emerging ability to conduct tests for minimal residual disease such as with cell-free DNA will provide a means of directly testing this hypothesis. If proven, it would open a pathway to future clinical trials of novel adjuvant treatments, such as checkpoint inhibitor therapy and other immunomodulatory treatments for these residually high-risk patients.

      References

      Smeltzer MP, et al. Association of Pathologic Nodal Staging Quality With Survival Among Patients With Non-Small Cell Lung Cancer After Resection With Curative Intent. JAMA Oncol. 2018 Jan 1;4(1):80-87.

      Allen JW, et al. Quality of surgical resection for nonsmall cell lung cancer in a US metropolitan area. Cancer. 2011 Jan 1; 117(1):134-42.

      Osarogiagbon RU, et al. Prognostic Value of National Comprehensive Cancer Network Lung Cancer Resection Quality Criteria. Ann Thorac Surg. 2017 May; 103(5):1557-1565.

      Osarogiagbon RU, et al. Survival Implications of Variation in the Thoroughness of Pathologic Lymph Node Examination in American College of Surgeons Oncology Group Z0030 (Alliance). Ann Thorac Surg. 2016 Aug;102(2):363-9.

      Rami-Porta, et al. Complete resection in lung cancer surgery: proposed definition. Lung Cancer. 2005 Jul;49(1):25-33.

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      MS06.05 - Transcervical Lymphadenectomies (Now Available) (ID 3471)

      11:00 - 12:30  |  Presenting Author(s): Marcin Zielinski

      • Abstract
      • Presentation
      • Slides

      Abstract

      Abstract

      Introduction:

      The aim of his study is to analyze the issue of transcervical lympadenectomies for Non-Small-Cell Lung Cancer performed by the techniques of Video-Assisted Mediastinoscopic Lymphadenectomy (VAMLA) and Transcervical Extended Mediastinal Lymphadenectomy (TEMLA).

      Methods

      The Pubmed search was performed and there were 27 articles found on VAMLA and 33 articles on TEMLA. After further analysis there were 13 original article on VAMLA and 18 original articles on TEMLA. In the current paper all proven and possible advantages of transcervical lymphadenectomies representd by VAMLA and TEMLA are described.

      Results

      The proven advantages of VAMLA and TEMLA:

      1. Superior diagnostic value in discovery of the metastatic mediastinal nodes for staging and restaging of NSCLC.

      2. bilateral mediastinal lymphadenectomy, more extensive than the techniques of lymphadenectomy used during standard thoracotomy or Video-Assisted Thoracic Surgery (VATS) approaches.

      Possible advantages include:

      1. Improved selection of patients for pulmonary resection for NSCLC

      2. Combination of VAMLA/TEMLA with VATS pulmonary resection,

      3. Combination of VAMLA/TEMLA with esophegeal resection,

      4. Combination of TEMLA and Stereotactic Radiotherapy (SBRT) for advanced NSCLC

      5. The use of TEMLA for preoperative staging of mesothelioma,

      6. Combination of TEMLA and pulmonary lobectomy through a sole transcevical approach

      7. Resection of various metastatic tumors, including thyroid cancer and metastatic mediastinal nodes.

      8. Possible impact of VAMLA/TEMLA on improvement of survival for NSCLC patients, which is the most important issue. In case of VAMLA superior survival of patients operated on with the use pulmonary resection with VAMLA in comparison to the pulmonary resection with addition of standard mediastinoscopy. In case of TEMLA no reports on survival has been published, yet

      Disadvantages of VAMLA/TEMLA include

      1. Possible complications, especially the left recurrent nerve palsy

      2. Possible delay or elimination of some patients from pulmonary resection due to postoperative complication in case of negative result of VAMLA/TEMLA

      3. Scar in the neck (cosmetic)

      4. Demanding surgical technique

      Conclusions

      1. Bilateral transcervical lymphadenectomies representd by VAMLA and TEMLA are more extensive than the techniques of lymphadenectomy used during standard thoracotomy or Video-Assisted Thoracic Surgery (VATS) approaches and superior to the other techniques of staging and restaging of NSCLC in regard to the diagnostic value.

      2. There are several other possible advantages of TEMLA/VAMLA for the treatment of NSCLC, esophageal cancer, mediastinal tumors and malignant mesothelioma.

      3. Possible impact of VAMLA/TEMLA on survival of NSCLC has not been proven, yet.

      References

      Hurtgen M, Friedel G, Toomes H et al: Radical video-assisted mediastinoscopic lymphadenectomy (VAMLA) – technique and first results. Eur J Cardiothorac Surg 2002;21:348-51

      Zielinski M, Szlubowski A, Kołodziej M, Orzechowski S, Laczynska E, Pankowski J, Jakubiak M, Obrochta A. Comparison of endobronchial ultrasound and/or endoesophageal ultrasound with transcervical extended mediastinal lymphadenectomy for staging and restaging of non-small-cell lung cancer. J Thorac Oncol. 2013 May;8(5):630-6.

      Zielinski M, Hauer J, Hauer L, Pankowski J, Nabialek T, Szlubowski A. Staging algorithm for diffuse malignant pleural mesothelioma. Interact Cardiovasc Thorac Surg. 2010;10:185-9

      Zieliński M, Pankowski J, Hauer L et al: The right upper lobe pulmonary resection performed through the transcervical approach. Eur J Cardiothorac Surg. 2007;32:766-769

      Singh AK, Hennon M, Ma SJ, Demmy TL, Picone A, Dexter EU, Nwogu C, Attwood K, Tan W,, Hermann GM, Fung-Kee-Fung S, Malhotra HK, Yendamuri S, Gomez-Suescun JA. A pilot study of stereotactic body radiation therapy (SBRT) after surgery for stage III non-small cell lung cancer. BMC Cancer. 2018 Nov 29;18(1):1183. doi: 10.1186/s12885-018-5039-5.

      Turna A, Demirkaya A, Ozkul S, Oz B, Gurses A, Kaynak K. Video-assisted mediastinoscopic lymphadenectomy is associated with better survival than mediastinoscopy in patients with resected non-small cell lung cancer. J Thorac Cardiovasc Surg. 2013 Oct;146(4):774-80. doi: 10.1016/j.jtcvs.2013.04.036. Epub 2013 Jun 15.

      Li X, Wang W,, Zhou Y, Yang D, Wu J, Zhang B, Wu Z, Tang J.. Efficacy comparison of transcervical video-assisted mediastinoscopic lymphadenectomy combined with left transthoracic esophagectomy versus right transthoracic esophagectomy for esophageal cancer treatment. World J Surg Oncol. 2018 Feb 9;16(1):25. doi: 10.1186/s12957-017-1268-3.

      Call S, Obiols C, Rami-Porta R, Trujilo-Reyes JC, Iglesias M, Saumench R, Gonzalez-Pont G, Serra-Mitjans M, Belda-Sanchís J. Video-Assisted Mediastinoscopic Lymphadenectomy for Staging Non-Small Cell Lung Cancer. Ann Thorac Surg. 2016 Apr;101(4):1326-33. doi: 10.1016/j.athoracsur.2015.10.073. Epub 2016 Jan 21.

      .Kim HJ, Kim YH, Choi SH, Kim HR, Kim DK, Park SI. Video-assisted mediastinoscopic lymphadenectomy combined with minimally invasive pulmonary resection for left-sided lung cancer: feasibility and clinical impacts on surgical outcomes†. Eur J Cardiothorac Surg. 2016 Jan;49(1):308-13. doi: 10.1093/ejcts/ezv077. Epub 2015 Mar 11

      Zielinski M. Transcervical Resection of the Mediastinal Tumors. In Zielinski M, Rami-Porta R (eds). Transcervical Approach in Thoracic Surgery. Springer 2014, pages 141-148.

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      MS06.06 - The Concept of Complete Resection (Now Available) (ID 3472)

      11:00 - 12:30  |  Presenting Author(s): John G Edwards

      • Abstract
      • Presentation
      • Slides

      Abstract

      The basis of the definition of complete resection is the Union for International Cancer Control (UICC) residual tumor classification (R classification), which considers the presence or absence of tumor in the primary site, lymph nodes and distant site following treatment. It has established clinical relevance, reflects the effectiveness of treatment, may be used to determine whether further therapy is indicated and has established prognostic relevance in lung cancer [1-3]. However, there are deficiencies in that locoregional recurrence may occur after an apparent R0 resection. The Complete Resection Subcommittee was tasked by the IASLC Staging Committee in 2001 to prepare a proposal of the definition of complete resection, based on expert opinion. The proposal that was derived [4] proposed the term uncertain resection, R(un), according to the following criteria:

      An uncertain resection is defined when resection margins are proved to be free of disease microscopically, but one of the following applies:

      (a) The intraoperative lymph node evaluation has been less rigorous than systematic nodal dissection or lobe-specific systematic nodal dissection.

      (b) The highest mediastinal node removed is positive.

      (c) The bronchial margin shows carcinoma in situ.

      (d) Pleural lavage cytology is positive (R1 cy+).

      In addition, this proposal considered cases with positive pleural lavage cytology (PLC) as R(un), rather than R1, and cases with extracapsular extension of tumor in nodes removed separately, or those at the margin of the main lung specimen, were considered R1, rather than R0.

      The analysis of the proposed R Classification using the database informing the 8thEdition of the TNM was presented at the 18thWorld Conference on Lung Cancer. The predominant reason for re-classification as R(un), performed in 56% of cases, was less than systematic nodal dissection (96% of cases). Survival in the R(un) category was significantly worse than R0 in node positive cases (median survival 50 and 70 months respectively, Hazard Ratio 1.27, Figure). The status of the highest lymph node station also had prognostic significance in pN2 cases (HR 1.32). Further work, that will require the submission of high quality data to the IASLC Lung Cancer Staging Project, will investigate again the impact of the individual R factors, particularly those for which the prevalence (or data completeness) in the previous dataset was low. Participation by institutions worldwide is essential to ensure success [5].

      However, there are several aspects about R Factor assessment that require clarification. These are being considered by the R Factor Subcommittee of the Staging and Prognostic Factors Committee. A survey of the current application and interpretation of the R Classification for NSCLC has been designed. The R Factor Sub-Committee will be determining and disseminating best methodological practice for intra-operative and histopathological aspects of R factor assessment.

      figure4.jpg

      References:

      1. Brierley JD, Gospodarowicz MK, Wittekind Ch (eds). UICC TNM Classification of Malignant Tumours, 8th edition. Oxford:Wiley Blackwell; 2017; p:10-11.

      2. Wittekind C, Compton CC, Greene FL, Sobin LH. TNM residual tumor classification revisited. Cancer 2002;94:2511—9.

      3. Smeltzer MP, Lin CC, Kong FS, Jemal A, Osarogiagbon RU. Survival impact of postoperative therapy modalities according to margin status in non-small cell lung cancer patients in the United States. J Thorac Cardiovasc Surg. 2017 Aug;154(2):661-672.e10. doi: 10.1016/j.jtcvs.2017.03.085

      4. Rami-Porta R, Wittekind C, Goldstraw P. Complete resection in lung cancer surgery: proposed definition. Lung Cancer 2005;49:25—33.

      5. Giroux DJ, Van Schil P, Asamura H, Rami-Porta R, Chansky K, Crowley JJ, Rusch VW, Kernstine K; International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee. The IASLC Lung Cancer Staging Project: A Renewed Call to Participation. J Thorac Oncol. 2018 Jun;13(6):801-809. doi: 10.1016/j.jtho.2018.02.012. Epub 2018 Feb 22.

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