Virtual Library

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    IBS08 - Role of Pathologist in the Era of Immunotherapies (Ticketed Session) (ID 39)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Pathology
    • Presentations: 2
    • Now Available
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      IBS08.01 - Harmonization of PD-L1 IHC Including LDT (Now Available) (ID 3338)

      07:00 - 08:00  |  Presenting Author(s): Lukas Bubendorf

      • Abstract
      • Presentation
      • Slides

      Abstract

      Given the great advances in immuno-oncology, systematic testing of virtually all NSCLC for PD-L1 expression by IHC has become a standard in many pathology laboratories. This has initially been driven by the approval of Pembrolizumab for first line monotherapy of metastatic NSCLC with a tumor proportion score (TPS) of at least 50%. At the same time, the pathology and oncology community has been challenged by as many as five different PD-L1 IHC assays related to different clinical trials with different PD1/PD-L1 checkpoint inhibitors in NSCLC and cancers of other organs. The use of different antibody clones and assays for IHC within different trials cannot be explained by a specific rationale but rather by economic reasons and opportunities. Unfortunately, most pharmaceutical companies would not adopt an assay that has previously been developed and used by a competitor. They rather team up with an antibody manufacturer to develop their own predictive marker for their own drug. Pathologist are then left with sorting out the dilemma and look for the most feasible solution to provide reliable predictive PD-L1 testing and enable the best possible treatment decisions. Clearly, it is out of question that pathology laboratories would be able or willing to provide all available assays using different automated immunostainer platforms for two major reasons: First, it is usually unknown to the pathologist at the time of testing, which particular PD1/PD-L1 inhibitor will be the chosen for an individual patient, as this depends on the preference of the medical oncologists and the actual result of the PD-L1 IH testing. Second, for many institutions, it is too expensive to maintain different automated immunstainer platforms and to establish different expensive PD-L1 assays in parallel, all of which need to undergo continuous or periodical internal and external quality control. Therefore, whenever possible, pathology laboratories try to establish one single PD-L1 IHC test that is as concordant as possible with several trial-related PD-L1 assays. Notably, the predictive IHC assays with the trial-related antibody clones are much more expensive than typical diagnostic antibodies used in pathology for decades, and this extra expense if often not properly reimbursed by the health insurance system. This explains why many laboratories still use laboratory developed tests (LDTs) for PD-L1 IHC using the non-clinical trial related antibody E1L3N (Cell Signaling) or concentrated, trial-related anti-PD-L1 antibodies.

      Given this apparent dilemma there have been numerous studies aiming at harmonizing the landscape of PD-L1 IHC testing. They have repeatedly shown that the concordance between the currently most relevant assays (DAKO 28-8, -DAKO 22C3, and Ventana SP263) was sufficient to allow for interchangeable use. This enables laboratories of to provide PD-L1 assay testing to select patients for treatment with Pembrolizumab, Nivolumab and Durvalumab on either the Ventana Benchmark Ultra or the DAKO AL48 immunostainer platform. On the other hand, the Ventana SP142 assay related to Atezolizumab has clearly lower sensitivity for PD-L1 expression on tumor cells (TC), and is thus suitable to select for treatment with nivolumab or pembrolizumab based on different TPS threshold. Similarly, the latest DAKO clone 73-10 that is related to Avelumab, appears to be the most sensitive one and might therefore not be interchangeable with any of the other PD-L1 assays. Published data and results from external quality assurance (EQA) programs indicate that it is possible to set up LDTs that match the staining results of the PD-L1 IHC assays. Nevertheless, LTDs still have higher failure rates emphasizing the necessity of rigorous validation and quality control. PD-L1 IHC has been adopted by several programs of external EQA programs including NordiQC, Quip, and UK NEQAS. Notably, NordiQC showed good results of trial-related related commercial PD-L1 IHC assays, and the results of LTDs improved over time. In particular, the sufficiency rate for E1L3N rose from a low 25% (2/9) in the first run to a high 89% (8/9) in the second run.

      Post-analytical PD-L1 scoring is also a challenge. Training and continuous exposure to PD-L1 IHC in routine practice can help to shorten the learning curve. In fact, the interobserver concordance of TC scoring was found to be higher among pathologist who had received specific training. Continuous monitoring of PD-L1 IHC values for comparison with the results of other institutions via an online database is emerging as another useful tool to control and fine tune of performance of PD-L1 IHC analysis of single pathologists or institutions, as demonstrated by the BIO-PATH biomarker tracker (https://www.biopath.ch/mha/).

      Literature

      Tsao MS, Kerr KM, Dacic S, et al., editors. IASLC Atlas of PD-L1 Immunohistochemistry testing in lung cancer, 1st edition 2017. International Association for the Study of Lung Cancer, Aurora, USA.

      Gaule P, Smithy JW, Toki M, , et al. A Quantitative Comparison of Antibodies to Programmed Cell Death 1 Ligand 1. JAMA Oncol. 2017 Feb 1;3(2):256-259.

      Scheel AH, Dietel M, Heukamp LC, et al. Harmonized PD-L1 immunohistochemistry for pulmonary squamous-cell and adenocarcinomas. Mod Pathol. 2016 Oct;29(10):1165-72.

      Tsao MS, Kerr KM, Kockx M, et al. PD-L1 Immunohistochemistry Comparability Study in Real-Life Clinical Samples: Results of Blueprint Phase 2 Project. J Thorac Oncol. 2018 Sep;13(9):1302-1311.

      Adam J, Le Stang N, Rouquette I, et al. Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer. Ann Oncol. 2018 Apr 1;29(4):953-958.

      Savic S, Berezowska S, Eppenberger-Castori S, et al. PD-L1 testing of non-small cell lung cancer using different antibodies and platforms: a Swiss cross-validation study. Virchows Arch. 2019 May 24 [Epub ahead of print]

      NordiQC results for quality assessment of PD-L1 in NSCLC, Available online: https://www.nordiqc.org/epitope.php?id=107

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      IBS08.02 - Beyond PD-L1 IHC (TMB, Immune Microenvironment) (Now Available) (ID 3339)

      07:00 - 08:00  |  Presenting Author(s): Mari Mino-Kenudsen

      • Abstract
      • Presentation
      • Slides

      Abstract

      PD-L1 expression by immunohistochemistry (IHC) is currently the only FDA-approved biomarker for immune checkpoint inhibitor therapy (ICI). However, there are multiple issues associated with PD-L1 IHC including the presence of multiple IHC platforms, each anti-PD-1/PD-L1 agent coupled to the specific PD-L1 IHC assay and spatial and temporal heterogeneity of PD-L1 expression in the tumor. Importantly, PD-L1 expression is not the best biomarker to predict response to PD-1/PD-L1 blockade given the relatively low specificity.(1) To improve the prediction of response to ICI, several biomarkers have been studied. Of those, tumor mutation burden (TMB) and immune microenvironment are emerging as predictive biomarkers.

      TMB is commonly defined as the total number of somatic coding mutations and is considered a surrogate for the amount of neoantigens based on the notion that the greater the number of nonsynonymous mutations in a given tumor, the more probable it is that some of the mutations will be immunogenic, providing targets for T-cell attack.(2) Rizvi and colleagues have shown higher synonymous mutation burden in tumors associated with improved objective response, durable clinical benefit, and progression-free survival (PFS) in two independent NSCLC patient cohorts treated with pembrolizumab.(3) Subsequently, the efficacy of TMB predicting response to ICI has been reported in several clinical trials. In the CheckMate 026,(4) which failed to confirm the efficacy of Nivolumab compared to the standard chemotherapy for advanced NSCLC patients as the first line, the biomarker subanalysis revealed that PFS of patients with high TMB was significantly longer than those with low and medium TMB when treated with Nivolumab, but the reverse was true when treated with chemotherapy. Further, upon stratified by both TMB and PD-L1 expression level, patients with both high TMB and high PD-L1 expression showed a high response rate (75%) and dramatically improved PFS compared to other groups when treated with Nivolumab, but there were no significant differences in PFS among the groups when treated with chemotherapy. Of note, TMB was measured using whole-exome sequencing (WES) in this study. In the CheckMate 227 study,(5) high TMB (>10 mutations/Mb) was associated with significantly improved outcomes with nivolumab/ipilimumab, with 1-year OFS of 43% versus 13% for chemotherapy, and the median PFS was 7.2 months versus 5.5 months (hazard ratio of 0.58, P<0.001). For patients with lower TMB, immunotherapy was not superior. Other studies have measured TMB in the blood and reported similar results for treatment with atezolizumab.(6) It is important to note that TMB and PD-L1 expression are independent variables and composite of TMB + PD-L1 expression further enrich for benefits from ICI.(7)

      Unfortunately, similar to PD-L1 IHC, the TMB assessment has not been standardized yet. Although conducting comprehensive WES is ideal to assess TMB, it is currently not feasible in daily practice given the high costs, long turn-around time and suboptimal quality and quantity of tissue available from advanced lung cancer patients. Now, targeted panel sequencing or next generation sequencing (NGS) has become a part of clinical practice; thus, it would be desirable to leverage it to assess TMB. However, size and composition of panels, and read depth and coverage are diverse between NGS platforms; thus, the cut-off for high TMB is plat-form dependent. Importantly, TMB values represent a continuum rather than distinct clusters, NGS platforms with small gene panels may be difficult to predict TMB comparably to WES, while larger panels such as the 468-gene MSK-IMPACT panel and 315-gene FoundationOne panel could. Currently, the harmonization efforts on TMB are being conducted in the US (Friends of Cancer Research [FoCR]) and Germany (Qualitatssicherungs-Initiative Pathologie QuIP GmbH [QuIP]) in hope of enabling international and cross-sector standardization of TMB measurement and reporting.(8)

      As for the immune microenvironment, there are many types of immune cells, including T cells, B cells, myeloid-derived suppressor cells, tumor-associated macrophages and neutrophils. Of those, CD8+ cytotoxic T cells have been recognized as an important player and their density and location have been reported in association with response to ICI.(9) However, not all CD8+ T cells are in the same functional status. For instance, they may be activated characterized by the production of Granzyme B and Perforin and high Ki-67 proliferative index, and they may be exhausted characterized by the expression of LAG3, TIM3 and/or B7H3, among others. Interestingly, Gettinger and colleagues using multiplexed quantitative immunofluorescence have shown that a dormant tumor infiltrating T lymphocyte (TIL) phenotype, characterized by elevated CD3+ TILs with low activation (Granzyme B in CD3) and low proliferation (Ki-67 in CD3), is associated with survival benefit in patients treated with ICI.(10) Thus, we need to evaluate multiple immune markers at the same time to understand the immune microenvironment, preferably using a multiplex platform.

      References:

      1. Mino-Kenudson M. Programmed cell death ligand-1 (PD-L1) expression by immunohistochemistry: could it be predictive and/or prognostic in non-small cell lung cancer? Cancer Biol Med. 2016;13:157-70.

      2. Chen DS, et al. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321-330.

      3. Rizvi NA, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.

      4. Carbone DP, et al. First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376:2415-2426.

      5. Hellmann MD, et al. Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden. N Engl J Med. 2018;378:2093-2104.

      6. Gandara DR, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24:1441-1448.

      7. Rizvi H, et al. Molecular Determinants of Response to Anti-Programmed Cell Death (PD)-1 and Anti-Programmed Death-Ligand 1 (PD-L1) Blockade in Patients With Non-Small-Cell Lung Cancer Profiled With Targeted Next-Generation Sequencing. J Clin Oncol. 2018;36:633-641.

      8. Allgäuer M, et al. Implementing tumor mutational burden (TMB) analysis in routine diagnostics-a primer for molecular pathologists and clinicians. Transl Lung Cancer Res. 2018;7:703-715.

      9. Tumeh PC, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515:568-71.

      10. Gettinger SN, et al. A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. Nat Commun. 2018;9:3196.

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    IBS14 - Best Management of Early Stage NSCLC in ILD Patients (Ticketed Session) (ID 45)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 2
    • Now Available
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      IBS14.01 - Surgery (Now Available) (ID 3357)

      07:00 - 08:00  |  Presenting Author(s): Masahiro Tsuboi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      IBS14.02 - Best Management of Early Stage NSCLC in ILD Patients (Now Available) (ID 3358)

      07:00 - 08:00  |  Presenting Author(s): Alexander Vincent Louie

      • Abstract
      • Presentation
      • Slides

      Abstract

      Interstitial lung disease (ILD) is characterized by diffuse inflammation and fibrosis within the lung parenchyma.1Although a heterogeneous group of diseases, invariably, it is associated with a restrictive defect on pulmonary function testing, and a reduced ability for gas exchange.2 On imaging, features of ILD can include reticulation, traction bronchiectasis and honeycombing. Interestingly, a diagnosis of ILD is an independent risk factor for the development of lung cancer.3

      Stereotactic ablative radiotherapy (SABR) is a common radical treatment modality for patients with early stage NSCLC and is characterized by its convenience, tolerability, and high efficacy.4 Given these features, it has been popularized as an attractive option in early stage NSCLC patients with significant medical co-morbidities. Early stage NSCLC patients with co-existing ILD, however, are a high-risk group for any type of treatment, both for treatment-related toxicities and for acute exacerbations of ILD. These toxicities can be severe, and in extreme scenarios, fatal. The focus of this abstract will be on the use of SABR for early stage NSCLC patients with ILD, with an aim to discuss emerging data and future research directions.

      Despite the generally favorable toxicity profile of SABR, there are an increasing number of reports of serious toxicities in patients with pre-existing ILD. These reports have largely been retrospective in nature, heterogeneous in the radiation doses employed, with findings of extreme ranges in treatment related death rates. Arguments can be made on whether some of these reports, especially in those with exceptionally high rates of extreme toxicity, confer an element of publication bias. This refers to the phenomenon whereby there is an inclination to report results that are more remarkable (i.e. major toxicity or treatment-related death). Therefore, although it is likely that SABR incurs a greater risk in this setting compared to standard lung SABR cases, the true risk is unclear.

      To further delve into this issue, our group recently performed a systematic review and meta-analysis of outcomes following several different treatment modalities for early-stage lung cancer patients with ILD.5 From this initiative, 13 studies assessing outcomes after SABR were identified, and recognizing the caveats of the available data, we concluded that there was a 1 in 4 risk of severe radiation pneumonitis (defined as grade ≥3), and a 15% risk of treatment-related grade 5 toxicity. A specific diagnosis of idiopathic pulmonary fibrosis (IPF) appeared to be associated with the greatest risk, whereby treatment related mortality was 1 in 3, as compared to 14% for non-IPF fibrotic ILD. When considering this potential increased risk, it is important to recognize that the IPF patient population has a significant background risk of acute exacerbations of their disease, with an annual reported range of 5-19%.6

      The Canadian Pulmonary Radiotherapy Investigators group (www.capriclinicaltrials.com) has designed a single arm phase II trial to evaluate the role of SABR in T1-2N0M0 NSCLC patients with co-existing ILD who are not surgical candidates. The trial (clinicaltirals.gov, NCT03485378) is entitled: Assessment of Precision Irradiation in Early Non-Small Cell Lung Cancer and Interstitial Lung Disease (ASPIRE-ILD). To our knowledge, this will be the first prospective trial evaluating this clinical scenario, and it is novel in that patients will be stratified using the ILD-GAP score, which is an index that incorporates ILD mortality risk according to Gender, Age and Physiology.7 The starting SABR dose will be 50 Gy in 5 fractions, and the dose fractionation will be escalated or de-escalated depending on toxicities observed in different cohorts of the trial.

      The appropriateness of SABR in any, or some of these patients can certainly be questioned in light of the potential serious toxicity. On the other hand, the median survival of untreated stage I NSCLC has consistently been reported to be less than 1 year in various studies.8 Therefore, the value of treatment would ideally be answered through a randomized controlled trial, however, this is probably unfeasible as patients and physicians alike may be uncomfortable with randomization. Given the inherent risks of both untreated cancer as well as any cancer-directed treatment, we encourage investigators to continue to report on their experiences in this challenging clinical dillemma, whether positive or negative, so that additional research can inform shared decision making.

      REFERENCES

      1. Maher EJ, Timothy A, Squire CJ, et al. Audit: the use of radiotherapy for NSCLC in the UK. Clin Oncol (R Coll Radiol)1993;5:72-79.

      2. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax2008;63 Suppl 5:v1-58.

      3. Naccache JM, Gibiot Q, Monnet I, et al. Lung cancer and interstitial lung disease: a literature review. J Thorac Dis2018;10:3829-3844.

      4. Louie AV, Palma DA, Dahele M, et al. Management of early-stage non-small cell lung cancer using stereotactic ablative radiotherapy: Controversies, insights, and changing horizons. Radiother Oncol2015;114:138-147.

      5. Chen H, Senan S, Nossent EJ, et al. Treatment-Related Toxicity in Patients with Early-Stage Non-Small Cell Lung Cancer and Co-Existing Interstitial Lung Disease: A Systematic Review. International Journal of Radiation Oncology*Biology*Physics.

      6. Hyzy R, Huang S, Myers J, et al. Acute exacerbation of idiopathic pulmonary fibrosis. Chest2007;132:1652-1658.

      7. Milne KM, Kwan JM, Guler S, et al. Frailty is common and strongly associated with dyspnoea severity in fibrotic interstitial lung disease. Respirology2017;22:728-734.

      8. Nanda RH, Liu Y, Gillespie TW, et al. Stereotactic body radiation therapy versus no treatment for early stage non-small cell lung cancer in medically inoperable elderly patients: A National Cancer Data Base analysis. Cancer2015.

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    IBS25 - Optimal GGO Management (Ticketed Session) (ID 56)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 2
    • Now Available
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      IBS25.01 - Eastern Perspective (Now Available) (ID 3392)

      07:00 - 08:00  |  Presenting Author(s): Hisao Asamura

      • Abstract
      • Presentation
      • Slides

      Abstract

      The term “ground glass opacity (GGO)” is being used more often to describe the CT appearance of a focal, non-calcified lesion with a slight/moderate increase in CT density. Usually, GGO is characterized on high-resolution CT scan images with a slice thickness of 1-3mm. The CT appearance of GGO is characterized by “focal, transparent” lesion. First, GGO refers to the localized or focal lesion regardless of the multicentricity, and the diffuse ground glass appearance seen for interstitial pneumonitis should be excluded from this category. Second, GGO lesions is well-characterized by a slight/mild increase in CT density, which does not obscure preexisting lung structures such as blood vessels and bronchi. This apperance refers to the CT-transparency. When the shape of the pulmonary vessels in the nodules is not recognized in the nodule, the lesion is no longer considered GGO, and instead is called a “solid” lesion. GGO lesion can be either homogeneous or heterogeneous. The GGO lesions are classified according to the absence/presence of the solid part. In case the GGO lesions are homogeneous, and does not contain solid part, it is called “non-solid GGO” or “pure GGO”. In case the GGO lesions contain a solid, cystic, or linear part inside the nodule, it is called “non-solid GGO” or “complex GGO”. The solid part is more likely to be located in the center of the nodule, and surrounded by the GGO part, which is a so-called “fried egg” appearance. The solid part might be scant or prominent with various proportions of solid to GGO parts. In the classic, solid tumor, the GGO part has no longer exist within the nodule.

      According to the recent studies on the relationship between CT appearance and histopathology of GGOs, not all, but considerable portion of these lesions correspond to the preivasive, non-invasive, or early forms of neoplastic growths, especially those on the adenocarcinoma lineage. The clinicopathological entity of these tumors are being established only recently, and it has never been the subject of clinical studies. The histopathology of GGO has been also studied, and they are either neoplastic or inflammatory. A focal inflammation of the lung panrenchyma sometimes presents with GGO on the CT image, and pathologically it is described as “organizing pneumonia”. These changes are more likely to be temporary. In contrast, the persisting GGOs are more likely to be neoplastic. According to the WHO histological classification of lung and pleural tumors, GGO lesions are associated with three pathological entities. “Atypical adenomatous hyperplasia (AAH)” is described as a preinvasive lesion, in which slightly atypical tumor cells line the involved alveoli and respiratory bronchioles. Adenocarcinoma in situ (AIS) is an adenocarcinoma with Clara cells and/or type II pneumocytes growing along alveolar walls and without stromal invasion. The important feature of AIS is “non-invasive” growth of the tumor, and therefore this lesion could be considered in situ carcinoma. The third category is adenocarcinoma with mixed subtypes, which shows a mixture of the histologic subtypes as well as obvious invasive growth.

      The intervention strategy for GGO lesions are being established very recently, and some of them still need future clincal trials. Several factors are related to the management stragety; the size of lesions, image characteristics (non-solid versus part-solid), and the history of previous lung cancer. Especially, the indolent nature of the small-sized, non-solid GGOs needs to be stressed. For these tumors, the immediate surgical intervention should be rather avoided. Furthermore, the physical condition of the patiets such as age, co-existing medical conditions also must be taken into consideration. When thinking of surgical interventions, the location of the lesion (outer versus inner) is also an iomportant issue from the technical point of view. For tumors located deeply in the lung parenchyma, the sublobar resection is generally amenable because of the lack in the enough surgical margin.

      1. Non-solid GGOs less than 15 mm in diameter. These small lesions without any solid part in the nodule termed as non-solid GGO are basically watched carefully with the repeated high-resolution CT. The appropriate intervals between repeated CTs have not been clearly demonstrated. It might rage from 3 to 6 moths. If the overt growth in size or the newly developping solid component is shown, the surgical intervention should be considered.

      2. Part-solid GGOs less than 15 mm in diameter. The solid component in the part-solid GGOs represents the fiborotic scar and/or collapse of the lung in which the proliferation of the collagen fibers and actrive gibroblast is generally seen, and thiese findings indicate the features of invasive growth. Therefore, tumors of this category should be resected, The careful watching should be indicated only for the poor physical conditions compromising the surgical resection. However, considering their minimally invasive nature and small size, the sublobar resection could be reasonablly choosed. For these tumors, the segementectomy rather than wedge resection is preferrable. The location of the tumor should be carefully evaluated. When the tumor is located in the inner two thirds of the lung panrenchyma, the segemetal resection shoul be reapected as amenable. The segmentectomy for this location cannot ensure the safe surgical margin. For such locations, the lobectomy, instead of segmentectomy, must be chosen.

      3. Non-solid GGOs larger than 15 mm in diameter. As non-solid GGOs of smaller size category, these lesions should not be resected immediately. However, the larger GGOs are known to be more likely to grow faster even if the lesions still do not contain solid part. There fore, if the lesion persists at least in the same size, after the appropriate follow-up period of 3-6 motnths, these GGOs should be resected. Similarly, the resection should be performed with sublobar resection.


      4. Part-solid GGOs larger than 15 mm in diameter. The part-solid GGOs of this size are more likely to be an invasive adenocarcinomas. Especially when the solid part exceeds 50% of the whole area of the lesion, the invasive features become more common. Therefore, the lobectomy might be better selected as the mode of resection. The evaluation of the hilar/mediastinal lymph nodes should be also performed during surgery.











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      IBS25.02 - Western Perspective (Now Available) (ID 3393)

      07:00 - 08:00  |  Presenting Author(s): Jessica S Donington

      • Abstract
      • Presentation
      • Slides

      Abstract

      Ground glass opacities (GGOs) are a 21st century diagnostic and therapeutic challenge. These are defined as focal areas of increased attenuation on computed tomography (CT), where visualization of normal parenchyma and pulmonary structures such as airways and vessels is preserved. Prior to the advent of high-resolution thin-slice CT scanning we had little evidence for the wide spread existence of these lesions or their association with adenocarcinomas of the lung. The opacities develop because of reduced volumes of air the alveolar airspaces due to partial by cells as they grow in a lepidic pattern along the alveolar surface, typically, the abnormal cells only occupy a portion of the airspace and therefore consolidation of the lung parenchyma does not occur. GGOs are typically divided into two categories: 1) pure GGOs, which contain no solid component and 2) part-solid GGOs, with both solid and pure ground glass regions.

      The introduction of CT screening for lung cancer should dramatically increase the number of patients presenting with small nodules and GGOs. Interpretation and management guidelines are essential and several have been developed and updated. They are derived by expert consensus and management recommendations are based primarily on the GGO’s size, percent solid component, and number in

      combination with the patient’s baseline risk for lung cancer development. The most prominent guidelines are from the British Thoracic Society1 and the Fleischner Society2.

      We have a growing understanding of the role of GGOs in the pathogenesis of adenocarcinomas of the lung. A strong correlation exists between CT appearance and the extent of histologic tumor invasion, which is outlined in the IASLC/ATS/ERS Classification of Lung Adenocarcinomas.3 There exists a continuum from pre-invasive lesions, atypical adenomatous hyperplasia (AAH) and adenocarcinoma in situ (AIS), to minimally invasive adenocarcinoma (MIA), and finally to invasive adenocarcinoma. This has also resulted in a new subclassification of T1 lesions in the 8th edition of lung cancer staging system4 that includes precise definitions for these pre-invasive and minimally invasive lesions.

      Although we all agree on terminology to define these lesions radiographically and pathologically, there is less consensus on the ideal management and more specifically when to intervene surgically and what type of resection is best. The Japanese Clinical Oncology Group have served as the leaders in this realm, carrying out a series of prospective trials to define the appropriate extent of resection and lymph node dissection for pure and part-solid GGOs.

      I believe one of the greatest disparity between eastern and western lung cancer treatment is in the management of small GGOs. The pre-invasive and minimally invasive lesions, those < 2cm and with solid component < 5mm or with consolidation to tumor ratio < 0.25. Numerous retrospective series and prospective trials from Asia outline the high potential for cure with a limited resection and no lymph node dissection, but most western thoracic surgeons would argue whether if resection is warranted at all for lesions that we reliably know are pre-invasive, or iss surgery for these lesions overtreatment for a “pseudo disease”?

      It is difficult to put forth the management ideology for the entire western hemisphere, but I believe that the concept of “do no harm” prevails with regard to these small lesions. The western thoracic community has a far greater tendency toward “watching and waiting” than our eastern counter parts. This is based on the understanding that even though these lesions exist within the adenocarcinoma spectrum, only a small percentage will become invasive cancers. Less than 30% of pure GGOs detected in the NELSON trial5 and only < 2% in the I-ELCAP cohort6 ever developed a solid component. We also take comfort in the fact that these lesions have slow doubling times >800 days7, allowing for change in appearance over time to help define the potential for invasion and risk to the patient.

      Some of the hesitation for rapid surgical intervention in these pre-malignant lesions is because thoracic resections are invasive, even simple wedge resections typically require general anesthesia and a hospital stay and carry a risk for complication especially in the frail or elderly. In addition, the lungs are vital organs, and in that sense quite different from the breast or prostate where we have taken on a much more aggressive approach to the treatment of pre-malignant and minimally invasive tumors. Even in those tumors, we are now investigating de-escalation of treatment protocols and active surveillance for lesions that may never affect a patient’s survival. There is also a tendency for multiplicity with GGOs and the potential for many interventions treatments over a patient’s lifetime, if each GGO is to be removed.

      We are in the early phase of our clinical proficiency with GGOs; as our experience and knowledge grows there will likely be a more uniformed approach to intervention, but in 2019, management varies by geography.

      Callister ME, Baldwin DR, Akram AR, et al. British Thoracic Society guidelines for the investigation and management of pulmonary nodules. Thorax 2015;70 Suppl 2:ii1-ii54.

      MacMahon H, Naidich DP, Goo JM, et al. Guidelines for Management of Incidental Pulmonary Nodules Detected on CT Images: From the Fleischner Society 2017. Radiology 2017;284:228-43.

      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;6:244-85.

      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.

      van Klaveren RJ, Oudkerk M, Prokop M, et al. Management of lung nodules detected by volume CT scanning. N Engl J Med 2009;361:2221-9.

      International Early Lung Cancer Action Program I, Henschke CI, Yankelevitz DF, et al. Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med 2006;355:1763-71.

      Lee SW, Leem CS, Kim TJ, et al. The long-term course of ground-glass opacities detected on thin- section computed tomography. Respir Med 2013;107:904-10.

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    MA05 - Update on Clinical Trials and Treatments (ID 123)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 11
    • Now Available
    • +

      MA05.01 - Second or Third Line Anti-PD-1 Therapy After Multimodality Therapy Including Total Pleurectomy in Malignant Pleural Mesothelioma (Now Available) (ID 1955)

      13:30 - 15:00  |  Presenting Author(s): loic Lang-Lazdunski  |  Author(s): Yu Zhi Zhang, Sanjay Popat, Mary O'Brien, Jeremy Steele, Tom Newsom-Davis, Arnaud Scherpereel, Hasna Bouchaab, Alexandra Rice, Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Surgical resection plays an important role in the management of selected patients with malignant pleural mesothelioma (MPM). Early experience with anti-PD-1 immunotherapy showed promise in MPM, but it is yet uncertain if it can improve outcomes when tumour relapses following surgical resection, radiotherapy and chemotherapy. We reviewed our experience in patients who received Pembrolizumab or Nivolumab following multimodality therapy.

      Method

      Retrospective study including patients with histologically-proven MPM having completed multimodality therapy and received anti-PD-1 immunotherapy as 2nd or 3rd line treatment. Data were retrieved from a prospective mesothelioma database. Histopathology, BAP1, MTAP and PD-L1 (22C3) immunohistochemistry were performed on surgical specimens and reported by a senior pathologist. All patients had chest computed tomography and positron emission tomography (PET-CT) as part of their normal follow-up. Response evaluation was determined using RECIST 1.1 criteria.

      Result

      16 patients received anti-PD-1 immunotherapy between August 2015 and March 2019. All patients had total pleurectomy/decortication, prophylactic radiotherapy (21Gy/3) and systemic chemotherapy based on pemetrexed and platinum. Median age was 68.5 years, with male predominance (13/16). 56% had epithelioid type, 44% had biphasic type. Median time to starting immunotherapy was 20 months (range 11-42) following surgery. Median ECOG performance status was 0. Twelve patients received Pembrolizumab and 4 received Nivolumab. Median number of cycles of anti-PD-1 therapy received was 5 (range 1-33). Disease control rate at 12 weeks was 56.2% and 7 (43.7%) patients had disease progression. Adverse events were observed in 6 patients (one Grade 3). Eight patients were alive by 1st April 2019. Median OS from starting immunotherapy was 13.5 months. Three patients received treatment for 14 months or more. Five patients started further therapy after discontinuing immunotherapy.

      Conclusion

      In our cohort, second or third-line anti-PD-1 immunotherapy showed efficacy with DCR comparable to non-surgical setting. Further studies are warranted to validate our preliminary findings.

      wclc 2019 figure 1anti pd1.jpg

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      MA05.02 - Log Odds of Positive Lymph Nodes Predicts Overall Survival and the Benefit of Postoperative Radiotherapy in Malignant Pleural Mesothelioma (Now Available) (ID 1059)

      13:30 - 15:00  |  Presenting Author(s): Yang Wo  |  Author(s): Yuanyong Wang, Tong Lu, Wenjie Jiao

      • Abstract
      • Presentation
      • Slides

      Background

      Nodal categories of malignant pleural mesothelioma (MPM) are mostly adopted from lung cancer staging criteria and the N descriptors in the eighth edition of TNM staging system have not been fully verified. We aimed to evaluate the effectiveness of the current N descriptors and a novel prognosticator—the log odds of positive lymph nodes (LODDS)—in predicting overall survival (OS) and postoperative radiotherapy (PORT) benefit in MPM.

      Method

      Patients in the Surveillance, Epidemiology, and End Results (SEER) database with MPM undergoing surgery and lymph nodes examination were extracted and restaged according to the 8th edition TNM staging system. LODDS was calculated as loge[(positive nodes count+0.5)/(negative nodes count+0.5)]. X-tile software determined the optimal cut-point for LODDS. Log-rank tests along with Cox regression analyses were adopted for survival analyses. Harrell's C-index statistic measured discriminatory ability and prognostic performance.

      Result

      A total of 534 patients were enrolled in this study. N descriptors were unevenly distributed. Most cases were staged as N0 (51.9%) and N1 (47.0%), with only 1.1% staged as N2. The eighth edition N descriptors failed to clarify the survival difference between adjacent categories and were incapable of predicting PORT benefit. The cut-points for LODDS were classified as follows: LODDS1 (≤-2.61), LODDS2 (-2.56≤LODDS≤0.62), and LODDS3 (≥0.87). The median survival of LODDS1 was 23.1 months compared with 17.9 months (HR=1.397, P=0.005) and 13.0 months (HR=2.317, P<0.001) for LODDS2 and LODDS3, respectively. The survival curves stratified by LODDS separated nicely without overlapping and the benefit of PORT was limited to cases with LODDS3 (≥0.87). LODDS also provided better C-index than the conventional N descriptors.

      layout 1.jpg

      Conclusion

      LODDS performs better than N descriptors for predicting survival and benefits of PORT in resected MPM, and it could be considered as a potential parameter to compensate for defects in the 8th AJCC TNM staging for MPM.

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      MA05.03 - Impact of Time to Surgery on Outcomes in Patients Undergoing Outright Resection for Malignant Pleural Mesothelioma (Now Available) (ID 648)

      13:30 - 15:00  |  Presenting Author(s): Chi-Fu Jeffrey Jeffrey Yang  |  Author(s): Soraya Voigt, Vignesh Raman, Oliver K Jawitz, Thomas A D’amico, David Harpole

      • Abstract
      • Presentation
      • Slides

      Background

      We hypothesized that a longer interval to surgery would be associated with worse overall survival for patients with malignant pleural mesothelioma (MPM).

      Method

      The National Cancer Database (NCDB) for patients with cT1-3N0-1M0 MPM who underwent surgery without induction therapy. Patients with interval of <1 or >180 days were excluded. Patients were grouped into quartiles based on distribution of time intervals to surgery: Q1 (1-30 days), Q2 (31-50 days), Q3 (51-80 days), and Q4 (>80 days). The primary outcome was overall survival. Secondary outcomes were upstaging to pN2 and margin-positive (>R0) resection rate. Survival was estimated using the Kaplan-Meier and Cox Proportional Hazards methods. Nodal upstaging and >R0 resection rates were modeled with multivariable logistic regression.

      Result

      A total of 812 patients met study criteria. The median interval from diagnosis to surgery was 52 days. The unadjusted median survival for Q1, 2, 3, and 4 was 16, 19, 20, and 27 months, respectively (log-rank p=0.004). In multivariable analysis, increased time to surgery was not associated with worse overall survival (Table 1), and Q4 (>80 days) was independently associated with improved survival compared to Q1. When modeled as a continuous variable, an increased time to surgery was associated with a small but clinically insignificant increase in survival (AHR 0.997; 95%CI 0.995-0.999; p=0.005). In a multivariable regression of factors predicting pathologic upstaging to N2, increased time to surgery was significantly associated with upstaging (adjusted odds ratio [AOR] for Q4 compared to Q1: 2.26; 95%CI 1.04-5.28). In a separate regression of >R0 resection, an increased interval to surgery was not associated with margin-positive resection (AOR 0.70; 95%CI 0.41-1.21).

      Conclusion

      An increasing interval from diagnosis to definitive surgery for MPM was not associated with worse overall survival or margin-positive resection, but was associated with higher likelihood of pathologic nodal upstaging in this analysis.

      Variable

      Adjusted HR

      95% CI

      P value

      Interval (ref:Q1)

      Q2

      Q3

      Q4

      1.07

      0.96

      0.74

      0.84-1.36

      0.76-1.22

      0.58-0.95

      0.61

      0.75

      0.02

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      MA05.04 - Discussant - MA05.01, MA05.02, MA05.03 (Now Available) (ID 3733)

      13:30 - 15:00  |  Presenting Author(s): Clarissa Baldotto  |  Author(s):

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA05.05 - Post-Discontinuation Treatments in IFCT-GFPC-0701 MAPS Trial: Real-World Effectiveness of 2nd-Line (2L) Treatments for Mesothelioma (Now Available) (ID 815)

      13:30 - 15:00  |  Presenting Author(s): Gerard Zalcman  |  Author(s): Solene Brosseau, Julien Mazieres, Jacques Margery, Laurent Greillier, Clarisse Audigier-Valette, Denis Moro-Sibilot, Olivier Molinier, Romain Corre, Isabelle Monnet, Valérie Gounant, Frédéric Rivière, Radj Gervais, Henri Janicot, Chrystele Locher, Alexandra Langlais, Jean-Jacques Parienti, Franck Morin, Arnaud Scherpereel

      • Abstract
      • Presentation
      • Slides

      Background

      MAPS phase 3 trial assessing the addition of bevacizumab to pemetrexed-cisplatin doublet set a new standard of care in malignant pleural mesothelioma (MPM) patients, showing 18.8 months median overall survival (OS) with triplet combo. While both arms were well balanced in terms of 2L treatments, the size of the OS benefit from second-line treatments remains controversial.

      Method

      Long-term survival data were collected in the 342 MAPS patients alive at the end of the first-line (1L) treatments, in both arms. Median OS and 2-year survivals were calculated from the initiation of 2L. Multivariate analysis using Cox model included the stratification variables of the MAPS trial, along with the treatment arm (with or without bevacizumab).

      Result

      342/442(77.4%) patients received 2L treatment for disease progression after MAPS trial, of which 324 received chemotherapy (CT), 18 palliative radiotherapy (RT), while 100/442 (22.6%) remained untreated. 160/342 patients (46.8%) had a platinum-based doublet CT. 163 patients (47.7%) received a single-drug CT. 172/324 (53.1%) received a pemetrexed-containing regimen (alone or with platinum), 84 (25.9%) a gemcitabine-based CT, 16 (4.9%) vinorelbin alone, 48 (14.8%) gemcitabine alone, while in 12 (3.7%) single-agent bevacizumab was resumed. Median age was lower in patients with doublet CT (64.4 years, IQR 60.2-68.9) vs. single-drug CT patients (66.3 years, IQR 61.5-70.3), patients receiving RT (68.5 years, IQR 63.3-70.5) or untreated patients (67.8 years, IQR 63.4-71) (p=0.007). There were more PS=2 patients (10%) in the untreated group, compared with 0.6%, 1.8% and 5.6% in those receiving doublet, monotherapy or radiotherapy, respectively (p<0.001). A lower proportion of patients receiving 2L doublet CT had sarcomatoid/biphasic MPM (11.2%) compared with 21.5%, 38.9% and 25% in those with single-arm agent, RT or untreated, respectively (p=0.002). When compared with those treated with 2L single-agent, patients with 2L doublet had more frequently objective response (11.9 vs. 3.1%, p=0.005) and disease control (60.3 vs. 34.6%, p<0.0001). From the date of 2L therapy initiation, median OS was 3.2 months, 95%CI [1.7-5.0] for RT vs. 7.0 months 95%CI[5.6-7.8] for single-agent CT, or 12.2 months 95%CI [9.5-14.1] for doublet CT. HRs were adjusted for 1L treatment type (bevacizumab-containing or not), PS, smoking, and histology. Adj.HR (single-agent vs. doublet) was 1.21, 95% CI(0.96-1.53), p=0.11. Adj.HR (monotherapy vs. RT) was 0.39, 95%CI[0.24-0.65], p=0.0003. Adj.HR (combination CT vs. RT) was 0.32 95%CI[0.19-0.54], p<0.0001. 1-year OS was 11.8%, 95%CI [0.0-27.1], 48.7%, 95%CI [39.9-57.5], and 32.9%, 95%CI [25.1-40.6], in patients with RT alone, single agent CT or combination CT, while 2-year OS was 0%, 14.2%, and 20.0% respectively.

      Conclusion

      Second-line monotherapy only gave a 7-months median OS in MPM patients, comparing unfavorably to 11.9 and 15.9-months median OS with 2nd/3rd-line nivolumab or nivolumab+ipilimumab respectively, in the IFCT-1501 MAPS-2 randomized phase 2 trial. Conversely, 2L platinum-based chemo, in younger fit patients, still gave a 12.2-months median OS, not statistically different from monotherapy in the multivariate analysis, as a consequence of PS influence, although clinically meaningful. Based on these results, immunotherapy might be preferred for 2L/3L MPM patients, while monotherapy CT shows limited survival benefit.

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      MA05.07 - Efficacy and Safety of Re-Treatment with Tremelimumab and Durvalumab Within the NIBIT-MESO-1 Study (Now Available) (ID 1867)

      13:30 - 15:00  |  Presenting Author(s): Luana Calabro'  |  Author(s): Giulia Rossi, ALDO Morra, Anna Maria Di Giacomo, Giovanni Amato, Claudio Rosati, Ornella Cutaia, Maria Grazia Daffinà, Diana Giannarelli, MICHELE Maio

      • Abstract
      • Presentation
      • Slides

      Background

      Targeting immune-checkpoint inhibitors (ICI) had proven effective in a variety of tumor types. However, primary and secondary resistance to treatment is emerging as a major limitation of ICI therapy, and scattered information is available on the therapeutic efficacy of re-treatment in ICI-resistant subjects. Here we investigated the efficacy and safety of re-treatment with tremelimumab and durvalumab in malignant mesothelioma (MM) patients who developed resistance to these agents in the phase II NIBIT-MESO-1 study (Calabrò L et al, Lancet Resp Med 2018).

      Method

      Patients eligible for re-treatment per the NIBIT-MESO-1 protocol were those who completed 4 dosing cycles of tremelimumab combined with durvalumab, and achieved partial response (PR) or stable disease (SD), followed by progressive disease (PD) during the maintenance with durvalumab or the follow-up phase. Subjects who met the re-treatment criteria received tremelimumab (1 mg/Kg, i.v.) and durvalumab (20 mg/Kg, i.v.) every 4 weeks (Q4W) for 4 doses (re-induction phase), followed by durvalumab (20 mg/Kg, i.v.) Q4W for additional 9 doses (maintenance phase). Objective response rate (ORR), disease control rate (DCR), per immune-related (ir)-modified RECIST criteria, overall survival (OS), and safety were evaluated. Adverse events (AEs) were recorded according to CTC v4.0.

      Result

      Seventeen (42.5%) of the 40 MM patients enrolled in the NIBIT-MESO-1 study met the criteria for re-treatment and received therapy. Among them 8 (47%) completed the re-induction phase, 7 (41.2.%) went on maintenance phase, and 1 (5%) entered the follow-up phase. As of April 1st 2019, 16/17 patients were discontinued during re-treatment because of PD, and 7 received additional lines of therapy. Seven out of the 17 (41.2%) re-treated subjects had an irSD, while no ir-ORR were observed. At a median follow-up of 35.8 months, median OS of re-treated patients was significantly (p=0.005) higher (25.6 months, 95% CI: 6.1-45.1) as compared to the 23 subjects who were not re-treated (9.9 months, 95% CI: 7.7-12.1). Grade 1-2 irAEs occurred in 6/17 (35%) re-treated patients, were most frequently dermatological and reversible per protocol guideline; no grade 3-4 irAEs were observed.

      Conclusion

      Re-treatment with tremelimumab and durvalumab of MM patients who developed resistance to therapy in the course of the NIBIT-MESO-1 study is clinically effective and safe in a sizeable proportion of re-treated subjects.

      Clinical trial infomation: NCT02588131

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      MA05.08 - Discussant - MA05.05, MA05.06, MA05.07 (Now Available) (ID 3734)

      13:30 - 15:00  |  Presenting Author(s): James Spicer

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA05.09 - Real-World Data of Nivolumab and Pembrolizumab in Chemotherapy Pre-Treated Mesothelioma Patients (Now Available) (ID 1918)

      13:30 - 15:00  |  Presenting Author(s): Daphne Dumoulin  |  Author(s): Luca Cantini, Robert anton Belderbos, Darlene Mercieca, Robin Cornelissen, Joachim G.J.V. Aerts

      • Abstract
      • Presentation
      • Slides

      Background

      Both nivolumab and pembrolizumab have shown positive results in phase II studies in patients following chemotherapy in mesothelioma patients. However, these studies were done in a limited number of patients with strict inclusion criteria, while reports show a difference between real life and study setting.

      Method

      In our mesothelioma center, we treated patients that progressed during or after chemotherapy treatment with nivolumab 3mg/kg once every 2 weeks independent of PD-L1 expression or with pembrolizumab 200mg once every 3 weeks when PD-L1 expression was ³1%, both in Early Patient Access programs. All patients were pre-treated with at least one cycle of platinum/folate treatment. CT scan evaluation was done using modified RECIST every 6 weeks.

      Result

      In total, we treated 78 patients with nivolumab and 13 patients with pembrolizumab. Median age of the patients was 71 years (29-85) at start of the checkpoint inhibitor treatment, 80 (88%) were male. Performance status was ECOG 0 in 19 patients, ECOG 1 in 57 patients, ECOG 2 in 9 patients. Data analysis thus far showed 9 partial responses (10%) and 31 patients with stable disease (29%) and therefore a disease control rate of 39% at twelve weeks of treatment. Median progression free survival is 2.4 months and median overall survival 6,3 months. Median duration of response had not been reached yet. These data will be updated for the meeting. Two cases of pseudoprogression were seen on checkpoint inhibition therapy where progression according to modified RECIST was followed by response during continuation of PD-1 therapy. Toxicity was in line with historical data.

      Conclusion

      We believe that this large dataset, using real-world data, can truly give an insight in the clinical benefit of these immune checkpoint inhibitors. In comparison with the published phase I and II trials on nivolumab and pembrolizumab, the response rates appear to be lower in a real-life setting. However, clinically meaningful and durable responses are seen in a population that has no other proven therapy options.

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      MA05.10 - Pembrolizumab in the Treatment of Patients with Malignant Pleural Mesothelioma Following Progression After Initial Chemotherapy (Now Available) (ID 2788)

      13:30 - 15:00  |  Presenting Author(s): Keith Cengel  |  Author(s): Sharyn I Katz, Leonid Roshkovan, Sally McNulty, Jinjiang Lian, Daniel Aleynick, Melissa Jane Culligan, Joseph Friedberg, Sunil Singhal, Charles B. Simone, Li, Christine Ciunci, Melina E Marmarelis, Evan Alley, Corey Jay Langer

      • Abstract
      • Presentation
      • Slides

      Background

      Checkpoint inhibitor (CPI) therapies have demonstrated clinical benefit in patients (pts) with malignant pleural mesothelioma (MPM) and are now included in the NCCN guidelines as an acceptable treatment option. Herein, we report our initial experience treating pts with MPM in the palliative second line or greater setting.

      Method

      Between January 2016 and November 2018, 74 pts with biopsy proven MPM were treated with pembrolizumab every three weeks until confirmed disease progression or unacceptable toxicity. Progression-free survival (PFS) and OS were defined as the time from first pembrolizumab dose to recurrence and death, respectively, or to last contact. Response rates (RR) were measured by a dedicated thoracic radiologist using modified RECIST 1.1 criteria. Adverse events were routinely recorded/scored at each follow up visit. according to CTCAE 4.0 with level of attribution to pembrolizumab.

      Result

      Demographics of the 74 pt cohort are shown in table 1. Twently-nine (39%) of pts experienceda total of 39 grade 1-2 adverse events, possibly or definitely related to therapy (Table 2). There was one grade 4pneumonitis that resulted in new requirement for oxygen, which resolved with steroids; and one patient experienced leukoencephalopathy that resulted in death. The overall response rate (including only partial responses by modified RECIST 1.1) for the entire cohort was 26%. Median progression free survival and overall survival for the entire cohort were 2.8 months and 7.9 months, respectively.

      Table 2: Adverse Events

      CTCAE 4.0 Grade

      AE Description

      1-2

      3-4

      5

      hypothroid

      5

      arthralgias

      8

      colitis

      3

      diarrhea

      2

      lip lesion

      1

      pneumonitis

      2

      1

      SICCA syndrome

      1

      thrombocytopenia

      1

      dermatitis

      1

      hypopigmentation

      1

      nephritis

      1

      fatigue

      1

      abdominal pain

      1

      uveitis

      1

      transaminitis

      1

      elvated alk phos

      1

      leukoencephalopathy

      1

      pruritis

      3

      hypercalcemia

      3

      rash

      2

      Table 1: Demographics

      Age in Years

      median (range)

      Min

      73

      (52-92)

      Gender

      Patients (N=74)

      Female

      29

      39%

      Male

      55

      74%

      Histology

      Epithelial

      58

      78%

      Sarcomatoid

      6

      8%

      Biphasic

      10

      14%

      # of chemotherapy courses

      0

      3

      4%

      1

      42

      57%

      2

      22

      30%

      3-4

      7

      9%

      # of radiotherapy courses

      0

      42

      57%

      1

      30

      41%

      2-3

      6

      8%

      Surgical Resection

      Have EPD

      24

      32%

      Did not have EPD

      50

      68%

      PDL1

      Negative

      21

      28%

      Positive

      12

      16%

      Not Determined

      42

      57%

      Conclusion

      Pembrolizumab in the Tx of MPM was reasonably well tolerated in this large, single institution experience. RR, PFS and OS appear remarkably similar to recent published data from a registry study of off-label use of pembrolizumab in pts with MPM in Switzerland and Australia (include reference). Ongoing studies include analysis of PDL-1 and other potential immunotherapy response biomarkers.

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      MA05.11 - Safety and Efficacy of Nintedanib in Combination with Pembrolizumab in Patients with Refractory/Relapsing Malignant Pleural Mesothelioma (Now Available) (ID 2170)

      13:30 - 15:00  |  Presenting Author(s): Andreea Varga  |  Author(s): Gerard Zalcman, Carlos Gomez-Roca, Samy Ammari, CAROLINE Caramella, Valérie Gounant, Audrey Rabeau, Xavier Paoletti, Capucine Baldini, Patricia Martin-Romano, Stephane Champiat, Perrine Vuagnat, Jean-Marie Michot, Laura Mezquita, Christophe Massard, Benjamin Besse, Jean Charles Soria, Aurelien Marabelle, David Planchard

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is an aggressive disease with no standard of care after progression to first line pemetrexed and platinum-based chemotherapy. Combinations between anti-angiogenic agents and immunotherapy are being developed as angiogenesis and immunosuppression influence each other leading to a more powerful anti-tumor response. Both Nintedanib and Pembrolizumab have been investigated as single agents or in different treatment combinations in MPM patients with interesting activity.

      Method

      The PEMBIB trial is a multi-centric open-label non-randomized basket phase 1 trial evaluating the combination of nintedanib with pembrolizumab in multiple tumor types. The safety and activity of the dose escalation part of the study were reported at AACR & ASCO meetings in 2018 with an established DLT defined as grade 3 alanine and/or aspartate aminotransferase elevation (ALT/AST). The recommended phase 2 dose is set at 150 mg BID of nintedanib with 200 mg flat dose of pembrolizumab. We would like to report the safety and activity of one of the expansion cohorts of patients with relapsing/refractory MPM which has now been completed. Eligible MPM patients were 18 years or older with an ECOG performance status of 0 or 1, histologically proven MPM that relapsed after at least one line of pemetrexed and platinum-based combination, specific anti-angiogenic eligibility criteria such as no radiographic evidence of cavitary/necrotic or tumors with local invasion of major blood vessels.

      Updated results on the safety profile and efficacy of this anti-angiogenic and anti-PD-1 combination therapy including overall response rate as per RECIST, irRC and mRECIST criteria, disease control rate will be presented at the meeting.

      Result

      The first patient from the MPM cohort was enrolled in July 2017 and the last one in April 2019. Thirty-one eligible MPM patients have been evaluable at the data cut off onJuly 2019, one of them had been enrolled since the dose-escalation part at dose level of 200mg. The age at inclusion was 68 (ranging from 38 to 85), 68% of the patients having an ECOG of 1 and 58% of the histological type was epithelioid. The most frequent adverse events (grades 1, 2 and 3) related to any of the combination drugs were liver enzymes increase, fatigue, decreased appetite, nausea, diarrhea and hypothyroidism. There were two cases of myocarditis, one of grade 3 (pembrolizumab related) and one of grade 5(pembrolizumab and nintedanib related). At the time of the data analysis the efficacy data shows six partial responses (overall response rate of 21%) and seventeen stable disease (disease control rate at 61%.).

      Conclusion

      The combination of Nintedanib with Pembrolizumab shows promising activity in relapsed MPM patients .The toxicity profile appear consistent with previous reports of anti-angiogenic agents and immunotherapy combination.

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      MA05.12 - Discussant - MA05.09, MA05.10, MA05.11 (Now Available) (ID 3735)

      13:30 - 15:00  |  Presenting Author(s): Anna K Nowak

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA09 - EGFR & MET (ID 128)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Targeted Therapy
    • Presentations: 12
    • Now Available
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      MA09.01 - A Phase I/II Trial of Dasatinib and Osimertinib in TKI Naïve Patients with Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2710)

      15:15 - 16:45  |  Presenting Author(s): Chul Kim  |  Author(s): Stephen V. Liu, Jeanette Crawford, Deepa S Subramaniam, Guiseppe Giaccone

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy is the standard of care in patients with EGFR-mutant NSCLC. However, a fraction of patients do not respond to EGFR-TKI therapy or have short duration of response. In addition, virtually all patients develop resistance. In a preclinical study, we have shown that overexpression of Cripto-1, a member of the EGF–CFC family, contributes to the development of resistance to EGFR-TKI therapy through the Src pathway and that the combination of EGFR-TKI therapy and Src inhibition works synergistically.

      Method

      This is an open-label, single-arm phase I/II trial of osimertinib and dasatinib, a Src inhibitor, in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02954523). Patients with pleural or pericardial effusions were excluded. The primary endpoint of the phase I portion was to establish a safe and tolerable phase II dose of osimertinib and dasatinib. Dose escalation includes 2 dose levels (DLs) (DL1: osimertinib 80 mg QD, dasatinib 50 mg BID, DL2: osimertinib 80 mg QD, dasatinib 70 mg BID). 2 DLs below the starting dose level (DL-1: osimertinib 80 mg QD, dasatinib 70 mg QD; DL-2: osimertinib 80 mg QD, dasatinib 50 mg QD) could be explored if necessary. Adverse events (AEs) were assessed per CTCAE 4.03.

      Result

      10 patients (DL2: 3, DL1: 6, DL -1: 1) were enrolled. None of the patients enrolled at DL2 had dose limiting toxicities (DLTs) but given the frequent dose reductions required and toxicities beyond the DLT period, DL1 was further assessed. 3 (50%) of 6 patients at DL1 experienced a DLT (grade 3 headaches and body pain, grade 3 neutropenia, grade 3 rash, one each). One patient was enrolled at DL -1 and did not have a DLT. The most common treatment-related adverse events (TRAEs) included pleural effusion (n=9), diarrhea (n=8), rash (n=7), AST elevation (n=6), ALT elevation (n=6), most of which were grade 1 or 2. 4/4/1 patients had grade 1/2/3 pleural effusion, respectively. 7 (70%) patients had grade 3 TRAEs. No grade 4 or 5 toxicities were observed. Eight (80%) patients had a partial response (including 1 unconfirmed partial response) and 2 had stable disease. Median PFS was 27.2 months; median OS was not reached. The recommended phase II dose was determined as osimertinib 80 mg QD and dasatinib 70 mg QD. Pharmacokinetics (PK) analysis is being performed and will be presented. Due to slow accrual after approval of osimertinib in first-line, the trial was closed to enrollment.

      Conclusion

      The combination of dasatinib and osimertinib demonstrated encouraging anticancer activity. Median PFS is longer than what is historically reported with osimertinib alone in first-line setting, although definitive conclusions cannot be drawn given the small sample size. The tolerability of the combination was limited by TRAEs, but they were generally manageable with dasatinib dose reductions and supportive measures.

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      MA09.02 - In Vivo, Ex Vivo and Early Clinical Activity of EGFR Monoclonal Antibody and Osimertinib in EGFR Exon 20 Insertion NSCLC (Now Available) (ID 968)

      15:15 - 16:45  |  Presenting Author(s): Jonathan Wesley Riess  |  Author(s): Nicolas Floch, Philip C. Mack, Matthew J. Martin, Daniel Vang, Paul D. Smith, Darren Cross, Mingshan Cheng, James Keck, Susan Groshen, Michael Rabin, Sukhmani Padda, Geoffrey R Oxnard, Jacob Sands, Kavitha Ramchandran, Mariana Koczywas, Jeffrey A. Moscow, Pasi A Jänne, Primo N. Lara, Edward Newman, David R Gandara

      • Abstract
      • Presentation
      • Slides

      Background

      EGFR Exon 20 insertions (Ex20Ins) are the 3rd most common class of EGFR activating mutation, but patients with NSCLC harboring EGFR Ex20Ins lack effective approved EGFR-TKIs. Newer-generation TKIs and combination strategies with EGFR-monoclonal antibodies (moAbs) may enhance activity against EGFR Ex20Ins.

      Method

      Xenografts derived from CRISPR-modified H2073 cells with Ex20Ins (A763_Y764InsFQEA, D770_N771InsSVD or V769_D770InsASV) and Ex20Ins patient-derived xenografts (PDXs) (D770_N771InsSVD, A797_V769dupASV, D770_N771_InsG, H773_V774_InsNPH) were treated with vehicle, osimertinib , cetuximab, and osimertinib+cetuximab. Ex20Ins spheroid models (D770_N771InsSVD and M766_A767InsASV) were treated with cetuximab at fixed dose and increasing concentrations of osimertinib. Ex20Ins PDX (A763_Y764InsFQEA) was also treated with afatinib and erlotinib; Ex20Ins PDX (D770_N771InsSVD) was treated with these combinations plus afatinib+cetuximab. Immunoblotting for pharmacodynamic studies of on-target and downstream proteins, phospho-proteins and apoptosis markers were performed at relevant timepoints for D770_N771InsSVD PDX and CRISPR model. A phase 1 clinical trial with a dose expansion cohort in Stage IV EGFR Ex20Ins NSCLC is currently open to accrual at osimertinib 80 mg qd and the EGFR-moAb necitumumab 800 mg IV D1 and D8 of 21D cycle with response assessment by RECIST 1.1 (NCT02496663).

      Result

      The combination of osimertinib and cetuximab achieved significant tumor growth inhibition compared to osimertinib alone across PDX and CRISPR cell line xenograft models (p=0.05), except for the A763_Y764InsFQEA PDX model where osimertinib alone and osimertinib+cetuximab were equivalently effective (both p<0.001 compared to control). Spheroid models for D770_N771InsSVD and M766_A767InsASV showed significantly increased cytotoxicity from the addition of cetuximab across multiple doses of osimertinib. Osimertinib+cetuximab was superior to erlotinib, cetuximab, afatinib and afatinib+cetuximab in a D770_N771InsSVD PDX model (p<0.001). In this model, inhibition of p-EGFR, p-ERK, p-HER2 and increased caspase 3 cleavage were noted, consistent with significant tumor growth inhibition. In the phase 1 EGFR Ex20Ins expansion cohort of necitumumab in combination with osimertinib, 6/18 patients enrolled with 4 patients evaluable for response; 2 patients achieved a partial response and median PFS was 5.3 months.

      Conclusion

      In vivo and ex vivo modeling in CRISPR cell line xenografts, PDXs and organoids demonstrated preclinical activity of dual EGFR blockade with osimertinib and EGFR monoclonal antibody in the 5 most common EGFR Ex20Ins representing a frequency of ~60% of detectable EGFR Ex20Ins in clinical practice. Osimertinib alone was as active as osimertinib plus cetuximab in A763_Y764InsFQEA, consistent with known sensitivity of this proximal insertion to single-agent EGFR-TKI. In a phase 1 study, osimertinib and the EGFR moAb necitumumab demonstrates preliminary clinically activity in EGFR Ex20Ins NSCLC.

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      MA09.03 - Identification of Mechanisms of Acquired Resistance to Poziotinib in EGFR Exon 20 Mutant Non-Small Cell Lung Cancer (NSCLC) (Now Available) (ID 2904)

      15:15 - 16:45  |  Presenting Author(s): Jacqulyne Ponville Robichaux  |  Author(s): Yasir Elamin, Brett Carter, Mehmet Altan, Don Lynn Gibbons, Frank Fossella, George R Simon, Vincent Lam, George Blumenschein Jr, Anne Tsao, Jonathan Kurie, Frank E Mott, Marcelo Vailati Negrao, Limei Hu, Junqin He, Monique Nilsson, Brent Roeck, Zane Yang, Vassiliki A Papadimitrakopoulou, John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      Insertions/mutations in exon 20 of EGFR occur in ~2% Insertions/mutations in exon 20 of EGFR occur in ~2% of all lung adenocarcinomas. These alterations are characterized by primary resistance to approved tyrosine kinase inhibitors (TKIs) with response rates of <12%. We have shown that exon 20 insertions restrict the size of the drug-binding pocket, limiting binding of large inhibitors. However, poziotinib can circumvent these steric changes and is a potent inhibitor of EGFR exon 20 mutants. In our investigator-initiated phase 2 trial of EGFR exon 20 mutant NSCLC, poziotinib was associated with a best objective response rate of 55% (Heymach et al, 19th WCLC). Herein, we use preclinical models and clinical samples from our phase 2 study to identify mechanisms of acquired poziotinib resistance (NCT03066206).

      Method

      EGFR exon 20 insertion (D770insNPG) genetically engineered mice (GEM) were treated with poziotinib until progression. Upon progression, tumor DNA and protein were analyzed using whole exome sequencing (WES) and reverse phase protein assay (RPPA). Mandatory and optional biopsies were obtained at baseline and progression, respectively, from patients treated in our phase 2 trial of poziotinib in EGFR exon 20 mutant NSCLC. Serial cfDNA was collected at baseline, 8 weeks of therapy, and on progression. Patient samples were analyzed using targeted next generation sequencing or WES.

      Result

      Poziotinib acquired-resistance GEM tumors acquired mutations in ErbB4, KRAS, and other genes which represent potential targetable bypass pathways. Resistant GEM tumors displayed increased activation of MAPK, AKT, ERK and MEK compared to sensitive tumors, suggesting that poziotinib acquired resistance is associated with reactivation of the MAPK/PI3K pathways. We enrolled 50 EGFR exon 20 mutant patients in our phase 2 trial. Analysis of matched pre-poziotinib and on-progression samples from 20 responding patients revealed acquired EGFR tyrosine kinase domain point mutations in 4 patients (T790M (2), V774A (1), D770A, (1)). Ba/F3 cells co-expressing EGFR exon 20 insertion (S768supSVD) and T790M were resistant to poziotinib, suggesting that T790M is a poziotinib resistance driver. Potential acquired EGFR-independent resistance mechanisms identified in patients to date include PIK3CA E545K (1), MAP2K2 S94L (1), MET amplification (1), EGFR amplification (2), and CDK6 amplification (2).

      Conclusion

      Parallel to acquired resistance mechanisms seen in classical EGFR mutation, acquired resistance to poziotinib can be mediated through EGFR-dependent mechanisms, notably T790M and other EGFR tyrosine kinase domain point mutations. EGFR-independent resistance mechanisms include activation of bypass pathways. Preclinical validation of resistance mechanisms and additional analysis of patient samples will be presented at the meeting.

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      MA09.04 - Discussant - MA09.01, MA09.02, MA09.03 (Now Available) (ID 3747)

      15:15 - 16:45  |  Presenting Author(s): Juergen Wolf

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA09.05 - Genomic Correlates of Differential Response to EGFR-Directed Tyrosine Kinase Inhibitors (Now Available) (ID 1169)

      15:15 - 16:45  |  Presenting Author(s): Natalie Vokes  |  Author(s): Tom Nguyen, Christine A Lydon, Emily Chambers, Lynette M Sholl, Mizuki Nishino, Eliezer M Van Allen, Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Background

      Oncogenic mutations in EGFR are powerful biomarkers of response to EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). However, there remains significant heterogeneity in duration of response to therapy and overall survival, and the molecular determinants of this differential response have been incompletely characterized.

      Method

      We identified NSCLC patients at our institution with sensitizing oncogenic EGFR mutations who had been treated with EGFR TKI(s) and who had at least one tumor specimen profiled via targeted next generation sequencing (OncoPanel). Duration of therapy (DOT) on first-line EGFR TKI and overall survival (OS) were assessed. Mutations associated with differential benefit to therapy were identified by comparing mutation rates in outliers with DOT or OS ≥75th percentile vs ≤25th percentile. Fisher’s exact test was used to calculate statistical significance, and the Benjamini-Hochberg method was used to correct for false discovery rate (FDR). Time to event outcomes were assessed with the Kaplan-Meier method.

      Result

      We identified 270 patients for inclusion in our cohort. 70% were female (190/270), 60% were never smokers (163/270), and median age was 62 (range 29-93). Sensitizing EGFR mutations were predominantly exon 19 deletion (51%, 138/270) or L858R (38%, 103/270). 94% of patients were treated with first-line erlotinib (253/270), and 30% received second-line osimertinib (82/270). The median DOT on first-line TKI was 12 months (range 0-72 months) and median OS was 28 months (range 1-133 months). Pre-treatment sequencing was available for 188 patients, 65 of whom also had documented assessment of resistance mechanism (T790M 78%, other 22%). Pre-existing concurrent TP53 mutations were associated with shorter DOT (median 10 vs 16 mo, p=0.0017), but there was no significant difference in OS (median 25 vs 36 mo, p=0.2) and no association with resistance mechanism (p=0.674). In addition to TP53, BCOR and SMARCA4 mutations were enriched in patients with shorter DOT, whereas MTOR mutations were enriched in patients with DOT in the top quartile, though these analyses did not pass FDR correction. Pre-treatment SMARCA4 mutations were more frequent in patients with survival in the bottom quartile (Fisher’s p=0.01), and were associated with decreased OS (median 32 vs 12 mo, log-rank p<0.0001).

      Conclusion

      Genomic features may contribute to differential outcomes in patients with EGFR-mutated NSCLC. In addition to TP53 mutations, pre-treatment SMARCA4 mutations may associate with worse outcomes in these patients.

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      MA09.06 - Adaptive Mechanisms of Resistance to Targeted Therapy in EGFR Mutant Brain Metastasis (Now Available) (ID 1329)

      15:15 - 16:45  |  Presenting Author(s): Don X. Nguyen  |  Author(s): Sally Adua, Minghui Zhao, Darren Cross, Paul Smith

      • Abstract
      • Presentation
      • Slides

      Background

      A subset of non-small cell lung cancers (NSCLCs) can be effectively treated with EGFR tyrosine kinase inhibitors (TKIs). However, a significant proportion of patients with brain metastasis progress after front-line treatment, underscoring the central nervous system (CNS) as a unique sanctuary site for persistent disease. Herein, we performed an integrated examination of the cellular, pharmacological, and molecular causes of resistance to targeted therapies in brain metastases.

      Method

      The efficacy of osimertinib, a brain penetrant third generation TKI, was studied in mice using EGFR mutant NSCLC models derived from cell lines or patient biopsies. Animals with multi-organ metastases were treated continuously until disease progression was detected in the brain parenchyma. We also developed an in situ transcriptomic approach, referred to as Brain Metastasis Xenograft-RNA Sequencing (BMX-seq), to distinguish the transcriptome of tumor versus stroma in vivo. Molecular and biological responses were integrated with pharmacological analysis of loco-regional distribution of osimertinib in and around brain lesions.

      Result

      In EGFR mutant models with multi-organ metastases, extra-cranial tumors could be effectively controlled, while brain metastases eventually progress despite strong osimertinib penetrance into the normal and tumor bearing CNS. Importantly, tumor cells isolated from progressing brain metastases did not exhibit resistance in vitro. However, these cells exhibited an enhanced resistant capacity when transplanted into the brain, demonstrating that this resistant phenotype is selected for and that exposure to the brain is a requirement for drug resistance in vivo.

      BMX-seq reveals that the stroma of drug resistant brain metastasis is characterized by activation of innate pro-inflammatory pathways. Reciprocally, we identified stromal induced activation of cytoskeletal and interferon response genes in drug resistant tumor cells. Interestingly, several of these genes are induced in situ independently of drug treatment, suggesting that the brain metastatic niche can precondition tumor cells for ensuing drug resistance. Finally, we demonstrate that inhibiting mediators of interferon and cystoskeletal signaling increases the sensitivity of brain metastasis to osimertinib in vivo.

      Conclusion

      Although advances have been made in the brain penetrating abilities of targeted therapies, acquired resistance in this unique TME still develops. Our results suggest that adaptive molecular interactions within the brain TME preconditions metastatic cells for TKI resistance and that targeting such pathways in combination with osimertinib should be explored to treat NSCLC patients suffering from or at risk for brain relapse.

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      MA09.07 - Activity of Larotrectinib in TRK Fusion Lung Cancer (Now Available) (ID 1600)

      15:15 - 16:45  |  Presenting Author(s): Anna F Farago  |  Author(s): Shivaani Kummar, Victor Moreno, Jyoti D Patel, Ulrik Lassen, Lee Rosen, Nora C. Ku, Michael C. Cox, Shivani Nanda, Barrett H. Childs, David M. Hyman, Alexander Drilon

      • Abstract
      • Presentation
      • Slides

      Background

      Tropomyosin receptor kinase (TRK) fusions involving NTRK1, NTRK2, and NTRK3 occur in a range of tumor types. Larotrectinib, the first FDA-approved highly selective TRK inhibitor, has demonstrated an overall response rate (ORR) of 75% by independent central review across a broad spectrum of tumors that harbor NTRK gene fusions (Drilon et al., NEJM 2018;378:731–9). Here, we report updated data on the patients with lung cancer who have been treated with larotrectinib.

      Method

      Patients with non-small cell lung cancer (NSCLC) in two clinical trials (NCT02122913 and NCT02576431) with TRK fusion cancer were included in this analysis. Larotrectinib (100 mg BID) was administered on a continuous 28-day schedule until withdrawal, unacceptable toxicity, or disease progression. Response was assessed by investigator (INV) and independent review committee (IRC) per RECIST v1.1.

      Result

      As of July 30, 2018, 11 patients with metastatic lung adenocarcinoma were enrolled. Median age was 52 years (range 25–76 years). Eight patients had fusions involving NTRK1 and diverse fusion partners: EPS15 (n=2), TPM3 (n=2), IRF2BP2 (n=2), TPR (n=1), and SQSTM1 (n=1). Three patients had fusions involving NTRK3 (fusion partner: SQSTM1 [n=2] and ETV6 [n=1]). Ten patients had prior systemic therapy (five patients had three or more prior therapies) with best responses on last prior therapy being one partial response, four with stable disease, three progressive disease, and three unknown or unevaluable. Seven patients were evaluable for response to larotrectinib. INV and IRC assessment were in agreement, with one complete response, four partial responses (including one patient with central nervous system [CNS] metastases), and two with stable disease (ORR 71%). Results from four patients not evaluable at the July 30, 2018 data cut-off due to insufficient follow-up are expected in April 2019 and will be presented at the meeting. The median time to response was 1.8 months. One patient with brain metastases had an intracranial near complete response (–95% reduction) to larotrectinib, as well as an extracranial response. The duration of response by IRC ranged from 7.4+ months to 25.8+ months; the median duration of response was not reached. One patient continued receiving treatment post-progression. Two patients discontinued treatment due to disease progression and one withdrew without cause. Larotrectinib was well tolerated, with treatment-related adverse events being predominantly grade 1–2.

      Conclusion

      Larotrectinib is highly active in advanced lung cancer patients harboring NTRK gene fusions, including those with CNS metastases, with a favorable safety profile. These results support the use of larotrectinib in NTRK fusion NSCLC.

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      MA09.08 - Discussant - MA09.05, MA09.06, MA09.07 (Now Available) (ID 3748)

      15:15 - 16:45  |  Presenting Author(s): Ana Vivancos

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA09.09 - Long-Term Outcomes to Tepotinib Plus Gefitinib in Patients with <i>EGFR</i>-Mutant NSCLC and MET Dysregulation: 18‑Month Follow-Up (Now Available) (ID 1783)

      15:15 - 16:45  |  Presenting Author(s): Yi-Long Wu  |  Author(s): Ying Cheng, Jianying Zhou, Shun Lu, Yiping Zhang, Jun Zhao, Dong-Wan Kim, Ross Soo, Sang-we Kim, Hongming Pan, Yuh-Min Chen, Chih-Feng Chian, Xiaoqing Liu, Daniel SW Tan, Rolf Bruns, Josef Straub, Andreas Johne, Jürgen Scheele, Keunchil Park, James Chih-Hsin Yang

      • Abstract
      • Presentation
      • Slides

      Background

      In EGFR-mutant NSCLC, MET amplification may cause resistance to EGFR tyrosine kinase inhibitors (TKIs). In a Phase Ib/II study in EGFR TKI-resistant patients with EGFR-mutant MET+ NSCLC, progression-free survival (PFS) and objective response rate (ORR) after ≥6 months of follow-up were improved with tepotinib (a highly selective MET TKI) plus gefitinib, compared with chemotherapy, particularly in patients with MET amplification. Here we present data at ≥18 months of follow-up.

      Method

      Asian patients with advanced, EGFR+, T790M-, MET+ NSCLC with resistance to prior EGFR TKIs were randomized to receive oral tepotinib 500 mg/day+gefitinib 250 mg/day or ≤6 cycles of cisplatin/carboplatin+pemetrexed chemotherapy±pemetrexed maintenance until confirmed progression, unacceptable toxicity, or withdrawal. Primary endpoint was investigator-assessed PFS. Secondary endpoints included ORR, overall survival (OS) and safety. Subgroup analyses were preplanned in MET IHC3+ and MET amplification populations (NCT01982955).

      Result

      Low recruitment halted full enrolment with 55 of 156 planned patients enrolled.

      As of 12-Dec-2018, median (range) duration of treatment with tepotinib+gefitinib was 21.4 (4.6, 110.9) weeks, with 3 patients still receiving treatment; and with pemetrexed was 18.0 (3.0, 60.4) weeks. 15 patients (62.5%) received ≥4 cisplatin/carboplatin cycles.

      Better outcomes were reported with tepotinib+gefitinib vs chemotherapy (Table), particularly in patients with MET IHC3+ (PFS: HR 0.35 [90% CI 0.17–0.74], OS: 0.32 [0.14–0.75]) or MET amplification (PFS: HR 0.13 [90% CI 0.04–0.43], OS: 0.08 [0.01–0.51]).

      Drug-related grade ≥3 adverse events (AEs) occurred in 17 (54.8%) patients receiving tepotinib+gefitinib and 12 (52.2%) patients receiving chemotherapy. Any-cause AEs leading to discontinuation occurred in 3 (9.7%) patients receiving tepotinib+gefitinib and 1 (4.3%) receiving chemotherapy. Dose reductions due to AEs were reported in 5 (16.1%) vs 4 (17.4%) patients.

      Conclusion

      Tepotinib+gefitinib has durable antitumor activity in patients with EGFR-mutant NSCLC with MET IHC3+ or MET amplification, and was generally well tolerated. MET amplification will be further explored as a biomarker for tepotinib.

      Table: Summary of efficacy data

      Population

      Tepotinib + gefitinib

      Chemotherapy

      HR/OR
      (90% CI)

      Overall MET+*

      Patients, n

      31

      24

      mPFS, months (90% CI)

      4.9 (3.9, 6.9)

      4.4 (4.2, 6.8)

      0.67 (0.35, 1.28)

      mOS, months (90% CI)

      17.3 (12.1, 37.3)

      18.7 (15.9, 20.7)

      0.67 (0.33, 1.37)

      ORR, n (%) [90% CI]

      14 (45.2) [29.7, 61.3]

      8 (33.3) [17.8, 52.1]

      1.99 (0.56, 6.87)

      MET IHC3+

      Patients, n

      19

      15

      mPFS, months (90% CI)

      8.3 (4.1, 21.2)

      4.4 (4.1, 6.8)

      0.35 (0.17, 0.74)

      mOS, months (90% CI)

      37.3 (24.2, 37.3)

      17.9 (12.0, 20.7)

      0.32 (0.14, 0.78)

      ORR, n (%) [90% CI]

      13 (68.4) [47.0, 85.3]

      5 (33.3) [14.2, 57.7]

      4.33 (1.03, 18.33)

      MET amplification

      Patients, n

      12

      7

      mPFS, months (90% CI)

      21.2 (8.3, NE)

      4.2 (1.4, 7.0)

      0.13 (0.04, 0.43)

      mOS, months (90% CI)

      37.3 (NE, NE)

      13.1 (3.3, NE)

      0.08 (0.01, 0.51)

      ORR, n (%) [90% CI]

      8 (66.7) [39.1, 87.7]

      3 (42.9) [12.9, 77.5]

      2.67 (0.37, 19.56)

      CEP-7, centromere protein 7; CI, confidence interval; EGFR, epidermal growth factor receptor; GCN, gene copy number; HR, hazard ratio; IHC, immunohistochemistry; IRC, independent review committee; ITT, intention to treat; MET, mesenchymal-epithelial transition factor; NE, not estimable; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival

      All efficacy outcomes are investigator-assessed by RECIST v1.1.

      *IHC2+/IHC3+/gene amplification.

      MET amplification is defined as GCN ≥5 and/or MET/CEP-7 ratio ≥2. 17 of 19 patients with MET amplification have MET overexpression (IHC3+).

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      MA09.10 - Comprehensive Analysis of Secondary Mutation as Resistance Mechanism to Seven MET-TKIs for MET Exon 14 Skipping in Vitro (Now Available) (ID 117)

      15:15 - 16:45  |  Presenting Author(s): Toshio Fujino  |  Author(s): Yoshihisa Kobayashi, Kenichi Suda, Takamasa Koga, Masaya Nishino, Shuta Ohara, Masato Chiba, Akira Hamada, Toshiki Takemoto, Junichi Soh, Tetsuya Misudomi

      • Abstract
      • Presentation
      • Slides

      Background

      MET exon 14 skipping mutation have been attracting attentions of thoracic oncologists as a new target of therapy for lung cancer. The efficacy of MET-TKI has been reported, while these tumors, almost always acquire resistance, as in the case of other oncogene-addicted lung cancers. However, its resistance mechanisms are not fully understood.

      Method

      MET exon14 skipping mutation was introduced to Ba/F3 cell retrovirally. Using N-ethyl-N-nitrosourea mutagenesis, we derived resistant clones to seven MET-TKIs and searched for secondary MET mutations. We evaluated their sensitivities to following different TKIs. Type Ia, crizotinib; Type Ib, capmatinib, tepotinib and savolitinib; Type II, cabozantinib, merestinib and glesatinib.

      Result

      We sequenced 201 resistant clones and could obtain 80 clones which had secondary mutations in the MET tyrosine kinase domain. A total of 26 different missense mutations occurring at 12 codons were identified. Of them, D1228 and Y1230 in the activation loop were common sites for type I TKIs that bind to active kinase form (DFG-in), while L1195 and F1200 were those for type II TKIs that bind to inactive form (DFG-out). In general, resistant mutations against type I were sensitive to type II, and vice versa.

      figure.png

      Conclusion

      We identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 skipping.

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      MA09.11 - Mechanisms of Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14 Mutant Non-Small Cell Lung Cancer (Now Available) (ID 1421)

      15:15 - 16:45  |  Presenting Author(s): Gonzalo Recondo Jr.  |  Author(s): Magda Bahcall, Lynette M Sholl, Giulia Constanza Leonardi, Biagio Ricciuti, Tom Nguyen, Deepti Venkatraman, Giuseppe Lamberti, Renato Umeton, Pasi A Jänne, Mark Awad

      • Abstract
      • Presentation
      • Slides

      Background

      Type I and II MET tyrosine kinase inhibitors (TKIs) are under development for patients with MET exon 14 mutant non-small cell lung cancer (NSCLC). Understanding the mechanisms driving resistance to MET TKIs is critical to design novel treatment strategies for this molecular subtype of NSCLC.

      Method

      Among patients with MET exon 14 mutant NSCLC treated with MET TKIs, pre- and post-TKI tumor tissue specimens and plasma samples were analyzed using next-generation sequencing (NGS) to explore genomic mechanisms of resistance upon disease progression.

      Result

      Between April 2014 to March 2019, 38 patients were treated with MET TKIs. Among these, paired samples from 15 individuals were evaluable for this study. Patients were treated with MET TKIs in the first-line (N=7; 46.7%), second-line (N=5; 33.3%), third-line (N=1; 6.7%) and fourth-line (N=2: 13.3%) setting. Eight patients were treated with one type I MET TKI and 7 patients received ≥2 MET TKIs. On target mechanisms of resistance were identified in 5 patients (33.3%), through secondary mutations in the MET tyrosine kinase domain (N=4) and MET amplification (N=1). Single MET kinase domain mutations D1228H/N were detected in 2 patients progressing on treatment with a type I MET TKI. In two cases, tumor tissue revealed only one resistance mutation (case #1 with Y1230H; case #2 with H1094Y), whereas paired plasma analysis demonstrated ≥3 resistance mutations in ctDNA (case #1 with G1163R, D1228N, Y1230H/S; case #2 with H1094Y, L1195F/V), reflecting the emergence of polyclonal on-target resistance. Off-target mechanisms of acquired resistance were identified in 7 patients treated with Type I MET TKI (46.7%) and involved amplification of EGFR (N=2), EGFR/HER2 (N=1), EGFR/HER3 (N=1), KRAS (N=1), EGFR/KRAS/BRAF (N=1), CCND1 (N=1). In 2 cases with bypass activation, sequential treatment with type II MET TKIs did not confer benefit. A concurrent NF1 mutation was present at baseline in a patient with primary resistance to MET TKI (6.7%). In 2 patients (13.3%), no genomic mechanisms of resistance were identified.

      Conclusion

      The landscape of resistance mechanisms to MET TKIs in NSCLC includes single and polyclonal secondary kinase domain mutations and bypass track activation by amplification of key oncogenes involving the ErbB/HER family of tyrosine kinase receptors and the MAPK signaling pathway. Given the complexity of resistance, therapeutic efforts to prevent acquired resistance in MET exon 14 mutant NSCLC should be developed.

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      MA09.12 - Discussant - MA09.09, MA09.010, MA09.11 (Now Available) (ID 3749)

      15:15 - 16:45  |  Presenting Author(s): Ravi Salgia

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 12
    • Now Available
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      MA12.01 - Redefining Malignant Pleural Mesothelioma Types as a Continuum Uncovers Immune-Vascular Interactions (Now Available) (ID 1773)

      14:00 - 15:30  |  Presenting Author(s): Matthieu Foll  |  Author(s): Nicolas Alcala, Lise Mangiante, Nolwenn Le Stang, Corinne Gustafson, Sandrine Boyault, Francesca Damiola, Karine Alcala, Julien Mazieres, Jean-Yves Blay, Sylvie Lantuejoul, Raphael Bueno, Christopher Caux, Nicolas Girard, James McKay, Francoise Galateau Sallé, Lynnette Fernandez-Cuesta

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a deadly disease. The current histopathologycal classification recognises three major types (epithelioid, biphasic, and sarcomatoid) with different prognosis, but showes high interobserver variability. This classification also has a role in the clinical decision-making although, ultimately, MPM becomes refractory to all conventional treatment modalities, and alternative therapeutic options have been evaluated with limited success.

      Method

      We have performed unsupervised analyses of publicly available RNA-seq data of 284 MPM tumours1,2 with no assumption of discreteness. We have performed an orthogonal validation in a subset of 187 samples, and we have replicated the findings in an independent series of 77 MPM from the French MESOBANK.

      Result

      A continuum of molecular profiles appeared to explain the prognosis of this disease better than discrete models based on the histopathological classification or on expression data. We identified the immune and vascular pathways as major sources of molecular variation, with strong differences in the expression of immune checkpoints and pro-angiogenic genes across samples; the extrema of this continuum had very specific molecular profiles: a "hot" bad-prognosis profile (median survival of 7 months), with high lymphocyte infiltration, and high expression of immune checkpoints and pro-angiogenic genes; a "cold" bad-prognosis profile (median survival of 10 months), with low lymphocyte infiltration and high expression of pro-angiogenic genes; and a better-prognosis profile (VEGFR2+/VISTA+, median survival of 36 months), with high expression of the immune checkpoint VISTA and the pro-angiogenic VEGFR2 gene. We selected five genes belonging to the immune and vascular pathways (CD8A, PDL1, VEGFR3, VEGFR2, and VISTA), which expression was enough to capture the three molecular profiles, to validate the expression of these genes at the protein level by immunohistochemistry on a subset of 187 samples from the discovery cohort, and to replicate the molecular profiles as well as their prognostic value in an independent series of 77 MPMs.

      picture copy.jpg

      Conclusion

      In this study we found that the prognosis of MPM is best explained by a continuous model, which extremes show characteristic molecular profiles with specific expression patterns of genes involved in the angiogenesis and immune response3. These data may inform future classifications of MPM and provides insights that may assist the clinical management of this disease.

      1Bueno et al., Nat Genet 2016; 2Hmeljak et al., Cancer Discov 2018; 3Alcala et al., under review in Cancer Res; NA and LM equally contributed to this work; MF, FGS, and LFC jointly supervised this work

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      MA12.02 - Growth Patterns in Epithelioid Malignant Pleural Mesothelioma: A Clinicopathological Review of 614 Cases Over 15 Years (Now Available) (ID 1595)

      14:00 - 15:30  |  Presenting Author(s): Yu Zhi Zhang  |  Author(s): Cecilia Brambilla, Alexandra Rice, Jan Lukas Robertus, Simon Jordan, Eric Lim, loic Lang-Lazdunski, Sanjay Popat, Miriam F Moffatt, William O.C Cookson, Andrew G Nicholson

      • Abstract
      • Presentation
      • Slides

      Background

      Nuclear grading system has been validated as a powerful prognostic tool for epithelioid malignant pleural mesothelioma (MPM) whilst growth patterns had demonstrated prognostic value in earlier studies. We aim to externally validate the previous findings and evaluate the utility of a composite architecture-nuclear grade scoring system.

      Method

      We retrospectively reviewed 614 consecutive cases of epithelioid MPM diagnosed at our institution over a 15-year period. Clinicopathological information including predominant growth pattern (Solid, Tubulo-papillary, Trabecular, Micropapillary, Microcystic, Discohesive, Pleomorphic) and 2-tier nuclear grade were retrieved from an institutional mesothelioma database. The tumours were categorised into High Grade (Solid, Micropapillary, Score=1) and Low Grade (All others, Score=0). A composite score (0-2) was generated based on growth pattern and 2-tier nuclear grade (0-1). Survival analysis was performed using Kaplan-Meier method.

      Result

      Pleomorphic epithelioid MPM was associated with the worst median overall survival (5.4 months), followed by micropapillary- (6.2 months), solid- (10.5 months), microcystic- (15.3 months), discohesive- (16.1 months), trabecular- (17.6 months) and tubulo-papillary- (18.6 months) patterns. The composite scoring system further improved stratification of overall survival based on 2-tier nuclear grade (19.8 vs. 13.4 vs. 8.1 months, p<0.001).

      growth patterns (except cribriform_wdpm).jpg

      composite architecture-ng score v2.jpg

      Conclusion

      Epithelioid MPM growth patterns predicted survival in our cohort. Composite architecture-nuclear grade scoring system further improved prognostic stratification.

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      MA12.03 - PARP Inhibitor Sensitivity Does Not Depend on BAP1 but Is Enhanced by Temozolomide in MGMT Deficient Human Mesothelioma Cells (Now Available) (ID 2492)

      14:00 - 15:30  |  Presenting Author(s): Raffit Hassan  |  Author(s): Daniel Rathkey, Manakamana Khanal, Junko Murai, Jingli Zhang, Qun Jiang, Betsy Morrow, Christine Evans, Raj Chari, Manjistha Sengupta, Anish Thomas, Yves Pommier

      • Abstract
      • Presentation
      • Slides

      Background

      BRCA1 associated protein 1 (BAP1), a nuclear deubiquitinase involved in DNA double-strand (DSB) break repair by homologous recombination (HR), is frequently mutated in mesotheliomas. Because poly (ADP-ribose) polymerase inhibitors (PARPIs) target PARP1 and PARP2 and induce synthetic lethality in BRCA1/2 mutant cancers deficient in HR, we evaluated whether BAP1 inactivating mutations confer sensitivity to PARPIs in mesotheliomas.

      Method

      Ten patient-derived mesothelioma cell lines were generated and characterized for BAP1 mutation status, protein expression and function. Cellular sensitivity to two clinical PARPIs, olaparib and talazoparib were tested as single agents, and in combination with temozolomide. BAP1-deleted mesothelioma cellular models were generated by CRISPR/Cas9 and assessed for sensitivity to PARPIs. Because Schlafen 11 (SLFN11) and O6-methylguanine methyltransferase (MGMT) also drive response to temozolomide and PARPIs, we tested their expression and relationship with drug response.

      Result

      BAP1 inactivating mutations were present in eight of ten cell lines, with two harboring homozygous deletion. Cell lines exhibiting BAP1 expression also showed deubiquitinase activity (DUB). IC50 of olaparib and talazoparib plot classified them into sensitive or resistant population irrespective of BAP1 status (Figure 1). Although BAP1 knockout led to the loss of DUB activity, it did not increase the sensitivity of the cell ines to PARPI. Interestingly, cellular sensitivity to PARPI was increased by temozolomide in MGMT-negative and SLFN11-positive cell lines (Table 1).

      figure 1.jpg

      Figure 1. IC50 of olaparib vs talazoparib – based plot shows a separation of sensitive (red oval) and resistant (blue oval) cell line clusters independent of BAP1 activity.

      table 1.jpg

      Table 1. Summary reflecting combination study between talazoparib and temozolomide in different cell lines having varying MGMT and SLFN11 expression status.

      Conclusion

      BAP1 status does not determine cellular sensitivity to PARPIs in patient-derived mesothelioma cell lines. In MGMT-deficient and SLFN11-positive cells, combination of PARPI and temozolomide is synergistic.

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      MA12.04 - Discussant - MA12.01, MA12.02, MA12.03 (Now Available) (ID 3771)

      14:00 - 15:30  |  Presenting Author(s): Erik Thunnissen

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA12.05 - Genomic Analysis of Long Term Malignant Pleura Mesothelioma Patients Treated with Palliative Chemotherapy (Now Available) (ID 2750)

      14:00 - 15:30  |  Presenting Author(s): Andrea Bille  |  Author(s): Federica Torricelli, Alka Saxena, Rosamond Nuamah, Michael Neat, Leanne Harling, Wen Ng, James Spicer, Alessia Ciarrocchi

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is an aggressive tumor related to asbestos exposure with a median survival of 9 months from diagnosis. The aim of this study was to evaluate correlation between genetic mutations and survival in patients who received only palliative chemotherapy.

      Method

      From 2005 to 2015, 720 patients underwent a surgical pleural biopsy and were diagnosed with malignant pleural mesothelioma. Among these, 27 patients survived longer than 30 months (long survival) from diagnosis and 113 survived less than 30 months. The pleural biopsy of the long term survival patients were reviewed and 12 FFPE samples were considered suitable and matched with 12 FFPE biopsy samples from patients who survived less than 12 months.

      Result

      The DNA of 24 patients was sequenced. One sample did not reach quality to be further considered and was excluded. The mean age of total population was 71.6±8.8 and 15 patients were males (table 1). Eleven patients had a mean overall survival of 5.5 months while 12 patients lived more than 30 months. The mutational analysis identified a total of 428 alterations of which 148, classified as somatic and functional, were further considered. Among these, 85% were missense variants, 8% were variants causing a stop gain, 6% were splice variants. UQCRC1 was significantly associated with a reduced survival of MPM patients (p=0.027); figure 1. Positive trend of correlation was observed between mutations in ACTR1 and CUL1 and short MPM survival. By contrast, no significant correlation was observed between gene mutations and long survival.

      Figure 1.

      figure 1 updated.jpg

      Table 1. patient characteristics.

      Variable

      Long survival

      n=12 (%)

      Short Survival

      n=11 (%)

      P value
      Age (median) 67 72 0.216
      Sex 0.193
      Female 6 (50) 2 (18.2)
      Male 6 (50) 9 (81.8)
      Side 0.684
      Right 7 (58.3) 5 (45.5)
      Left 5 (41.7) 6 (54.5)

      Conclusion

      This is the first study that focusing on MPM patients not suitable for multimodality treatment investigated differences in mutational profile between short and long survivors. Our results suggest a possible role of mitochondria metabolism in mesothelioma aggressiveness.

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      MA12.06 - Patient-Derived Organotypic Tumor Spheroids (PDOTS) Facilitate Therapeutic Screening for Malignant Pleural Mesothelioma (Now Available) (ID 2561)

      14:00 - 15:30  |  Presenting Author(s): Raphael Bueno  |  Author(s): Dalia Larios, Elena Ivanova, Amir Aref, Andrew Portell, Assunta De Rienzo, David Barbie, Cloud P Paweletz

      • Abstract
      • Presentation
      • Slides

      Background

      While genotype directed therapies are an essential aspect of personalized medicine in non-small cell lung cancer (NSCLC), this modality is not currently an option in mesothelioma. Instead there is a need for improved functional testing via predictive platforms that can help identify the susceptibility of patient tumors to drug therapies. Here, we demonstrate the use of a novel ex vivo functional system utilizing 3D microfluidic culture and patient-derived organotypic tumor spheroids (PDOTS) as a platform to study the tumor microenvironment and predict tumor responses to treatment in mesothelioma.

      Method

      We evaluated 31 mesothelioma patient specimens under an IRB approved protocol. PDOTS of mesothelioma were generated as previously described (Larios et al. AACR. 2017; Jenkins et al. Cancer Discovery. 2017). Samples were treated with standard chemotherapy (pemetrexed and cisplatin combined) as well as immunotherapy (ipilimumab and pembrolizumab combined) and live/dead quantification was conducted using dual labeling de-convolution fluorescence microscopy. Positive responses ex vivo included samples with significant cell death to control while positive in vivo responses were based on radiologic lack of tumor recurrence using the response evaluation criteria in solid tumors (RECIST, version 1.1) to assess for disease progression.

      Result

      We found that in treatment naïve specimens prolonged ischemic times were associated with decreased tissue viability (ischemia >25 minutes resulted in decrease of live cells from an average of 81% to 56%), lower tumor yield (< 50% tumor content), and decreased generation of spheroids (< 20 spheroids/well). Specimens with prior treatment were consistently associated with low tissue viability irrespective of ischemic times. Of the 31 specimens studied, 10 samples met viability and tumor content standards to undergo further treatment with standard chemotherapy and immunotherapy, and 5 of those samples were tracked to available patient-treatment response data. Ultimately, comparison of ex vivo and in vivo treatment responses demonstrated that 4 of 5 samples treated with standard chemotherapy had concordant responses to those of patients who received the same or similar post-operative therapy. Notably, our discordant sample exhibited large variation in standard deviations due to technical variability.

      Conclusion

      Here we demonstrate that analysis of ex vivo mesothelioma tissue correlates to in vivo responses. These results suggest that PDOTS can serve as a predictive platform for therapies. Further work streamlining human tissue collection and optimizing factors that affect formation of PDOTS prior to ex vivo treatment analysis should be further investigated.

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      MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)

      14:00 - 15:30  |  Presenting Author(s): Ania Alay  |  Author(s): David Cordero, Elisabeth Aliagas, S Hijazo-Pechero, Victor Moreno, Ramon Palmero Sánchez, Jose Carlos Ruffinelli, Ricard Ramos, Ivan Macia, Xavier Solé, Ernest Nadal

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.

      Method

      Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.

      Result

      T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).

      kaplanmeier_immunegroups.png

      IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.

      Conclusion

      Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.

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      MA12.08 - Discussant - MA12.05, MA12.06, MA12.07 (Now Available) (ID 3772)

      14:00 - 15:30  |  Presenting Author(s): Ying Liang

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA12.09 - Checkpoint Inhibitors Synergize with Dendritic Cell-Therapy in Pre-Clinical Models and Mesothelioma Patients (Now Available) (ID 2425)

      14:00 - 15:30  |  Presenting Author(s): Robert anton Belderbos  |  Author(s): Floris Dammeijer, Mandy Gulijk, melanie Lukkes, Daphne Dumoulin, Robin Cornelissen, Joachim G.J.V. Aerts

      • Abstract
      • Presentation
      • Slides

      Background

      Malignant Pleural Mesothelioma (MPM) is a lethal, treatment resistant neoplasm. Checkpoint inhibitors (CI) have shown promising clinical effects in a minority of patients. It is hypothesized that low response rates to CI are correlated to low numbers of tumor-infiltrating T-cells in MPM patients. Dendritic cell (DC) therapy instigates an immune response and activates tumor-specific T-cells. DC therapy has proven to be effective in pre-clinical models and in a subset of MPM patients. Upregulation of PD-L1 and PD-1 co-inhibitory checkpoints may suppress DC-therapy induced anti-tumor immune response and limit clinical efficacy. To investigate this, we conducted a preclinical and clinical study to evaluate the clinical and immunological effects of DC therapy combined with CI.

      Method

      Immune competent CBA/J mice were orthotopically injected with a syngeneic mesothelioma cell line. Mice were treated with DC-therapy alone or in combination anti-PD-L1 antibodies at high tumor load when DC-monotherapy was found to be ineffective. Peripheral blood and tumors were obtained for flow cytometric analysis and survival was monitored.
      In a clinical setting, nine patients that received DC therapy were sequentially treated with CI. Progression free survival (PFS) was determined from start of CI, using the modified RECIST criteria.

      Result

      Tumors of mice treated with DC-therapy exhibited a three-fold increase in CD8+ T-cell infiltration which was paralleled by heightened expression of PD-L1 on tumor cells (r2=0.69, p=0.0015). Whereas both anti-PD-L1 and DC-monotherapies were ineffective in prolonging survival in our model, combination immunotherapy did (median OS: 24 vs 35 days, p=0.0063). Immune monitoring analyses demonstrated a synergistic increase in proliferation and activation of circulating T-cell following combination therapy. In the clinical trial 3 patients had partial response, 5 patients had stable disease and 1 patient had progressive disease. Median PFS was 5,2 months and median OS was 17,5 months. Currently 3 patients are still alive and two patients are still progression free. There were no grade 3/4 adverse events. PD-L1 expression in tumor biopsies was increased after DC therapy in two of the three responders to CI.

      Conclusion

      In a murine model the synergy between DC therapy and CI was proven and efficacy was driven by activation of CD4+ and CD8+ positive cells. In humans, CI after DC therapy is safe and feasible. Disease control was seen in 8 out of 9 patients treated with CI after DC therapy. DC therapy induces tumor-specific CD8+ T-cell proliferation which is correlated to PD-L1 expression on tumor cells and possibly synergizes with CI treatment.

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      MA12.10 - Novel Germline Mutations in DNA-Damage Repair and DNA Replication Identified in Patients with Malignant Pleural Mesothelioma (MPM) (Now Available) (ID 1419)

      14:00 - 15:30  |  Presenting Author(s): Robin Guo  |  Author(s): Mariel Duboff, Mark G. Kris, Marc Ladanyi, Diana Mandelker, Marjorie Zauderer

      • Abstract
      • Presentation
      • Slides

      Background

      Recent efforts to characterize the germline genetic landscape of MPM have uncovered a surprising prevalence of pathogenic variants in DNA-damage sensing and repair genes. Increasingly, next-generation sequencing has helped bring new insight into critical mutations or pathways involved in the development of MPM. Additionally, observations from these studies could direct new screening, prevention, and therapeutic approaches for patients and families.

      Method

      With IRB approval, we performed deidentified analysis on 87 additional cancer-predisposing genes on our NGS platform among patients with MPM previously consented to a BAP1 germline testing protocol. Additionally, germline variants in an additional 380 genes associated with somatic alterations in cancer, but not associated with hereditary cancer predisposition, were screened for loss of function variant or pathogenic entries in ClinVar. All variants were reviewed according to the American College of Medical Genetics and Genomics and Association for Molecular Pathology consensus guidelines. Founder mutations were excluded. Clinicopathologic information was also collected. Comparisons were done using Fisher’s exact test. P values <0.05 were considered significant.

      Result

      Of 88 patients with MPM analyzed, 11% (10/88) had pathogenic variants. Clinical characteristics such as age, sex, histology, and self-reported asbestos exposure, were similar between patients with and without pathogenic variants (Table 1). Pathogenic variants previously unreported in mesothelioma were identified: MSH3 1/88 (1%; 95% CI: 0-7%), BARD1 1/88 (1%; 95% CI: 0-7%), and RECQL4 2/88 (2%; 95% CI: 0-8%). We also identified pathogenic variants previously associated with mesothelioma: BAP1 in 3/88 (3%; 95% CI: 1-10%), BRCA2 1/88 (1%; 95% CI: 0-7%), and MRE11A 1/88 (1%; 95% CI: 0-7%). One patient had a potentially pathogenic alteration in SHQ1, which has not been associated with a heightened susceptibility to cancer. Patients with germline pathogenic variants were more likely to have more than 2 first-degree family members with cancer compared to those without germline mutations (40% vs 13%; p = 0.049).

      Conclusion

      While the overall incidence of germline mutations identified is similar to prior reports, we identified germline pathogenic alterations in three DNA damage repair and replication genes not previously reported in mesothelioma. Furthermore, we describe a novel germline alteration in SHQ1, which has not been reported with hereditary cancer predisposition. Whether these variants increase the risk of mesothelioma is still under investigation, but given the high rate of germline pathogenic variant in individuals with pleural mesothelioma, germline testing for hereditary cancer susceptibility should be considered in all patients with MPM.

      wclc2019.mesobap1.table-min.jpg

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      MA12.11 - Anti-Tumor Efficacy of Mesothelin Targeted Immunotoxin LMB-100 Plus Pembrolizumab in Mesothelioma Patients and Mouse Models (Now Available) (ID 2316)

      14:00 - 15:30  |  Presenting Author(s): Raffit Hassan  |  Author(s): Qun Jiang, Azam Ghafoor, Daniel Rathkey, Idrees Mian, Jingli Zhang, Betsy Morrow, Ira Pastan

      • Abstract
      • Presentation
      • Slides

      Background

      LMB-100 is an immunotoxin targeting mesothelin (MSLN) that is highly expressed in malignant mesothelioma and lung adenocarcinoma. Given the clinical efficacy of immune checkpoint inhibitors in these cancers, we aimed to evaluate if LMB-100 in combination with αPD-1 antibody will result in greater anti-tumor efficacy.

      Method

      Patients who were treated on a phase I clinical trial of LMB-100 and then received pembrolizumab were evaluated for anti-tumor response and overall survival. We also evaluated LMB-100/αPD-1 combination efficacy in humanized mouse model transplanted with the tumor cells derived from the mesothelioma patient who achieved complete response and healthy donor’s PBMCs. Immune gene expression in pre- and post- LMB-100-treated mesothelioma patient tumor biopsies was detected with NanoString. To further understand the mechanisms of anti-tumor efficacy of LMB-100 plus αPD-1 therapy,we established a human MSLN expressing lung adenocarcinoma syngeneic mouse model with mouse lung adenocarcinoma cell line 531LN2 stably transfected with a vector encoding hMSLN. Using NanoString gene expression assay and flow cytometry, we analyzed drug induced cancer immune responses in 531LN2-hMSLN tumors. Finally, to understand the role of CD8+ T cells in the anti-tumor effects, we depleted CD8+ T cells in LMB-100 plus anti-PD-1 treated 531LN2-hMSLN bearing mice.

      Result

      Nine mesothelioma patients received pembrolizumab, off-protocol, within 3-4 weeks post LMB-100 treatment. Two patients had disease progression before they could be evaluated for tumor response. Out of the 7 patients who were evaluable for response, 4 had durable objective tumor response including 1 complete and 3 partial responses with progression free survival of 104.3+, 49.6, 49.2 and 37.7 weeks. The overall survival of patients with response was 30.2+, 27.7, 23.8+, and 13.8 months from the start of LMB-100 treatments. The immune cell type signature scores including CD45+, CD8+ T cells, exhausted CD8+ T cells, dendritic cells and macrophages were increased in 4 of 6 patients post LMB-100 treatments. The enhanced anti-tumor effects with LMB-100/αPD1 combination were also observed in the PBMC humanized mouse model transplanted with the tumor cells derived the patient with complete response. In the 531LN2-hMSLN mouse syngeneic model, tumor growth was significantly inhibited by LMB-100/αPD-1 treatments than either monotherapy and overall survival was improved in the combination treated mice. The median tumor volume was 865mm3, 420mm3, 277mm3, and 65mm3 in untreated, LMB-100-treated, αPD-1-treated, and combination treated groups respectively on day 34 post tumor inoculation (p<0.001). We observed increased expression of genes related to CD8+T cells and antigen presentation in tumors treated with LMB-100/αPD-1 compared to either agent alone. Flow cytometry confirmed the CD8+T cells increase in LMB-100 /αPD-1 treated 531LN2-hMSLN tumor. Depletion of CD8+T cells significantly negated the anti-tumor benefits in LMB-100/αPD-1-treated mice.

      Conclusion

      Pembrolizumab following LMB-100 is associated with durable tumor response in mesothelioma patients as well as pre-clinical models of mesothelioma and lung cancer. This combination is currently being evaluated in a prospective clinical trial in patients with mesothelioma (clinicaltrials.gov # NCT03644550).

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      MA12.12 - Discussant - MA12.09, MA12.10, MA12.11 (Now Available) (ID 3773)

      14:00 - 15:30  |  Presenting Author(s): Steven Belinsky

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA17 - Molecular Mechanisms and Therapies (ID 143)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 12
    • Now Available
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      MA17.01 - Cell Lineage and Chromatin Landscape of Lung Cancer Are Controlled by GATA6 (Now Available) (ID 59)

      15:45 - 17:15  |  Presenting Author(s): Anna Arnal Estapé  |  Author(s): Wesley L. Cai, Alexandra E. Albert, Francesc López-Giráldez, Minghui Zhao, Laura E. Stevens, Kiran D. Patel, Don X. Nguyen

      • Abstract
      • Presentation
      • Slides

      Background

      Thoracic malignancies are histologically and biologically heterogeneous. The underlying causes of this heterogeneity are believed to be linked to the complex cellular ontogenies of lung cancers and their relationship to pulmonary development. Lineage selective transcription factors (TFs) are critical determinants of airway cell differentiation and homeostasis, but their biological requirements are often conditional. Analogously, several developmental TFs can paradoxically enhance or inhibit lung cancer progression, depending on cellular and epigenetic contexts which remain largely undefined. In this study, we report a novel function for the endodermal and pulmonary specifying TF GATA6 in lung cancer.

      Method

      To understand the role of GATA6 in lung tumorigenesis we used a genetically engineer mouse model (GEMMs) harboring Kras p53 mutations using progenitor cell specific gene targeting. We combined GEMMs biology with integrated analysis of the transcriptome and the chromatin landscape of lung cells derived from GATA6 deficient tumors.

      Result

      In this study, we uncover a conditional role for the endodermal and pulmonary specifying TF GATA6 during the initiation and progression of Kras mutant lung adenocarcinoma (LUAD). Inhibition of Gata6 in genetically engineered mouse models dampens the proliferation and increases the differentiation of LUAD tumors. These effects are influenced by the epithelial cell type that is targeted for transformation, demonstrating that GATA6 expression is an important molecular determinant of the cell of origin in Kras mutant lung cancer. In LUAD cells derived from surfactant protein C expressing progenitors, we identify multiple genomic loci that are bound by GATA6. Moreover, suppression of Gata6 in these cells significantly alters chromatin accessibility, particularly at distal enhancer elements. Analogous to its paradoxical activity in the developing lungs, GATA6 expression fluctuates during different stages of LUAD progression and can epigenetically control diverse lineage programs associated with cell proliferation, alveolar specification, BMP signaling, and epithelial plasticity.

      In summary:

      1) GATA6 expression varies during different stages of disease progression in the lung adenocarcinoma (LUAD) subtype

      2) Suppression of Gata6 can diminish the proliferation and progression of LUAD in a manner that is influenced by the transforming progenitor of origin

      3) GATA6 differentially modulates chromatin accessibility across the genome of LUAD cells

      4) This epigenomic mechanism results in the activation of different lineage specific programs, including the BMP signaling pathway.

      Conclusion

      These findings reveal how GATA6 can modulate the chromatin landscape of lung cancer cells to control their divergent lineage dependencies during tumor progression.

      D.X.N. has received research funding from AstraZeneca, Inc.

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      MA17.02 - Identify Vulnerable Pathways and Improve Treatment Outcomes in LKB1-Deficient Lung Tumors (Now Available) (ID 2067)

      15:45 - 17:15  |  Presenting Author(s): Meng Xu Welliver  |  Author(s): Feng Jin, Joseph M Amann, Michael Koenig, Xiaokui Mo, David P Carbone

      • Abstract
      • Presentation
      • Slides

      Background

      The LKB1 tumor suppressor is inactivated in about 20% of non-small cell lung cancers (NSCLC) by mutations. Cancer cells with LKB1 deficiency exert complex effects on signal transduction and transcriptional regulation, which may cause these cells more susceptible to certain therapies comparing to cells with intact LKB1 function. Phenformin, an antidiabetic medicine from the biguanides class, has shown activities against NSCLC. Phenformin as a single agent has been shown to reduce tumor burden and prolonged survival in Kras;Lkb1 compound mutant mice but not Kras;p53 mice, suggesting specific activities in tumor with LKB1 deficiency. Currently patients with unresectable locally advanced NSCLC are treated standardly with concurrent chemoradiotherapy followed by checkpoint inhibitor, durvalumab. In this project, we test treatment sensitivity to radiotherapy and/or phenformin in lung cancer cells with intact or deficient LKB1.

      Method

      Human lung cancer cell lines described below were used in (1) clonogenic survival assays as well as (2) generating tumor xenograft on nude mice for tumor growth delay experiments. A549, HCC15 and Calu-1 cell lines obtained from ATCC were cultured in RPMI1640 containing 5% FBS, without antibiotics. A549 cells (LKB1 deficient, TP53 WT and KRAS mutated) or HCC15 (LKB1 deficient, TP53 mutated and KRAS WT) were transfected with empty vector or WT LKB1 or LKB1-K78I plasmids; Calu-1 (LKB1 WT, KRAS mutated and p53 deleted) transfected with empty vector or LKB1 CRIPR KO were generated as described previously.

      Result

      A549 cells with transfected WT-LKB1 were significantly more resistant to ionizing radiation (IR) induced cell kill (8.7% survival at 8 Gy) comparing to cells transfected with empty vector (3.7%) or kinase-dead LKB1 genes (4.2%). Similarly, HCC15 cells with transfected WT-LKB1 are significantly more resistant to IR induced cell kill (7.5%) comparing to cells transfected with empty vector (4.1%) or kinase-dead LKB1 genes (3.4%). Calu-1 cells harbor WT LKB1, and it is significantly more resistant to IR induced cell kill (8.3%) comparing to their counterpart with LKB1 KO (Calu-1 transfected with LKB1 CRIPR KO) (4.1%). When A549 cells were pretreated with 30 μM phenformin prior to, during and after IR, there was no change in survival in cells transfected with WT LKB1; however there was significant further reduction in survival in cells transfected with empty vector (LKB1 deficient). Xenograft tumors were generated in nude mice with A549 cells with the above genetic alterations. There was significant further tumor growth delay in those with A549 with deficient LKB1 comparing to those with A549 with WT LKB1 gene add-back. This tumor growth delay was further enhanced when these mice were treated with oral phenformin prior to, during and after IR treatment, confirming the in vitro experimental results.

      Conclusion

      Human lung cancer with deficient LKB1 are more sensitive to ionizing radiation in vitro and in vivo. This was regardless of the TP53 or KRAS mutation status. A549 cells with deficient LKB1 were also more sensitive to phenformin treatment. Phenformin treatment further sensitized LKB1 deficient lung cancer cells to IR. This suggested that LKB1 can serve as a predictive biomarker to triage patient treatments.

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      MA17.03 - Importance of Cullin4 Ubiquitin Ligase in Malignant Pleural Mesothelioma (Now Available) (ID 2349)

      15:45 - 17:15  |  Presenting Author(s): Mayura Meerang  |  Author(s): Jessica Kreienbühl, Vanessa Orlowski, Michaela B Kirschner, Walter Weder, Isabelle Opitz

      • Abstract
      • Presentation
      • Slides

      Background

      Loss of the tumor suppressor NF2 is frequent in malignant pleural mesothelioma (MPM). NF2 suppresses tumorigenesis in part by inhibiting Cullin4 ubiquitin ligase (CUL4) complex. Here we aimed to evaluate an importance of CUL4 in MPM.

      Method

      We evaluated the expression of CUL4A and CUL4B in tissue microarrays using immunohistochemistry. We tested the efficacy of cullin inhibition by pevonedistat, a small molecule inhibiting cullin neddylation, in 13 cell lines and 3 primary cells in 2D and 3D culture. Four groups of SCID mice haboring intraperitoneal (ip.) pevonedistat sensitive (MSTO211H) or resistant (ACC-Meso1) cell lines were treated with pevonedistat (50 mg/kg; ip.) on a 5day on/5day off schedule for 3 cycles. Treatment efficacy was assessed by means of overall survival.

      Result

      CUL4B expression was associated with clinical outcomes (figure 1). Five MPM cell lines (38%) were highly sensitive to pevonedistat (IC50<500 nM). This remained true in 3D spheroid culture. The treatment induced S/G2 cell cycle arrest and accumulation of cells undergoing DNA re-replication (containing >4N DNA content) known to be mediated by p21 and CDT1 accumulation. Indeed the accumulation of p21 and CDT1 was more pronounced in pevonedistat sensitive cell lines after the treatment. Two of primary cells (67%) were sensitive to pevonedistat and also showed higher CDT1 accumulation following the treatment compared to the resistant cells. In vivo, pevonedistat treatment significantly prolonged survival of mice bearing both sensitive and resistant MPM tumors. Pevonedistat treatment reduced growth (phosphorylated histoneH3 positive) in pevonedistat sensitive tumor but increased apoptosis (cleaved–caspase3 positive) in pevonedistat resistant tumor.

      fig1 wclc2019.jpg

      Conclusion

      High CUL4B expression may play a role in MPM progression. Inhibition of cullins by pevonedistat induced growth arrest and DNA re-replication strongly in a subset of MPM. The major mechanism seems to be mediated by p21 and CDT1 accumulation in vitro. Investigation of mechanisms in vivo is ongoing.

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      MA17.04 - Discussant - MA17.01, MA17.02, MA17.03 (Now Available) (ID 3786)

      15:45 - 17:15  |  Presenting Author(s): Julian Carretero

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA17.05 - DNA-Binding and Gene Expression Profiles in Max Deficient Small Cell Lung Cancer (Now Available) (ID 377)

      15:45 - 17:15  |  Presenting Author(s): Paula Llabata  |  Author(s): Manuel Torres-Diz, Antonio Gomez, Montse Sanchez-Cespedes

      • Abstract
      • Presentation
      • Slides

      Background

      The MYC pathway is frequently altered in cancer, mostly by gene activation of the MYC-family of oncogenes (fMYC) but also by genetic inactivation of MAX, the obligate partner of MYC. While the oncogenic properties of fMYC have been extensively studied, the tumour suppressor role of MAX and the function of fMYC in MAX-mutant cells remain unclear. Further, inactivating mutations in MGA, a gene that codes for another MAX-binding partner, have been found in lung cancer. MGA is a component of the non-canonical polycomb repressive complex 1 (ncPRC1) but its precise role in lung cancer development is unknown.

      Method

      RNA-sequencing, chromatin immunoprecipitation and proteomic analysis were performed to identify and compare the DNA binding and gene expression profiles of MYC, MGA and MAX in MAX-restituted human small cell lung cancer (SCLC)-derived cell lines.

      Result

      SCLC is a high-grade neuroendocrine type of lung cancer with recurrent inactivating mutations in MAX. Recent findings have described two major SCLC subtypes based on the high expression of either ASCL1 or NEUROD1 transcription factors. According to this, ASCL1 and NEUROD1 control the expression of different set of genes which defines the two subgroups of SCLC. Here, we found that MAX-mutant SCLC cells belong to the ASCL1-transcription factor dependent group of SCLCs. In the absence of MAX, even after ectopic overexpression of MYC, there was no recruitment of MYC to the DNA. The DNA binding profile of MAX in MAX-restituted cells remained unaltered after co-overexpression of MYC, despite opposed effects in gene expression. Moreover, restitution of MAX significantly shifted the DNA occupancy of MGA, from E2F6 consensus binding sites to MYC-consensus binding sites (E-boxes). Our observations also demonstrated that ncPRC1 complex is formed regardless of the presence or absence of MAX.

      Conclusion

      Our data supports that MYC lacks transactivation capabilities in the absence of MAX and that the tumour suppressor role of MAX relies on its capability to counteract the gene expression triggered by its partnering with fMYC. Further, we conclude that the tumor suppressor role of MGA may be related, in part, to the regulation of E2F6 promoters.

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      MA17.06 - Plakophilin 1 Enhances MYC Expression, Promoting Squamous Cell Lung Cancer (Now Available) (ID 823)

      15:45 - 17:15  |  Presenting Author(s): Pedro Pablo Medina  |  Author(s): Joel Martin-Padron, Laura Boyero, María Isabel Rodríguez, Alvaro Andrades, Inés Díaz-Cano, Paola Peinado, Carlos Baliñas, Juan Carlos Alvarez Álvarez Pérez, Isabel Fernández Coira, María Esther Fárez-Vidal

      • Abstract
      • Presentation
      • Slides

      Background

      Plakophilin 1 (PKP1) is a member of the arm-repeat (armadillo) and plakophilin gene families, being an important component of the desmosome. Although desmosomes loss-of-function has been associated with increased cell migration and pro-oncogenic activity, we have observed consistent PKP1 overexpression in patient samples of squamous cell lung cancer (SqCLC) in comparison with lung adenocarcinoma (LUAD) and non-tumoral controls from two datasets achieved by our group, and also from three additional independent datasets.

      Method

      In order to explore this paradox, we developed in vitro and in vivo PKP1 gain/loss functional models in SqCLC cell lines and also we challenged our hypothesis in some LUAD cell lines.

      Result

      Greater cell dissemination but reduced cell proliferation was observed in CRISPR-Cas9 induced, PKP1-knockout clones. Furthermore, PKP1 expression promoted cell proliferation, cell survival, and in vivo xenograft engraftment.

      Interestingly, we demonstrated through several functional experiments (chromatin immunoprecipitation, RNA immunoprecipitation, direct mutagenesis combined with luciferase assays, Western blot, qPCR... among others), and in 7 cell lines from different lung cancer subtypes (5 SqCLC and 2 LUAD cell lines), and different contexts (with and without PKP1 basal expression in order to set up gain and loss expression assays), that these pro-oncogenic activities were mediated by the functional direct relationship between PKP1 and the oncogene MYC. Specifically, PKP1 enhances MYC translation, and MYC increases PKP1 transcription, linking both proteins in a positive feedforward loop.

      Conclusion

      These observations provide a new molecular mechanism of cancer development, revealing PKP1 as a novel oncogene in SqCLC, and as an effective post-transcriptional regulator of MYC, which has been described as overexpressed in around 70% of NSCLC tumors.

      Moreover, PKP1 unveiled as a valuable diagnostic biomarker and a potential therapeutic target for SqCLC. Importantly, PKP1 inhibition may open up the possibility of indirectly targeting MYC, not only in NSCLC (where, as mentioned before, is frequently overexpressed), but also in other tumors. This is of particular interest, because MYC is an oncogene that is dysregulated in most human cancers and is acknowledged as a “most wanted” target for cancer therapy.

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      MA17.07 - Identification of AHR as a Novel Regulator of Lung Cancer Metastasis (Now Available) (ID 2331)

      15:45 - 17:15  |  Presenting Author(s): Silke Nothdurft  |  Author(s): Frank Breitenbuecher, Ross A Okimoto, Trever G Bivona, Barbara M Gruener, Michael Hoelzel, Jan Forster, Sophie Kalmbach, Alexander Schramm, Martin Schuler

      • Abstract
      • Presentation
      • Slides

      Background

      Curative treatment of early stage and locally advanced non-small cell lung cancer (NSCLC) relies on surgery and radiotherapy. Adjuvant or simultaneous platin-based chemotherapy is used for risk reduction in patients with large tumors and/or lymph node metastases. Still a large fraction of curatively treated patients dies from metastatic relapse. A better mechanistic understanding of lung cancer metastasis is expected to guide the development of novel rational interventions from prevention, early detection and treatment.

      Method

      Using a barcoded shRNA library we performed a functional in vivo screen in an orthotopic NSCLC mouse model to find target genes involved in metastatic processes. Barcoded shRNAs with significantly different representation between primary tumors and metastases were identified by next generation sequencing. Prioritized hits were functionally validated by targeted suppression in NCI-H1975 cells. Mechanistic studies were conducted in several NSCLC models in vivo and in vitro.

      Result

      We identified AHR, a ligand-activated transcription factor involved in regulation of biological responses to planar aromatic hydrocarbons, as potential modulator of lung cancer metastasis. Suppression of endogenous AHR by shRNA enhanced the migratory and invasive capacity of NSCLC cells in vitro. Importantly, NCI-H1975 with targeted suppression of AHR showed increased metastasis formation in an orthotopic model in vivo. High RNA expression of AHR correlates with lower likelihood of progression and superior overall survival in patients with stage I NSCLC. Mechanistically, AHR impacts matrix remodeling genes (MMP19, MMP24) as well as asparagine synthetase (ASNS), all of which have been implied in metastatic progression.

      Conclusion

      AHR is a novel metastasis-modulating factor in NSCLC. Its mechanism of action provides rational targets for diagnostic and therapeutic interventions.

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      MA17.08 - Discussant - MA17.05, MA17.06, MA17.07 (Now Available) (ID 3787)

      15:45 - 17:15  |  Presenting Author(s): Paul Paik

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA17.09 - 5-Azacytidine Inhaled Dry Powder Formulation Profoundly Improves Pharmacokinetics and Efficacy for Lung Cancer Therapy (Now Available) (ID 172)

      15:45 - 17:15  |  Presenting Author(s): Steven Belinsky  |  Author(s): Philip J Kuehl, Carmen S Tellez, Marcie J Grimes, Michael Burke, Aaron Badenoch, Devon Dubose

      • Abstract
      • Presentation
      • Slides

      Background

      Epigenetic therapy through its ability to activate hundreds of genes silenced by promoter hypermethylation in lung cancer could produce durable and sustained tumor regression. The demethylating agent 5-azacytidine (5AZA) is unstable in aqueous solution and subject to hydrolysis and catabolism by cytidine deaminase (CDA) in liver, thereby reducing drug concentration after systemic administration prior to reaching the lung. Delivering 5AZA by inhalation could mitigate these barriers.

      Method

      A stable, respirable (3.5 µM) dry powder formulation of 5AZA was generated. Pharmacokinetic (PK) studies in rats compared systemic dosing to inhaled delivery of a dry powder or aqueous formulation of 5AZA in the presence and absence of the CDA inhibitor tetrahyroduridine (THU). An orthotopic nude rat lung cancer model compared efficacy of inhaled dry powder versus aqueous 5AZA for treatment of engrafted human adenocarcinoma (Calu6, Calu3), adenocarcinoma in situ (H358), and squamous cell (RH2) tumor lines. Three weeks following engraftment (lungs contain multiple tumors), rats were treated 4 times weekly for 4 weeks, then sacrificed to assess tumor burden and genome-wide effects on the methylome in vehicle and treated tumors using the Illumina EPIC array.

      Result

      Plasma PK showed a ~10-fold increase in area under the curve (AUC) and a 1.5 and 5-fold increase in maximum concentration (Cmax) comparing inhaled dry powder (0.6 mg/kg) to systemic (2 mg/kg, equivalent to the human injectable dose of 75 mg/m2) and inhaled aqueous (0.6 mg/kg) 5AZA that was augmented by THU. Inhaled dry powder and aqueous 5AZA PK in lung were similar and greatly exceeded systemic (30-fold Cmax; 47-fold AUC). PK in liver and brain were superior for dry powder with 7- and 26-fold increase in AUC and 7- and 3.3-fold increase in Cmax compared to systemic or aqueous dosing. The efficacy study comparing inhaled delivery of equivalent doses (0.6 mg/kg lung dose) showed dry powder was significantly better than aqueous with a 70–80% compared to 33–50% reduction in tumor burden for Calu6, Calu3, and RH2 and equally effective in largely curing H358 tumors. A significantly increased median number of genes (175–320 versus 25–270) exhibiting ≥30% demethylation of CpGs across their promoter region was seen for Calu6, Calu3, and H358 tumors exposed to dry powder versus aqueous 5AZA, with equivalent numbers of genes demethylated for RH2.

      Conclusion

      Delivery of a dry powder formulation of 5AZA via an inhaler could be used to treat local and metastatic lung cancer (Support–CA196590).

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      MA17.10 - Lactate Transporter Blockade as a Strategy to Overcome VEGF Inhibitor-Resistance in LKB1-Deficient NSCLC (Now Available) (ID 2647)

      15:45 - 17:15  |  Presenting Author(s): John Victor Heymach  |  Author(s): Irene Guijarro, Alissa Poteete, Sungnam Cho, Teng Zhou, You-Hong Fan, Emily Roarty, Monique Nilsson, Edwin Parra, Barbara Mino, Ignacio Wistuba, Jing Wang, Ferdinandos Skoulidis

      • Abstract
      • Presentation
      • Slides

      Background

      STK11/LKB1 alterations are found in 20-30% of NSCLC and used to co-occur with KRAS mutations. Because LKB1 activates AMPK, many of the best known functions of LKB1 are attributed to its ability to control metabolic alterations in cells. Our laboratory have previously reported that loss of LKB1 promotes enhanced glycolysis and elevated lactate production and more recently we demonstrated that STK11/LKB1 mutations are the strongest predictors of de novo resistance to immunotherapy in NSCLC. Prior studies have revealed an association between alterations in the LKB1/AMPK pathway and worse clinical outcomes in NSCLC and in patients treated with chemotherapy and bevacizumab. Given the roles of LKB1 in the regulation of cell metabolism and resistance to immunotherapy, it is feasible that LKB1 also impacts on the response to anti-angiogenic therapies.

      Method

      Xenograft mouse models were established by subcutaneous injection of H460 cells (LKB1-deficient) and H460 LKB1-expressing in nude mice and LKR10 (KRASG12D) LKB1 wild-type (K) or LKB1- knockout (KL) into 129Svmice. Mice were randomized to vehicle or B20-4.1.1 anti-VEGF antibody. Glycolytic activity of LKB1-intact and -deficient NSCLC cells was measured by Seahorse assay. We analyzed gene expression of SLC16A3 (MCT4) by qPCR and Western blot. Genetic disruption of MCT4 in the K and KL cell lines was done using CRISPR-Cas9 and mouse models were established by subcutaneous injection into mice.

      Result

      Mice bearing LKB1-expressing H460 xenografts treated with anti-VEGF antibody showed a significant decrease in tumor volume (p<0.05) compared with their vehicle-treated counterparts. However, mice bearing LKB1-deficient H460 xenografts showed markedly reduced efficacy of anti-VEGF therapy compared with that in LKB1-expressing xenografts. Anti-VEGF therapy significantly reduced growth of LKR10 K tumors (p<0.001) but not in LKR10 KL tumors. Microvascular density was not increased in KL tumors following anti-VEGF treatment compared to K. Human isogenic LKB1-deficient cells showed a significantly increased rate of glycolysis and lactate secretion compared with cells expressing LKB1. Human and murine LKB1-deficient cells also had increased MCT4 expression compared to K cells. Immunofluorescence and RPPA analysis of tumor samples from the K and KL mouse models showed that KL tumors upregulated MCT4 protein expression compared with K tumors (p<0.0001). The genetic disruption of MCT4 KL tumors significantly improved tumor volume reduction to anti-VEGF therapies in vivo (p<0.001).

      Conclusion

      LKB1 loss is associated with increased lactate secretion and resistance to VEGF inhibition in NSCLC. The targeting of the lactate transporter MCT4 enhance the sensitivity of LKB1-deficient NSCLC to anti-VEGF therapy.

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      MA17.11 - High Sensitivity to PD-1 Blockade Therapy After Ld1 Depletion in KRAS-Driven Lung Cancer Through CD8+/CD3+ Tumor Infiltration and PD-L1 Induction (Now Available) (ID 2562)

      15:45 - 17:15  |  Presenting Author(s): Iosune Baraibar  |  Author(s): Marta Román, Inés López-Erdozain, Ana Oliver, Anna Vilalta, Daniel Ajona, Silvestre Vicent, Carlos De Andrea, Ruben Pio, Juan José Lasarte, Alfonso Calvo, Ignacio Gil-Bazo

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1/PDL-1 inhibitors are approved for non-small cell lung cancer (NSCLC). However, many patients do not benefit and therapeutic combinations are under investigation. We have previously described Id1, involved in proliferation, angiogenesis and immunosuppression, as a prognostic factor in lung adenocarcinoma (LUAD) (Ponz-Sarvise, Clin Cancer Res 2011), Id1’s role in lung cancer metastasis (Castanon, Cancer Letters 2017) and more recently shown that Id1 sustains mutant KRAS-driven progression and metastasis in NSCLC (Roman, Cancer Res 2019).

      In a previous syngeneic murine lung cancer model with depleted levels of Id1 using Id1-/- and Id1 wildtype C57BL/6 mice inoculated with Lewis Lung Carcinoma (LLC), we tested a combined therapeutic strategy targeting PD-1 and Id1, showing impaired tumor growth and increased survival (Gil-Bazo, presented at WCLC 2018).

      Here we study a combined strategy targeting PD-1 and Id1 in a KRAS-mutant murine LUAD model and the immune-related mechanisms involved.

      Method

      First, a correlation between Id1 and PD-L1 mRNA expression was studied in mutant and wild-type KRAS LUAD cohorts from The Cancer Genome Atlas data set (TCGA).

      Secondly, a syngeneic tumor model using Balb/c mice through subcutaneous injection of KRAS-mutant LUAD (Lacun3) cells and Id1-silenced Lacun3 (Id1sh) cells. In vitro, proliferation was measured in both cell lines through MTS assays. IFNg-induced PD-L1 expression in both cell lines and flow cytometry was used to evaluate its mechanistic effects on the immune response.

      After tumor cells injection, mice were treated with an anti-PD-1 (RMP-1-14) monoclonal antibody or PBS, i.p. Tumor volumes according to Id1 status in tumor cells and the treatment administered were quantified. Vectra 3.0™ multispectral microscopy was used to characterize the tumor associated immune cells in paraffin-embedded tissues from our previous syngeneic murine lung cancer model using Id1-/- and Id1 wildtype C57BL/6 mice inoculated with LLC in which the combined blockade had been reported as effective. Immune marker antibodies were used to study expression of CD3, CD4 and CD8.

      Result

      An inverse, moderate and statistically significant correlation between Id1 and PD-L1 expression in mutant and wild-type KRAS LUAD cohorts from TCGA was found in both cohorts (-0.367 and -0.351, respectively, p<0.001), indicating that Id1 depletion may lead to PD-L1 expression induction.

      In vitro assays showed that Id1 silencing reduced Lacun3 cells proliferation (p<0.001). Up-regulation of surface PD-L1 expression occurred in Id1sh cells, but not in Lacun3 cells, after receiving IFNg (p=0.0022). Mechanistically, in the syngeneic murine model, Id1 inhibition in the injected cells, combined with anti-PD-1 treatment, significantly induced a tumor growth impairment (p<0.001). An intense CD8+ and CD3+ immune cell infiltration was observed in LLC Id1-/- C57BL/6 mice treated with anti-PD1 (p<0.05 for CD3+ TILS), compared the control groups, possibly explaining the dramatic tumor growth impairment previously shown on the treated animals.

      Conclusion

      Id1 silencing may induce PD-L1 overexpression according to in silico and in vitro results. Id1 and PD-1 combined blockade in our KRAS-mutant syngeneic murine LUAD model significantly impaired tumor growth, compared to each strategy alone. A significantly increased CD3+ and CD8+ tumor infiltration and IFNg-induced PD-L1 tumor expression after the combined blockade may explain these findings.

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      MA17.12 - Discussant - MA17.09, MA17.10, MA17.11 (Now Available) (ID 3788)

      15:45 - 17:15  |  Presenting Author(s): Shantanu Banerji

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA24 - Initiatives to Improve Health in Lung Cancer Patients (ID 354)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advocacy
    • Presentations: 12
    • Now Available
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      MA24.01 - Challenges in Lung Cancer Clinical Trials: A European Perspective  (Now Available) (ID 1873)

      14:30 - 16:00  |  Presenting Author(s): Anne-Marie Baird  |  Author(s): Diego Villalón, Alfonso Aguarón, Christian Smitt-Plank, Tommy Björk, Regine Deniel Ihlen, Ewelina Szmytke, Stefania Vallone

      • Abstract
      • Presentation
      • Slides

      Background

      Lung Cancer Europe (LuCE) is the voice of people impacted by lung cancer at the European level. LuCE aims to increase knowledge of lung cancer, and provide a platform to raise awareness regarding disparities in detection, diagnosis, treatment and care across Europe. This study was undertaken to gain a better insight in to the clinical trial experience from a patient perspective, and improve our understanding of patients’ awareness and attitudes towards clinical trials.

      Method

      Surveys and qualitative interview questions were designed based on a review of relevant literature and policy sources. Online surveys were constructed and shared with lung cancer advocates (n=13; covering 12 different countries) and patients with lung cancer (n=262; covering 15 European countries). Qualitative interviews were also undertaken with 15 individuals, covering the medical community, representatives from patient advocate organisations and the pharmaceutical industry.

      Result

      The majority of patient respondents were aged between 56-65 years of age (37%), with women accounting for 70% of total respondents. Most of those who took part resided in Poland (19.5%), Italy (18.7%), Denmark (9.9%) and Spain (9.2%). A number of concerning figures emerged from the data. Overall, 50% did not fully understand what a clinical trial was, and 22% of respondents had never heard of clinical trials. Only 11% of those surveyed had participated, or were actively participating in a lung cancer clinical trial. Over 50% of these respondents stated that their trial experience was positive. The Internet was the primary source used by patients to find trial information (89%), however only 10% stated that they could always find the information they needed. This is critical, as the more information patients obtained, the more willing they were to participate in clinical trials. Overall 80% wanted to find out more about clinical trials, and 75% believed that it would be beneficial for patients to work together with researchers in the clinical trial development process. Key areas identified by this research included difficulties in cross-border access, language barriers, lack of accurate accessible information, lack of awareness by patients and clinicians, and disparities in access across Europe.

      Conclusion

      A number of barriers were identified in accessing lung cancer clinical trials across Europe and within individual countries. These obstacles are multifaceted and exist at a protocol, clinical and patient level. The lung cancer community must work together to overcome these barriers and ensure access to clinical trials for all people impacted by lung cancer.

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      MA24.02 - Developing Regional Activity for a National Charity: The Lung Cancer Canada Experience (Now Available) (ID 962)

      14:30 - 16:00  |  Presenting Author(s): Paul Wheatley-Price  |  Author(s): Paul Robertson, Michelle Brennan, Jill Hamer-Wilson, Andrea Redway, Mariel Bouris, Diane Manii, Jacques Ricard, Shem Singh

      • Abstract
      • Presentation
      • Slides

      Background

      Lung Cancer Canada (LCC) is the only national charity solely committed to the most common cancer in Canada. Its mission is to raise awareness; to advocate; and to provide support and educational resources for lung cancer patients and caregivers. At a strategic planning event the LCC Board held in 2017, the goal of building regional hubs was identified - to deliver the charities mandate within local contexts.

      Method

      A group of key stakeholders (patients, caregivers, fundraisers, social workers, nurses and physicians) met to identify local priorities. Specific programs were developed, with other initiatives flowing from that initial effort. Here we describe the group's achievements.

      Result

      From the initial stakeholder meeting two prime opportunities were identified.

      1. Create a support group for women with lung cancer.

      2. Take advantage of being in the national capital to more purposefully engage with Federal politicians.

      In addition to the stakeholder meeting, subsequent social gatherings of key individuals helped build momentum.

      Through partnership with a local charity (Ottawa Regional Cancer Foundation), marketing through LCC, recruitment through the cancer centre, and program development from a senior psychosocial oncology social worker, the support group was formed for an initial 12 week period, and has now grown to an established permanent fixture. The benefits have been previously reported, but out of this group further local initiatives have included: regular patient-led lung cancer information sessions in the cancer centre; a regional patient summit for all lung cancer patients to learn latest research, patient testimonies and psychosocial challenges; the funding and initiation of an LCC podcast series.

      Concurrently more individuals and families have become engaged in fundraising for lung cancer: events including quiz nights, makeovers, golf days, wine raffles and more, which in addition to raising funds also builds awareness and builds the local community.

      These individuals have partnered with physicians to stimulate the second goal, initiating regular meetings with municipal, provincial, federal and senatorial politicians, in addition to military leadership and indigenous groups. This itself helped the national organization to hone the advocacy message we share (lung cancer awareness, lung cancer screening, access to treatments, and the establishment of a national registry).

      Conclusion

      Through identification of local champions who effectively work together, many initiatives have successfully developed. With funding and support from LCC, the charity’s mandate is being delivered within the local context. This serves as a model for other centres across Canada to develop local programs.

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      MA24.03 - Factors Impacting Patients’ Worries (Accessing Treatment, Treatment Toxicity, &amp; Emotional Burden) Associated with Lung Cancer Treatments (Now Available) (ID 2589)

      14:30 - 16:00  |  Presenting Author(s): Andrea S Ferris  |  Author(s): Upal Basu Roy, Sarah A Janse, Ellen M Janssen, Alexa Meara, Carolyn J Presley, Peter J Kneuertz, John FP Bridges

      • Abstract
      • Presentation
      • Slides

      Background

      Understanding patient experiences with lung cancer can guide research, treatment, and policy decisions. Conducted as part of a larger study (Project Transform) that aimed to quantified patient experiences, we sought to study the primary concerns of lung cancer patients and their caregivers and to determine what demographic and clinical factors impact these worries.

      Method

      Lung-cancer worries were identified from patient interviews and the literature. A novel an instrument assessing 13 potential worries on a 3-point importance scale was incorporated as part a national survey of lung cancer patients (inclusive of all types/stages of disease) and caregivers recruited through LUNGevity Foundation. Factor analyses was used to identify key constructs among the 13 worries. We then explored variation in the standardized factor scores across demographic and clinical indicators collected in the survey.

      Result

      Of the 426 participants in the survey, there were 385 patients and 41 caregivers. The average age of respondents was 58.9 years, 54% earned less than $75,000 per year, and 67.6% had completed college. Three factors were identified associated with worrying: 1) “accessing treatments” (incorporating knowledge, communication, access); 2) “treatment toxicity” (incorporating both side-effects and financial impact); and 3) “emotional burden” (including worries about dying, emotional toll, and being a burden), with Cronbach’s alphas of 0.89, 0.73, and 0.74 respectively. Worries about accessing treatment were lower among NSCLC (P=0.006), presence of MET mutations (P = 0.027) and those not currently receiving therapy (P=0.033). Worries about treatment toxicity were higher among non-white (P<0.001), non-retired (P<0.001), those earning less than $75,000 (P<0.001), younger patients (P<0.001), and those with ALK (P=0.026) or HER2 (P=0.041) mutations. Worries about treatment toxicity were lower among patients on Medicare or Medicaid during treatment (P = 0.023) and NSCLC patients (P=0.018). Worries about the emotional burden of treatment were lower among those >=60 years (P=0.002) and those who are retired (P=0.021) and higher among those having surgery (P=0.039).

      Table 1: Marginal effects of patient factors on standardized worry scores

      Factor

      Accessing Treatment

      Treatment toxicity

      Emotional burden

      Patient

      -0.052 (0.16)

      -0.144 (0.16)

      -0.224 (0.16)

      Age >= 60

      -0.1 (0.1)

      -0.336 (0.1)***

      -0.309 (0.1)**

      Female

      0.003 (0.12)

      0.239 (0.12)

      0.158 (0.12)

      Non-white

      -0.022 (0.16)

      0.56 (0.16)***

      0.048 (0.16)

      Hispanic, Latino, or Spanish

      -0.003 (0.22)

      0.233 (0.22)

      0.161 (0.21)

      Primary Language - Spanish

      0.116 (0.7)

      0.879 (0.69)

      0.423 (0.67)

      Armed Forces

      -0.103 (0.18)

      -0.134 (0.18)

      0.055 (0.18)

      Marries

      0.139 (0.11)

      -0.177 (0.11)

      0.073 (0.11)

      Has children

      0.004 (0.13)

      -0.031 (0.13)

      0.203 (0.12)

      College or professional degree

      0.208 (0.11)

      -0.096 (0.11)

      -0.104 (0.1)

      Retired

      -0.048 (0.1)

      -0.488 (0.1)***

      -0.233 (0.1)*

      Household Income < $75,000

      0.031 (0.11)

      0.376 (0.11)***

      0.025 (0.11)

      Population < 2,500

      -0.168 (0.22)

      -0.099 (0.22)

      0.193 (0.21)

      Chronic conditions as diagnosis

      -0.078 (0.12)

      -0.021 (0.12)

      0.146 (0.12)

      NSCLC

      -0.308 (0.11)**

      -0.263 (0.11)*

      -0.111 (0.11)

      Private Insurance

      0.084 (0.11)

      0.139 (0.11)

      0.057 (0.11)

      Medicare or Medicaid

      0.02 (0.1)

      -0.235 (0.1)*

      -0.079 (0.1)

      Other Insurance

      -0.092 (0.17)

      -0.144 (0.17)

      -0.128 (0.17)

      No Insurance

      0.363 (0.58)

      0.56 (0.58)

      -0.083 (0.58)

      Participated in a clinical trial

      -0.029 (0.12)

      -0.134 (0.12)

      0.077 (0.12)

      ALK

      0.143 (0.14)

      0.295 (0.13)*

      0.041 (0.12)

      BRAF

      -0.241 (0.56)

      -0.663 (0.55)

      -0.345 (0.52)

      EGFR

      -0.038 (0.13)

      -0.109 (0.13)

      0.121 (0.12)

      HER2

      0.689 (0.48)

      0.973 (0.47)*

      0.439 (0.45)

      KRAS

      -0.201 (0.21)

      -0.067 (0.21)

      -0.113 (0.2)

      MET

      -0.765 (0.34)*

      -0.389 (0.34)

      0.19 (0.32)

      NTRK

      0.767 (0.68)

      0.467 (0.67)

      0.101 (0.63)

      RET

      0.154 (0.4)

      -0.47 (0.39)

      -0.69 (0.36)

      ROS1

      0.149 (0.26)

      -0.053 (0.25)

      0.202 (0.24)

      More than 2 lines of treatment

      0.09 (0.1)

      0.026 (0.1)

      0.03 (0.1)

      Chemotherapy

      0.019 (0.16)

      0.008 (0.16)

      0.007 (0.16)

      Radiation

      0.197 (0.29)

      0.339 (0.3)

      0.101 (0.3)

      Targeted therapy

      0.143 (0.1)

      0.038 (0.1)

      0.129 (0.1)

      Immunotherapy

      0.124 (0.18)

      0.188 (0.19)

      -0.125 (0.19)

      Surgery

      0.454 (0.29)

      0.407 (0.3)

      0.612 (0.29)*

      Angiogenesis inhibitors

      0.081 (0.41)

      0.101 (0.42)

      0.268 (0.42)

      No current treatment

      -0.214 (0.1)*

      -0.192 (0.1)

      -0.163 (0.1)

      Notes: Standard errors in parentheses, * p<0.05, ** p<0.01, ***p<0.001

      Conclusion

      Conclusion:

      Patients worry to differing extents about accessing treatment, treatment toxicity, and the emotional burden of lung cancer, yet caregivers and patients (on the whole) have similar worries. Lung cancer researchers, clinicians, and policymakers should make decisions in ways that address the heterogeneous experience of patients. Patients worries vary across a confluence of demographic, disease, and treatment factors, hence greater attention to the individual needs of the patient is needed.

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      MA24.04 - Discussant - MA24.01, MA24.02, MA24.03 (Now Available) (ID 3820)

      14:30 - 16:00  |  Presenting Author(s): Deb Whippen

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA24.05 - Lung Cancer in Europe:  Strengthening Policy Responses One Country at a Time (Now Available) (ID 2381)

      14:30 - 16:00  |  Presenting Author(s): Mary E Bussell  |  Author(s): Alan D Lovell

      • Abstract
      • Presentation
      • Slides

      Background

      Despite diagnostic and treatment progress in lung cancer, outcomes remain poor and costs remain high. Prevalence and mortality rates in Europe are higher than the global average and five-year survival rates stand at a mere 11.2% for men and 13.9% for women. The Economist Intelligence Unit is conducting research to identify the impact of policy on lung cancer incidence and outcomes, sponsored by MSD. Recommendations stemming from our research will support countries to build improved systemic responses for lung cancer.

      Method

      Our research centres on twelve countries: Austria, Belgium, Finland, Germany, Greece, Netherlands, Norway, Poland, Romania, Spain, Sweden, and the UK. Following an initial literature review using evidence from internationally-recognised sources (e.g. Globocan, OECD, and proprietary Economist Intelligence Unit sources), we organised our thinking into five domains. This is operationalised by quantitative and qualitative indicators to provide insight into how each country addresses cancer planning and guideline usage as well as how strategic thinking impacts behaviour and access.

      At a meeting with leading European experts, we presented our initial findings and validated our framework. The next step was to populate our scorecard to compare policy and practice in each country. Individual country profiles were developed from our findings, examining local barriers to progress in terms of service delivery, systems, access, financing and governance. Workshops were then held in each country. Meeting with a range of leading clinicians, patient organisations, and other key stakeholders ensured a detailed examination of our preliminary findings and, most importantly, enabled us to obtain further information on conditions within each country. This nuanced information provides us with a clearer grasp on approaches to the provision of lung cancer care to a greater degree than we could have obtained from desk research alone.

      Result

      Preliminary results indicate patches of good practice, yet no country scores highly across all of our measurements and each country has several opportunities for improvement. For example, all but one country has a national cancer control plan: of eleven plans, nine are over five years old which means that they are not taking account of recent oncological innovations. Often, a country’s national lung cancer clinical guidelines lack details regarding fast-tracking suspected patients for diagnosis as well as referral pathways for moving a patient to secondary/tertiary care, supportive/palliative care, shared decision-making, and provision of psychological support in specific time periods. Cancer registries exist in each country, yet clinicians report that clinically-focused cancer registries could provide useful information on patient care. Finally, reimbursement for all four commonly used biomarkers for lung cancer is available in only five countries.

      Conclusion

      Significant room for improvement in lung cancer policy exists across all of the countries and domains we have studied. Our country-based workshops have ensured that our research focuses on the most important opportunities for improving the delivery of lung cancer care from the standpoint of each country. We are now entering the policy development phase of our research where our goal is to assist policy-makers to improve care for people living with lung cancer in Europe.

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      MA24.06 - Using Global Data as an Advocacy Tool – The Global Lung Cancer Coalition’s E-Atlas of Lung Cancer (Now Available) (ID 593)

      14:30 - 16:00  |  Presenting Author(s): Winfield Boerckel  |  Author(s): Sarah Elizabeth Winstone, Maureen Rigney, Jesme Fox, Peter Horton-Fawkes

      • Abstract
      • Presentation
      • Slides

      Background

      The Global Lung Cancer Coalition is the international voice of lung cancer patients and is committed to improving disease outcomes for all. The Coalition's work includes activities to support lung cancer advocates in campaigning for actions that will improve research, information, treatment, and care for people living with lung cancer.

      Significant variations exist both between and within different countries in lung cancer incidence, mortality and survival. Advocates can use evidence of these variations to make the case for legislative, policy or regulatory change.

      In 2014 the GLCC brought together multiple, comparable, statistical sources about lung cancer’s impact and outcomes in different nations in the first Global Lung Cancer E-Atlas. For the first time, national lung cancer data became easily accessible in a single place online.

      In 2019, a new edition was published incorporating more recent global data, breakdowns by gender and age, and features to make it easier for advocates to use.

      Method

      Incidence and mortality data were drawn from GLOBOCAN 2018, which provides estimates, by age and gender, for 185 countries of the world.

      Survival data were drawn from: CONCORD-2, covering 67 countries; the EUROCARE-5 study, covering 29 European countries; and the International Cancer Benchmarking Partnership (ICBP), comprising Australia, Canada, Denmark, Norway, Sweden and the United Kingdom.

      The E-Atlas also details whether countries operate a cancer plan, have national cancer registries in place, or have implemented the WHO Framework Convention on Tobacco Control.

      GLCC members were invited to validate their country’s data. Any more recent national data identified was included alongside the data from other sources.

      Result

      The Lung Cancer E-Atlas is publicly accessible on the GLCC’s website for anyone in the world to use.

      Data can be compared, turned into graphs and infographics, and shared via social media. It can also be downloaded ready for use in presentations.

      Clinicians have used the data in presentations to national and regional congresses. Patient advocacy groups are using it to support their engagement with national policymakers and media.

      Conclusion

      Feedback from GLCC members confirms that the E-Atlas continues to be an essential resource in their campaigning and advocacy. Policymakers respond positively to being able to see how their country’s national data compares to that of other countries.

      The GLCC is keen to increase the profile of the E-Atlas so that any lung cancer advocate – whether a clinician, patient, carer, researcher, advocacy group or journalist – is aware of it and able to use it.

      The GLCC is also keen to receive feedback on national data for inclusion or suggestions for further development.

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      MA24.07 - Impact of Radiologist Recommendations on Timeliness of Lung Cancer Referral: Baseline Data to Guide a Quality Improvement Initiative (Now Available) (ID 828)

      14:30 - 16:00  |  Presenting Author(s): Monica Lynn Laginha Mullin  |  Author(s): Thomas Howard, Gurmohan Rob Dhillon, Genevieve C Digby

      • Abstract
      • Presentation
      • Slides

      Background

      Lung cancer (LC) diagnostic pathways are typically initiated following suspicious radiographic imaging. In southeastern Ontario, Canada, we identified delays from first thoracic imaging suspicious for LC to referral for evaluation at our regional LC rapid assessment clinic, the Lung Diagnostic Assessment Program (LDAP). Given that delays in diagnosis of LC are associated with worse patient outcomes, we sought to characterize local processes to guide Quality Improvement (QI) initiatives.

      Method

      We retrospectively reviewed all patients referred to the LDAP between January and October 2018. Collected data included dates of: first imaging suspicious for LC, first CT chest (if different from first suspicious imaging), LDAP referral, LDAP assessment, and details regarding Radiologist recommendations in the report. Data are reported as mean days (± standard error); unpaired t-tests were used to assess for significance.

      Result

      Of 558 patients referred to the LDAP, 509 (91.2%) patients had a CT chest performed prior to LDAP referral. Of these, 110 (21.6%) had a CT chest report issuing a specific Radiologist recommendation for LDAP referral. When such a recommendation was made, time from CT chest to LDAP referral was significantly faster than if no recommendation was made (6.9 versus 12.9 days, p=0.017), as was time from CT Chest to LDAP assessment (21.4 versus 25.6 days, p=0.026). Of all patients with a Radiologist recommended LDAP referral, 38 (34.5%) were not assessed in the LDAP for reasons including: patient followed by the LDAP, a Respirologist, or an Oncologist, inpatient status, or patient refusing assessment. Data are presented in Figure 1.

      figure 1.png

      Conclusion

      We identified that a Radiologist recommendation for LDAP referral leads to significantly faster patient referral and assessment for evaluation of suspected LC. A QI initiative is underway, consisting of knowledge sharing and regional standardization of radiologist reporting recommendations for imaging suspicious for LC in order to expedite LDAP referral.

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      MA24.08 - Discussant - MA24.05, MA24.06, MA24.07 (Now Available) (ID 3821)

      14:30 - 16:00  |  Presenting Author(s): Merel N. Mountain

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA24.09 - Stigma in Early Stage Lung Cancer (Now Available) (ID 2883)

      14:30 - 16:00  |  Presenting Author(s): Eric LR Bedard  |  Author(s): Jessica Culling, Sarah Bedard, Simon R Turner, S Johnson, Janelle Pellizzari

      • Abstract
      • Presentation
      • Slides

      Background

      Lung cancer stigma, arising from the causative relationship between smoking and lung cancer, can result in those with a lung cancer diagnosis being seen by themselves and others as responsible for and even deserving of their condition. Lung cancer stigma is linked to adverse outcomes for patients, including decreased quality of life and depression. Most studies have focused on stigma in patients with advanced lung cancer, whose experiences may differ from earlier stage, surgical patients with better prognosis. The objective of this study is to establish a baseline of stigma related experiences for patients presenting with early stage lung cancer. The overarching goal is to assist in determining appropriate interventions to decrease harmful stigma for patients with lung cancer.

      Method

      This study is a descriptive cross-sectional design using the 25-item previously validated Lung Cancer Stigma Inventory (LCSI). The LCSI was self-administered by patients with newly diagnosed lung cancer at a tertiary referral thoracic surgical clinic to quantitatively measure their experience of lung cancer stigma. Statistical comparisons were performed with Student’s t-test.

      Result

      128 patients were approached to participate and 53 completed the LCSI (response rate= 41.4%), 33 were women. All had resected early stage lung cancer except one patient staged pIIIA (I=41, II=11). 38 patients (71.7%) met the established threshold of a total LCSI score of 37.5, indicating a clinically meaningful level of stigma. Stigma was experienced predominantly on the Internalized Stigma subscale (mean 2.64/5), whereas scores on the Constrained Disclosure and Perceived Stigma subscales were lower (mean 1.84/5, 1.66/5). There was a trend towards higher overall stigma scores in current and former smokers compared to never smokers (mean 53.9 vs 39.8, p=0.12) There was no difference in stigma experience based on gender or stage, surgical approach or use of adjuvant chemotherapy.

      Conclusion

      A surgical population of patients with early stage lung cancer experienced lung cancer stigma at a high rate, and at a level similar to previously studied populations with more advanced disease. Respondents experienced more internal stigma than stigma stemming from society or others. Exploratory analysis of this study’s results have informed the development of a further study, currently underway, using patient interviews to better understand patients’ experiences of lung cancer stigma, which may help to identify potential interventions to decrease lung cancer stigma and its impacts.

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      MA24.10 - Estimation of Deaths Due to Lack of Access to Immunotherapy for Brazilian Patients Diagnosed with Advanced NSCLC Without Any Driver Mutation (ID 2967)

      14:30 - 16:00  |  Presenting Author(s): Vinicius Knackfuss Goncalves  |  Author(s): Vinicius Lorandi, Stephen Doral Stefani, Leonardo Paludo, Rafaela Kirchner Piccoli

      • Abstract
      • Slides

      Background

      Lung cancer is a major cause of cancer worldwide. Despite efforts to curtail risk factors such as tobacco consumption, it remains both common and lethal. More recently novel targeted therapies and the development of immunotherapy provided a substantial increase in the expected survival of patients diagnosed with advanced lung cancer. Nonetheless, the lack of access to these medications, especially in low and middle-income countries, is a trending concern.

      Brazil is considered to be a middle-income country and its citizens have access to a universal healthcare system (Sistema Único de Saúde – SUS) – fully funded by the government. Around 75% of the population rely exclusively on this public system when treating their diseases. Many high-cost drugs, such as immunotherapy and TKI’s, are not provided due to budget constraints.

      This study has the goal of estimating the impact in premature lives lost in the Brazilian population due to lack of access to the best currently available therapy for patients with advanced non-small cell lung cancer (NSCLC) without driver mutations.

      Method

      Firstly, we searched for data regarding the incidence of lung cancer in the Brazilian population using INCA’s (Brazilian National Cancer Institute) database, demographic data from the Brazilian Government and compiled staging and histologic data from different private and public oncologic centers. For analytic reasons, we compared the incidence data with the ones observed in the American Surveillance, Epidemiology, and End Results (SEER).

      Using survival data from the pivotal phase 3 studies for immunotherapy in NSCLC (PACIFIC, Keynote 189 and 407) we estimated the expected total number of patients alive one year after diagnosed with stage III or IV NSCLC (excluding those with driver mutations) considering they had received the best treatment available according to the NCCN guidelines. This number was compared with the expected survival for patients receiving the standard treatment in the Brazilian SUS (chemoradiation followed by observation for stage III NSCLC and palliative Carboplatin + Paclitaxel for stage IV NSCLC without driver mutations).

      Result

      After compiling all data of interest, we estimated that 2.332 premature deaths would occur in Brazilian patients with advanced NSCLC one year after diagnosis, exclusively due to lack of access to immunotherapy. Comparing Brazilian incidence data with the American data from SEER, this number may actually be underestimated and can reach up to 11.193 premature deaths in a single year.

      Conclusion

      The lack of access to immunotherapy is a major concern for countries in development and this can lead to an enormous impact on survival of patients with lung cancer. Further studies are needed to best estimate the economic impact and provide data to help decide when to adopt new technologies and drugs to treat these patients. Strategies may rapidly be implemented in order to avoid further unnecessary premature deaths of NSCLC patients.

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      MA24.11 - A Project to Control Passive Smoking by Lung Cancer Patients "Don't Smoke Near Me! Don't Be Like Me!" (Now Available) (ID 2483)

      14:30 - 16:00  |  Presenting Author(s): Kazuo Hasegawa  |  Author(s): Hiroko Saito, FUsayo Miyake, Chigusa Nakamura, Yuko Tanaka, Tomomi Ito, Seiko Inaba, Chikako Endo, Koji Onishi, Masayo Onishi, Nobuyuki Kishimoto, Yuko Komatsu, Isamu Tanaka, Makiko Tanaka, Takehiko Hatsuda

      • Abstract
      • Presentation
      • Slides

      Background

      According to a survey of patient group members (n = 215, 2017), 31% of lung cancer patients who continue to work were exposed to passive smoking at workplaces.
      Once Japanese tobacco industry used to be a national monopoly, so Japan is one of the countries where a ban on indoor smoking has not been realized. Although education on smoke prevention in elementary and junior high schools tells the fact that smoking is one of the risks for lung cancer, it is unknown that lung cancer patients are living frightened of cancer relapse, especially with the fear of being exposed of passive smoking.

      Lung cancer patients encourage highly dependent smokers who cannot stop smoking despite they have colleagues or families suffering from lung cancer to visit smoking cessation clinics.

      Method

      Intervention to close persons is difficult. In order to overcome the difficulties, we select ambassadors from each patient group. Then we provide training on education, action guidelines and tool development, have them participate in tool development, and have them become mentors when scaling up. The state of the activity is published on the Internet, and we spread media interview invitations in parallel. We let families, colleagues, community members, professionals, medical professionals, media and politicians know that lung cancer patients are frightened of passive smoking.

      The activities already done are as follows.

      -Granted Global Bridge grant of tobacco control personnel development department in Mayo Clinic, USA

      Ambassador briefing session was held twice. (Kobe and Tokyo)

      Selected 13 ambassadors from 11 lung cancer patient group and held 5 workshops.

      Planned communication strategies

      Communication tactics currently developing

      Result

      [Activity (project) evaluation]

      Won 13 ambassadors from all over Japan

      No withdrawal of the ambassador

      One of the ambassadors changed job to be in charge of tobacco control in a public administration.

      One of the ambassadors was appointed as a member of patient information evaluation committee of National Cancer Center Japan.

      Conclusion

      [Future plans]

      Completion of Tool

      Hold briefing session to member in each patient group

      Campaign implementation

      Campaign evaluation

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      MA24.12 - Discussant - MA24.09, MA24.10, MA24.11 (Now Available) (ID 3822)

      14:30 - 16:00  |  Presenting Author(s): Bonnie Addario

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    OA01 - Advanced Diagnostic Approaches for Intrathoracic Lymph Nodes and Peripheral Lung Tumors (ID 117)

    • Event: WCLC 2019
    • Type: Oral Session
    • Track: Interventional Diagnostics/Pulmonology
    • Presentations: 8
    • Now Available
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      OA01.01 - Predictive Value of EBUS Strain Elastography in Mediastinal Lymph Node Staging; The E-Predict Multicenter Study Results (Now Available) (ID 1620)

      10:30 - 12:00  |  Presenting Author(s): Roel L.J. Verhoeven  |  Author(s): Rocco Trisolini, Fausto Leoncini, Michela Bezzi, Piero Candoli, Alessandro Messi, Mark Krasnik, Jouke Annema, Chris de Korte, Erik H.F.M. Van Der Heijden

      • Abstract
      • Presentation
      • Slides

      Background

      Systematic assessment of lymph nodal involvement by EBUS-TBNA is indicated for suspected and proven lung cancers. Nodal size and PET characteristics help guide which lymph nodes to sample. Especially smaller lymph nodes remain challenging, since PET is of limited value due to low resolution. Additional ultrasound B-mode features such as lymph node size, margin or node heterogeneity have shown variable predictive outcomes. Ultrasound strain elastography (EBUS-SE) is a promising technique. By monitoring tissue deformation over time using ultrasound imaging, a relative tissue strain can be computed. Lower tissue strain is shown to correlate to malignancy. Using a standardized measurement procedure (RespirationDOI: 10.1159/000494143), we aimed to assess the value of strain elastography for predicting lymph node malignancy in addition to size information.

      Method

      This multicenter prospective international trial [NCT02488928] included patient with suspected or proven lung cancer in five hospitals. Measurements were obtained following to a standardized operating procedure using Pentax-Hitachi EBUS systems. Nodal cytopathology combined with follow up imaging (>6 months) or surgery were used as reference standard. If uncertainty in outcome remained, nodes were excluded in final analysis.

      Result

      EBUS-SE was performed in 416 patients and 525 lymph nodes (June 2016 – July 2018). Final diagnoses showed 272 benign and 253 malignant nodes. Mean lymph node size was 12.3 mm. B-mode size and mean strain correlated to risk of malignancy with AUC of 78% and 76.8% (95% CI 0.73-0.81). Using a clinical work-up setting with 10mm and 8mm size cut-offs for aspiration, short axis size higher than 8 or 10mm resulted in respective sensitivity of 85% and 72%, specificity of 52% and 71%, PPV of 62% and 70% and NPV of 79% and 73%. Addition of strain elastography (mean<90) to EBUS-short-axis size (<10mm) increased overall sensitivity from 72% to 90% and NPV from 73% to 81%. More nodes were found false positive, specificity decreased from 71% to 42% and PPV went from 70% to 59%. Addition of strain (mean<78) to EBUS-size (<8mm) increased sensitivity from 85% to 94% and NPV from 79% to 85%. Specificity decreased from 52% to 32% and PPV from 63% to 55%.

      Conclusion

      EBUS strain elastography is of added value in guiding nodal sampling. Strain and size combined can help identify more malignant nodes, although it will ultimately also lead to more false positive sampling. Strain information may especially be of potential value in nodes of small size, where PET resolution is limited.

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      OA01.02 - Endobronchial Ultrasound Staging of Operable NSCLC: Triple Negative Lymph Nodes May Not Require Routine Biopsy (Now Available) (ID 2621)

      10:30 - 12:00  |  Presenting Author(s): Danielle Hylton  |  Author(s): Kaesavan Selvakumaran, Biniam Kidane, Jonathan D. Spicer, Simon R Turner, Daniel French, Chuck Wen, James Masters, Yogita S. Patel, Jenelle Taylor, Christian Finley, Yaron Shargall, Forough Farrokhyar, John Agzarian, Andrew Seely, Kazuhiro Yasufuku, Wael C. Hanna

      • Abstract
      • Presentation
      • Slides

      Background

      Current staging guidelines with endobronchial ultrasound (EBUS) still recommend systematic biopsy of at least 3 mediastinal stations prior to surgical resection. Recently, a 4-point ultrasonographic score (Canada Lymph Node Score- CLNS) was developed to determine the probability of nodal metastasis in any given lymph node. A LN with CLNS<2 is considered very low probability for malignancy. We hypothesized that, during EBUS assessment of patients with cN0 non-small cell lung cancer, individual nodal stations that have CLNS<2 do not require routine biopsy because they are likely to represent true pN0 disease.

      iaslc 2019 - clns lymph node figure.png

      Method

      The CLNS is a prospectively validated score that uses four ultrasonographic features to accurately predict LN malignancy. LNs were evaluated for ultrasonographic features at the time of EBUS and the CLNS was applied. “Triple Negative” LNs were defined as cN0 on CT (LN≤1cm), PET (no hypermetabolic activity) and EBUS (CLNS<2). Specificity, NPV, and false-negative rates were calculated against the gold-standard pathological diagnosis from surgically excised specimens.

      Result

      In total, 122 LNs in 58 cN0 patients were assessed. Triple Negative LNs were associated with the following T-stage distribution (T1a=12.07%, T1b=24.14%, T2a=34.38%, T2b=10.34%, T3=17.24%, T4=1.72%). Triple Negative LNs had a specificity, NPV, and false-negative rate of 86.10% (95%CI: 78.40-91.80%), 93.40% (95%CI: 86.90-97.30%), and 6.60%, respectively when using <2 as the CLNS malignancy cut-off. In total, only 5.74%(n=7) Triple Negative nodes were actually proven to be malignant, 6/7 (85.71%) on EBUS-TBNA, and 1/7 (14.29%) only after surgical resection.

      Conclusion

      Triple Negative LNs have a high NPV for malignancy. At the time of EBUS in cN0 patients, it may be possible that Triple Negative LNs do not require tissue sampling, thereby saving procedural time, cost, and discomfort. Findings also suggest that Triple Negative LNs with inconclusive biopsy results may not require repeat sampling. A prospective comparative trial is required to confirm these findings.

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      OA01.03 - Probability Model for Malignancy in Hilar and Mediastinal Lymph Nodes in Lung Cancer Based on PET-CT and EBUS (Now Available) (ID 133)

      10:30 - 12:00  |  Presenting Author(s): Jaume Bordas-Martinez  |  Author(s): Jose Luis Vercher Conejero, Guillermo Rodríguez Gonzalez, Paula Notta, Cristian Tebé Cordomi, Cristina Martín Cabeza, Noelia Cubero De Frutos, María Rosa López-Lisbona, Marta Díez-Ferrer, Nuria Baixeras Gonzalez, Cristina Gamez Cenzano, Jordi Dorca Sargatal, Antoni Rosell

      • Abstract
      • Presentation
      • Slides

      Background

      The mediastinal lymph nodes (LN) staging is routinely performed by PET-CT and EBUS- TBNA. Nevertheless, there are no studies that explore the diagnostic capacity of both techniques together. This study aims is to find an algorithm based on combined PET-CT and EBUS image variables together with clinical criteria that provides the most accurate probability of malignancy for each LN explored.

      Method

      Retrospective study of mediastinal staging of non-small cell lung cancer, based on PET-CT and EBUS-TBNA. The LN were identified by level (N1, N2 and N3) and by anatomical region (AR) (subcarinal, not subcarinal, and hilar). Standardized Uptake Value (SUV) was determined for each sampled LN (maximum, medium and peak) as well as for pulmonary mass, liver, and blood pool. The ultrasound features collected were: diameter in the short axis (DSA), morphology, border, ecogeneicity and presence of the vascular hilium. For the construction of the predictive algorithm a mixed model of logistic regression of Firth was used.

      Result

      116 consecutive patients were included and a total of 358 LN were evaluated. The set of variables that presented the best discrimination were: age, DSA, SUVmax and AR. The model determines the probability for malignancy for each LN, using the following formula = (-9.26) constant + (-0.21) Age + (4.29) SUVmax + (0.52) DSA + AR. The discrimination power of the model measured by the Area Under the Roc curve was = 0.95.

      distribution density of diameter (mm) and suvmax of positive and negative lymph nodes  .png

      Conclusion

      The model including age, DSA, SUVmax and AR provide the probability of malignancy for each LN with the highest accuracy. All other variables can be discarded when combining PET-CT and EBUS image features.

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      OA01.04 - Discussant - OA01.01, OA01.02, OA01.03 (Now Available) (ID 3721)

      10:30 - 12:00  |  Presenting Author(s): Rocco Trisolini

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      OA01.05 - Cryobiopsy Compared with Forceps Biopsy in Pathological Diagnosis and Biomarker Research in Lung Cancer: A Prospective, Single-Arm Study (Now Available) (ID 1564)

      10:30 - 12:00  |  Presenting Author(s): Tomoyuki Naito  |  Author(s): Hibiki Udagawa, Keisuke Kirita, Takaya Ikeda, Yoshitaka Zenke, Shingo Matsumoto, Kiyotaka Yoh, Seiji Niho, Genichiro Ishii, Koichi Goto

      • Abstract
      • Presentation
      • Slides

      Background

      Cryobiopsy is a novel transbronchial biopsy tool that enables the collection of larger samples than forceps biopsy. We evaluated the usefulness of cryobiopsy compared with forceps biopsy in pathological diagnosis and biomarker research in lung cancer.

      Method

      In this prospective single-arm study, 121 patients with or suspected of having lung cancer underwent concurrent transbronchial biopsy using a cryoprobe (ERBECRYO2) and forceps from the same lesion. Sample size and morphological classification were determined for patients whose cryobiopsy and forceps biopsy samples both contained tumor cells (n = 81). Patients diagnosed with non-small-cell lung carcinoma (NSCLC) with adequate samples from the two procedures (n = 65) were analyzed for programmed death ligand 1 (PD-L1) expression score (22C3). Genomic DNA and RNA were extracted from cryobiopsy and forceps biopsy formalin-fixed paraffin-embedded samples (20 NSCLC patients, 20 sections, 10 µm thick each) for whole-exome sequencing and RNA sequencing.

      Result

      Cryobiopsy samples were significantly larger than forceps biopsy samples (median 11.1 mm2[range: 3.3–135.0] vs. 2.0 mm2[0.7–6.6], p < 0.01). The confirmation rate of morphological classification of cryobiopsy samples was significantly higher than that of forceps biopsy samples (86% vs. 79%, p < 0.01, adenocarcinoma/squamous-cell carcinoma/small-cell carcinoma/other = 35/19/12/4 and 30/15/11/4, respectively). The success rate for evaluating PD-L1 score using cryobiopsy and forceps biopsy samples was 94% and 95%, respectively. A greater proportion of cryobiopsy samples tended to have PD-L1 > 1% than forceps biopsy samples (51% vs. 42%, p = 0.06). Significantly larger amounts of DNA (median 1.60μg vs. 0.58μg, p = 0.02) and RNA (median 0.62μg vs. 0.17μg, p < 0.01) were extracted from cryobiopsy samples than forceps biopsy samples. The success rate for whole-exome sequencing (90% vs. 15%, p < 0.01) and RNA sequencing (75% vs. 10%, p < 0.01) was higher for cryobiopsy samples than forceps biopsy samples. The median tumor-mutation burden in cryobiopsy samples was 84 (range 3–2396).

      Conclusion

      Cryobiopsy provided larger sample sizes compared with forceps biopsy, and were more useful for morphological classification, PD-L1 evaluation and genetic analysis.

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      OA01.06 - Cone Beam CT Imaging for Transbronchial Navigation in Small Peripheral Pulmonary Lesions (Now Available) (ID 1659)

      10:30 - 12:00  |  Presenting Author(s): Erik H.F.M. Van Der Heijden  |  Author(s): Roel L.J. Verhoeven, Jurgen Fütterer, Wouter Hoefsloot

      • Abstract
      • Presentation
      • Slides

      Background

      Small peripheral lung lesions have historically been identified and followed according to risk of malignancy. Ideally an accurate minimally invasive diagnostic procedure would become the more common first approach. The bronchoscopic approach herein remains of limited widespread use, and reported pooled diagnostic yields remain at approximately 70% even with the help of additional advanced guiding technology. We evaluated if inter-procedural cone beam CT (CBCT) improves yield in two prospective trials: CBCT assisted navigation bronchoscopy with electromagnetic navigation (EMN) guidance (CONTROL-E, NCT03355586) and without EMN using augmented CBCT fluoroscopy alone (CONTROL-A, NCT03274609).

      Method

      All patients with an indication for a minimal invasive diagnostic procedure of their peripheral pulmonary lesion as found by our multi-disciplinary tumor board between Dec 2017 and Jan 2019 were included. A total of 84 patients (100 nodules) were included and had a navigation bronchoscopy in the hybrid operating room under general anesthesia. Procedural workflow was as follows: CONTROL-A started off with a CBCT scan. The lesion and pathway were then segmented on a separate workstation. Afterwards, both pathway and nodule were projected 2D on live fluoroscopy for navigation and biopsy guidance. CONTROL-E workflow started with electromagnetic navigation (EMN). Upon reaching the planned target or concluding upon unsuccessful navigation, CBCT imaging was performed for verification (or if applicable; consecutive repositioning guidance). In both workflows, r-EBUS mini probe imaging and ROSE were available for additional guidance and verification.

      Result

      The mean lesion size in CONTROL-A (46 patients) was 16.7mm (range 5-43 mm), and 11.5mm (range 4-33 mm) in CONTROL-E (38 patients). A bronchus sign was seen in 62% and 71% of cases, respectively. The CONTROL-E study showed that EMN with r-EBUS had an approximate navigation success rate of 58%. Addition of live 3D-CBCT guidance was performed in all cases, increasing navigation success to 88%. The CONTROL-A study had navigation success of 80% by utilizing only r-EBUS and augmented CBCT-fluoroscopy. However, additional EMN (cross-over) was needed in several cases for navigation guidance, increasing navigation success to 88%. In follow up, both studies showed a diagnostic yield lower than the navigation success: in CONTROL-E 71% and in CONTROL-A, 72% had a biopsy outcome correlating to golden standard follow up.

      Conclusion

      Cone beam CT is of significant added value for transbronchial navigation to small peripheral lung lesions, with or without trans-parenchymal access. Diagnostic yield however remains approximately 71%. Additional refining of navigation and biopsy tools is necessary to further increase intuitiveness and accuracy.

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      OA01.07 - Ultrathin Bronchoscopy Combined with VBN and EBUS for the Diagnosis of PPLs With or Without Fluoroscopy: A Randomized Trial (Now Available) (ID 2242)

      10:30 - 12:00  |  Presenting Author(s): Jiayuan Sun  |  Author(s): Xiaoxuan Zheng, Fangfang Xie

      • Abstract
      • Presentation
      • Slides

      Background

      Since the utility of low‑dose computed tomography screening for lung cancer, the detection rate of ground‑glass nodules (GGNs) has increased.Transbronchial biopsy for peripheral pulmonary lesions is generally performed using ultrathin bronchoscopy combined with virtual bronchoscopic navigation (VBN) and endobronchial ultrasound (EBUS). The use of fluoroscopy with this method has not yet been explored. The study was designed as a randomized trial to determine the role of fluoroscopy in this method.

      Method

      Patients with peripheral pulmonary lesions suspicious for malignant were enrolled in the study and randomized to two groups, fluoroscopy group and non-fluoroscopy group. Fluoroscopy group was performed with a 3.0 mm external diameter and 1.7 mm internal diameter ultrathin bronchoscope, EBUS, VBN guidance and fluoroscopy. Non-fluoroscopy group was performed with the same ultrathin bronchoscopy combined with EBUS and VBN guidance, but without fluoroscopy. Biopsies Cytological and histological examinations were performed in both groups.

      Result

      A total of 126 patients were enrolled and randomized, of whom 120 patients (60, non-fluoroscopy group; 60, fluoroscopy group) were analyzed. The diagnostic yield was 75% (14 benign and 46 malignant lesions) in the non-fluoroscopy group and 83.3% (6 benign and 54 malignant lesions) in the fluoroscopy group (P=0.37). There were no obvious complications including pneumothorax, bleeding, chest pain and pneumonia in both groups.

      Conclusion

      There was no difference in the diagnostic yield of the non-fluoroscopy group method compared to the FG method using ultrathin bronchoscopy, navigational technology and EBUS for transbronchial biopsy to diagnose peripheral pulmonary lesions.

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      OA01.08 - Discussant - OA01.05, OA01.06, OA01.07 (Now Available) (ID 3722)

      10:30 - 12:00  |  Presenting Author(s): Mehrnaz Asadi

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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