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    CS01 - Controversies in NSCLC OMD (ID 3)

    • Event: WCLC 2019
    • Type: Controversy Session
    • Track: Oligometastatic NSCLC
    • Presentations: 4
    • Now Available
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      CS01.01 - "Hunting a Ghost for 25 Years – Will We Ever Catch OMD?" - No (Now Available) (ID 3144)

      11:00 - 12:30  |  Presenting Author(s): Tom Treasure

      • Abstract
      • Presentation
      • Slides

      Abstract

      Oligometastatic disease (OMD) is no more and no less than what it say on the label. It is cancer with few metastases, no more than can be counted on the fingers of one hand. A few metastases can be locally eradicated with surgery, image guided thermal ablation (IGTA) or with stereotactic ablative radiotherapy (SABR) but beyond five it becomes increasingly impractical to attempt local control. Total eradication is unlikely and systemic treatment makes more sense. So five or fewer identified metastases fit a working definition of OMD as treatable by local interventions.

      'Framing’ disease according to suitability for treatment has always been part of clinical practice. Diagnostic frames shift over time. A classic example is the emergence of 'ESRD' (end stage renal disease) as a diagnosis. 18thC diagnoses depended on clinical descriptions. 'Dropsy’ was illness characterised by water retention; what we call oedema. William Withering observed that some of those sick with dropsy were helped by infusions of foxglove. Later Richard Bright discovered protein in the urine of others. At autopsy he found shrivelled kidneys and dropsy had to be reframed, depending on whether it was the heart or the kidneys that were failing. Aetiology, pathophysiology, and histology sequentially framed the many types of kidney disease through the 1960s but effective treatment only became available with dialysis and transplantation. Long-term survival was possible but was too costly for nearly all individuals and their families. In 1972 US Congress passed Public Law 92-603 which framed a new diagnosis: ESRD. Patients with end stage renal disease were entitled to federal funding. In 1974 ESRD appeared for the first time in PubMed in a paper about public financing. ESRD has been used in titles or abstracts 15,282 times since and runs at over a thousand citations a year.

      Hellman and Weichselbaum proposed the term ‘oligometastases’ in 1995 to describe a clinical state between freedom from metastases and their ‘extensive and widespread’ presence. (Figure) A search for <oligometas*> reveals very few publications for about 10 years. Improving resolution of CT, and then PET imaging, allowed the counting of macroscopic metastases by being more confident of the absence of further macroscopic metastases. That was a prerequisite to diagnose OMD. Weichselbaum had in mind that “recognition ... of a state of oligometastases is necessary to invite active clinical investigation of new and potentially curative therapeutic strategies”. In practical terms it is the therapeutic opportunity that makes OMD a useful working diagnosis, summarised as few enough to 'zap'. In 2015 Joseph Salama surveyed radiation oncologists on their clinical practice and opinions; 99% of 1007 regarded OMD as something for them to treat.

      It is the feasibility of treatment which characterises OMD. Many diseases are framed and reframed by whether they are amenable to treatment. A familiar example was the emergence of non small-cell lung cancer (NSCLC) as a diagnostic frame. In the 1970s, adenocarcinoma, squamous cell, and large cell anaplastic cancer had 25-30% five-year survival after lobectomy, but surgery for small-cell cancers nearly always failed. Conversely chemotherapy for lung cancer, then associated with modest responses, caused small-cell carcinoma to melt away, if only temporarily. It may seem strange to frame a disease by what it is not, but that is how NSCLC was framed. Lung cancer was dichotomised on the basis of response to treatments.

      We used use 'SBE' for subacute bacterial endocarditis and 'CVA' for cerebrovascular accident. In the modern world of heart surgery and antibiotic resistance, SBE is no longer a serviceable diagnostic frame. We must be specific about organisms, underlying lesions, and prostheses. With therapeutic interventions available for stroke we have to distinguish bleeding from embolism. The catch-all term 'CVA' will no longer serve. In time NSCLC will no doubt be unbundled on the basis of tumour markers, genomics, and targeted treatments. But in an era when we talk of precision medicine, it is remarkable that the 99 patients in SABR-COMET had more than five different primary and secondary sites, bundled as OMD.

      At Guy’s our lung cancer meetings were chaired by a lady radiologist who steered us with incisive clarity. She and I discussed treatment of metastases. She was just back from a trip to the US where she had many similar conversations. “It always ends up with the same question” she told me “Can you charge for it?”. So that is the reality. The 1007 radiation oncologists will view the SABR-COMET trial results as the evidence they need. People with ESRD demonstrably survive due to treatment but OMD does no more than identify patients at the tail of the survival distribution, those most likely to live a while longer. Attributing their survival to treatment of a few metastases that can be seen is largely illusory. If sound biological science is the Ghost we seek, we haven't caught it yet.

      nscl omd for iaslc abstract.jpg

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      CS01.02 - "Hunting a Ghost for 25 Years – Will We Ever Catch OMD?" - Yes (Now Available) (ID 3145)

      11:00 - 12:30  |  Presenting Author(s): José Belderbos

      • Abstract
      • Presentation
      • Slides

      Abstract

      The treatment options for NSCLC patients with a limited number of metastases at diagnosis (oligometastatic disease) have increased the past decade. The focus lies at combining systemic- and local radical treatments. With the introduction of oligometastatic disease (OMD) as a separate entity, a more radical treatment approach is increasingly applied. For OMD we distinguish synchronous OMD (in case of OMD at diagnosis) and metachronous OMD (in case of a limited amount of metastases as first event of an initially locally limited disease). There is also the term oligometastatic progression in which case during systemic treatment of a pluri-metastatic disease only few metastases progress. Finally there could be a situation called oligo persistence in case of remaining metastatic lesions. The existing literature is seriously flawed by the lack of consensus on the definition of oligometastatic disease. Often a maximum of 2-3 metastases are referred to as oligometastatic disease, but ≤5 metastases are also selected and considered for radical treatment.

      Important developments of local consolidative therapies in OMD

      Since 2016 several retrospective and prospective trials reported favorable progression free survival (PFS) for OMD treated with systemic therapy followed by local consolidative therapy (LCT). The intrathoracic disease is generally locally treated with radical radiotherapy or resection. Treatment of the metastases consists of radical or stereotactic radiotherapy, surgical resection or local ablative therapies. In an observational study radical local treatment for a selected group of NSCLC patients (n=91) with good performance status presenting with synchronous oligometastatic disease resulted in 14 months PFS and 32 months overall survival (OS).These results are comparable to outcomes for stage III NSCLC disease.

      De Ruysscher et.al. [2] reported a prospective single arm phase II study for synchronous oligometastatic disease treated with radical local treatment (radiotherapy or surgery) after first line chemotherapy. The median PFS and OS in this study were 12.1 months and 13.5 months respectively. After 24 months 15% of the patients did not show disease progression.

      In a trial Iyengar et al [4] randomized 29 metastatic NSCLC patients with up to 6 sites of extracranial disease (including primary) and a good performance. After induction chemotherapy non-progressive patients were randomized for maintenance chemotherapy or stereotactic radiotherapy. In an unplanned interim analysis, the median PFS was 9.7 months in the stereotactic radiotherapy arm versus 3.5 months in the maintenance chemotherapy arm.

      In a randomized phase II trial Gomez included 49 patients with stage IV NSCLC with three or fewer metastases, and no progression after first-line systemic therapy. The trial investigated LCT with stereotactic or conventionally fractionated radiotherapy or surgery versus maintenance therapy or observation. Patients in the LCT arm experienced improved PFS as well as improved OS [5].The trial was closed early because of a significant PFS and OS benefit in the LCT arm. With a median follow-up time of 38.8 months the PFS benefit with additional local therapy was 14.2 months versus 4.4 months in the maintenance therapy/observation arm (p=0.022). They also reported an impressive OS benefit in the LCT arm: 41.2 months versus 17.0 months (p=0.017). This OS benefit was achieved despite the fact that 41% of the patients in the maintenance therapy/observation arm crossed over to the local consolidative therapy arm at the time of progression. No additional grade 3 or greater toxicities were observed. It is important to know that these studies were performed in the pre-immunotherapy era.

      In patients with metachronous OMD (controlled primary tumour and 1-5 oligometastatic lesions) the effect of LCT on survival, toxicity, and quality of life in 99 patients was recently reported in the SABR-COMET trial: a randomized, phase 2 trial [4]. Patients were randomly assigned (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus stereotactic or conventional radiotherapy to all metastatic lesions (SABR group). Median overall survival was 28 months in the control group versus 41 months in the SABR group (p=0.090).

      Several reasons could explain the benefit by adding LCT for OMD in these trials:

      1) LCT potentiates the effects of systemic therapy

      2) By reducing the residual tumor burden, LCT delays the growth of distant micrometastatic disease

      3) LCT reduced the amount of treatment-resistant lung cancer cells

      4) Necrosis caused by LCT allows the immune system to induce an immune-specific reaction that affects distant cancer cells

      Conclusion: The synergy of local consolidative therapies combined with systemic treatments in oligometastatic patients is currently one of the most exciting developments in lung cancer treatment.

      Ref:

      1. Kwint M et al. Outcome of radical local treatment of non-small cell lung cancer patients with synchronous oligometastases. Lung Cancer. 2017 Oct;112:134-139. doi: 10.1016/j.lungcan.2017.08.006.

      2. De Ruysscher D et al. Progression-Free-Survival and Overall Survival beyond 5 years of non-small cell lung cancer patients with synchronous oligometastases treated in a prospective phase II trial (NCT 01282450). JTO 2018 doi: 10.1016/j.jtho.2018.07.098.

      3. Iyengar P et al. Consolidative Radiotherapy for Limited Metastatic Non-Small-Cell Lung Cancer: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2018 Jan 11;4(1):e173501. doi:10.1001/jamaoncol.2017.3501. Epub 2018 Jan 11.

      4. Gomez D et al. Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a Multi-Institutional, Phase II, Randomized Study. J Clin Oncol. 2019 Jun 20;37(18):1558-1565. doi: 10.1200/JCO.19.00201. Epub 2019 May 8.

      5. Palma D et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial.Lancet. 2019 May 18;393(10185):2051-2058. doi: 10.1016/S0140-6736(18)32487-5. Epub 2019 Apr 11

      6. Gu X et al. Cryoablation combined with molecular target therapy improves the curative effect in patients with advanced non-small cell lung cancer J Int Med Res. 2011;39(5):1736-43​

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      CS01.03 - Technical Reasons of Local Treatment Define the Limits of NSCLC OMD in Terms of Number of Metastases, Not a Fixed Number (Now Available) (ID 3146)

      11:00 - 12:30  |  Presenting Author(s): Marta Scorsetti

      • Abstract
      • Presentation
      • Slides

      Abstract

      Currently there is no consensus on the definition of oligometastatic disease in NSCLC, with 3 or 5 lesions historically considered as the upper limit [1]. A low number of metastases, indeed, is a good although not perfect surrogate of the biology behind the oligometastatic state. In real life practice, the number of metastatic lesions is often misleading, since it is possible to find patients with more than 5 metastases affected by a slowly progressing disease, potentially taking advantage from local treatments. On the contrary, patients affected by just one or two metastases can progress very rapidly with a dismal prognosis, despite the apparent low disease burden.

      Since the number of metastases is not a perfect indicator of oligometastatic state and biomarkers really able to identify this disease are lacking, there is a trend favoring the technical feasibility of local treatment over the number of metastases to treat. This approach has pros and cons. On one side, the idea of killing all visible cancer cells independently by their number is appealing and possibly with a positive impact on patient prognosis. On the other side, clinical data supporting such an aggressive local treatment have still a low level of evidence. Moreover, the definition of “technically feasible” is quite vague, particularly in the world of radiation oncology. Indeed, radiotherapy is strongly related to technological development. The innovations in this setting have dramatically increased the possible indications of radiotherapy, also for oligometastases. With state of the art radiotherapy, we are now able to treat virtually all sites in the body and it is becoming really difficult to define an upper limit to the number of lesions that can be treated. However, this is feasible only with advanced technologies, like image guided radiotherapy (IGRT), motion management (4D CT, gating, tracking, etc.), and heavy particles in particular clinical settings (retreatment for instance). This trend is creating a gap between Radiation Therapy Departments, since some treatments are becoming safely deliverable only in well selected Institutions with high expertise in this field.

      Despite all recent technological achievements, some clinical settings remain in which the risk-benefit ratio should be carefully weighted before delivering ablative dose to a metastatic patient. For instance, there are still uncertainties in the treatment of central lung lesions abutting on the main bronchus [2] or, changing scenario, the amount of remaining healthy liver is still limiting liver metastases treatment in some situations [3]. More importantly, the goal of local treatment of an oligometastatic patient should be to change the natural history of the tumor, independently from the number of metastases we are able to treat. Treating all the metastases, even though safely feasible, remains just a technical exercise if no impact on prognosis, quality of life or symptoms control is achievable. Oligometastatic disease has definitely a different biology, and every effort should be in the direction of identifying this biology [4]. Technologies have developed faster than our clinical and biological knowledge, and this should be kept in mind.

      In conclusion, the number of metastases remains a good clinical indication of oligometastatic state, but this number should not be an insuperable limit in clinical practice. Technical feasibility of local treatments (as radiotherapy) should be always carefully weighted accounting for risk-benefit ratio. Being able to treat any number of metastases should not be considered as a good reason for doing it indiscriminately. Physicians should always consider the clinical and biological reasons for a local ablative treatment in a metastatic patient, independently by technical issues.

      [1] Hong JC, Salama JK. The expanding role of stereotactic body radiation therapy in oligometastatic solid tumors: What do we know and where are we going? Cancer Treatment Reviews 52 (2017) 22–32

      [2] Videtic GM, Donington J, Giuliani M et al. Stereotactic body radiation therapy for early stage non-small cell lung cancer: Executive Summary of an ASTRO Evidence-Based Guideline. Practical Radiation Oncology (2017) 7, 295-301

      [3] Mondlane G, Ureba A, Gubanski M et al. Estimation of the risk for radiation-induced liver disease following photon- or proton-beam radiosurgery of liver metastases. Radiat Oncol. 2018 Oct 22;13(1):206. doi: 10.1186/s13014-018-1151-6

      [4] Correa RJ, Salama JK, Milano MT et al. Stereotactic Body Radiotherapy for Oligometastasis Opportunities for Biology to Guide Clinical Management. Cancer J. 2016 Jul-Aug;22(4):247-56.

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      CS01.04 - NSCLC OMD is Defined by a Fixed Maximum Number of Metastases, Not Technical Reasons of Local Treatment (Now Available) (ID 3147)

      11:00 - 12:30  |  Presenting Author(s): GAVIN Michael WRIGHT

      • Abstract
      • Presentation
      • Slides

      Abstract

      Other than a select group of patients with solitary brain metastases and cT1-2a N0 resectable primary cancers, the idea of aggressively ablating metastatic non-small cell lung cancer (NSCLC) has always been considered unconventional. The resectable solitary cerebral metastasis has traditionally yielded better results than any other M1b disease, and this has been put down to careful selection and perhaps a different biology in these rare cases. It wasn’t until the publication of a large individual patient data meta analysis in 20141 that more general treatment of OMD could be benchmarked and taken seriously enough to consider clinical trials. This confirmed that in select populations, long-term survival was achievable by surgical or radio-ablation of a small number of metastases. Only 1.9% of the series had more than 3 metastases and only 3% of the series had multi-organ disease. A main finding of multivariate analysis was that those with any nodal disease (effectively another metastatic site) did poorly.

      The definition of the oligometastatic disease state (OMD) has always been elusive. In principle, it is defined as M1a-c disease with low metastatic burden (usually up to three or five lesions) and limited organ involvement (usually up to two sites). It is considered an intermediate condition between truly localized disease and widely metastatic disease. The reporting bias of 1-3 metastases seen in so many published treatment series is tacit acknowledgement that OMD only encompasses three or fewer metastases, and probably to just a single organ. Our own IALSC TNM staging system recognizes this in our M1 sub-stages.

      Unlike oligo-metastatic colorectal carcinoma, sarcoma or renal cell carcinoma, which have reproducibly achieved long term survival after pulmonary metastasectomy (and/or hepatic metastasectomy) for several decades, the pace of disease and apparent inevitability of shortened lifespan in a patient with metastatic NSCLC has led to self-regulation of this practice for our tumour specialty. The relatively poorer average cardio-pulmonary fitness of patients with lung cancer and the maxim of ‘first do no harm’ largely tempered any enthusiasm.

      As surgery has become increasingly less invasive/morbid, and therapies such as stereotactic ablative body radiotherapy (SABR) and radiofrequency ablation have become more readily available, the temptation is to expand indications for intervention well beyond their evidence base and/or cost-benefit ratio. The last 5 years has seen a proliferation of publications of eyebrow-raising SABR series outside of any clinical trial protocols. This is a slippery slope that surgeons have been accused of sliding down in pulmonary metastasectomy for colorectal carcinoma2. We must not let our enhanced ability to inflict therapy dictate whether or not a condition is appropriate to treat. The definition of OMD cannot be stretched arbitrarily to match our technological capabilities or we will waste huge resources and inevitably cause some harm by way of futile overtreatment.

      The ‘breakthrough’ SABR-COMET trial3 has invigorated discussion and enthusiasm for treating NSCLC oligometastatic disease on the basis that overall survival was superior with ablation of OMD (41 months) compared to the control group treated with palliative measures (28 months). This enthusiasm does need to be tempered by a few salient observations. Firstly, this was a phase 2 trial of mixed histologies with 66 recruits in the treatment arm and 33 in the control arm. In all, only 18 enrolled patients had NSCLC, with 12 in the treatment arm. It is indeterminate from the paper how well these particular NSCLC patients performed and the confidence intervals would be wide. The follow-up tail becomes decidedly ‘bushy’ after 1 year due to censorship. There were three treatment-related deaths and four other serious adverse effects not seen in the control arm. The control rate was less optimistic than in Rusthoven’s phase 1 trial4, with 75% having no progression in targeted lesions (compared to 49% in the control arm).

      The most telling information supporting the ≤3 metastasis OMD hypothesis is the number of metastases and number of organs involved in the recruited SABR-COMET patients. Only 7 recruits had more than 3 metastases, with 5 of these receiving SABR. It is not clear if ANY of these had NSCLC, but these are not dissimilar numbers to the aforementioned NSCLC meta analysis1.

      Historically, there is far more data on survival after metastasectomy for series excluding NSCLC. Only 1% of pulmonary metastasectomies in the International Registry of Lung Metastases5 had NSCLC and some may have been second primaries. Whilst 26% of cases had ≥4 metastases resected, this was largely confined to sarcoma and germ cell tumours, where aggressive resection and re-resection is considered standard of care. Their survival was still inferior to patients with either solitary or 2-3 metastases. This is despite the likelihood that patients with ≥4 metastases are “hyper-selected’, based on survival characteristics such as performance status, younger age, excellent fitness, anatomical location and favourable observed tumour behaviour. This creates a false impression that this group is receiving not dissimilar survival benefit as the cohort with ablation of 1-3 metastases.

      OMD as a hypothesis is very reasonable and deserves to be tested. Diluting the potential benefits by expanding that definition to match our technological wizardry is not. Clinical trial resources would be better mobilized to further study surgical and/or SABR metastasectomy in lung cancer with ≤3 metastases in a single organ before expanding umbrella trials to ≥4 metastases.

      References

      1. Ashworth, A. B. et al. An individual patient data metaanalysis of outcomes and prognostic factors after treatment of oligometastatic non–small-cell lung cancer. Clin Lung Cancer 15, 346–355 (2014).

      2. Treasure, T., Internullo, E. & Utley, M. Resection of pulmonary metastases: a growth industry. Cancer Imaging 8, 121–124 (2008).

      3. Palma, D. A. et al. Stereotactic ablative radiotherapy for comprehensive treatment of oligometastatic tumors (SABR-COMET): Study protocol for a randomized phase II trial. BMC Cancer 12, 8 (2012).

      4. Rusthoven, K. E. et al. Multi-institutional phase I/II trial of stereotactic body radiation therapy for lung metastases. J. Clin. Oncol. 27, 1579–1584 (2009).

      5. Pastorino, U. et al. Long-term results of lung metastasectomy: prognostic analyses based on 5206 cases. The Journal of Thoracic and Cardiovascular Surgery 113, 37–49 (1997).

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    ES11 - Lung Cancer Plasticity and Drug Resistance (ID 14)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Biology
    • Presentations: 6
    • Now Available
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      ES11.01 - Lung Adenocarcinoma to Squamous Cell Carcinoma Transdifferentiation and Drug Resistance (Now Available) (ID 3211)

      15:15 - 16:45  |  Presenting Author(s): Hongbin Ji

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancer is notorious for high heterogeneity and strong plasticity, which might contribute to the development of drug resistance. Lineage transition from lung adenocarcinoma (ADC) to squamous cell carcinoma (SCC), as implicated by clinical observation of mixed ADC and SCC pathologies in adenosquamous cell carcinoma (Ad-SCC), reflects strong cancer plasticity and potentially links to drug resistance. Using Genetically Engineered Murine Model (GEMM), we have provided in vivo evidence in supporting the ADC to SCC transdifferentiation (AST): Lkb1-deficient mouse lung ADC transdifferentiates into SCC progressively via pathologically mixed Ad-SCC. Mechanistically, we find that down-regulation of reactive oxygen species (ROS) level through N-acetyl cysteine (NAC) treatment or NRF2 expression inhibits this transition, highlighting the functional importance of ROS in regulating cancer plasticity. Pentose phosphate pathway deregulation and impaired fatty acid oxidation collectively contribute to the redox imbalance and functionally affect the AST process. Importantly, similar tumor and redox heterogeneity are also found in human LKB1-inactivated lung cancer. In preclinical trials toward metabolic stress, Lkb1-inactivated ADC can develop drug resistance through squamous transdifferentiation. Recent observations in clinic further suggest that such pathological transition might be responsible for resistance to tyrosine kinase inhibitor (TKI) therapy and chemotherapy in relapsed EGFR-mutant lung ADC patients. These findings demonstrate that lung cancer plasticity potentially affects therapeutic response and precision medicine through histological transition.

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      ES11.02 - SCLC Lineage Transformation in Lung Adenocarcinoma and Resistance to Targeted Therapies (Now Available) (ID 3212)

      15:15 - 16:45  |  Presenting Author(s): William Lockwood  |  Author(s): Yusuke Inoue

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung cancers are typically divided into two main histological types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of all cases and lung adenocarcinoma (LUAD) is the most frequent subtype. Current treatments of LUAD aim to inhibit driver oncogene alterations and have shown unprecedented success. Among the oncogenic alterations in LUAD, EGFR kinase domain mutations are found in ~40-50% of patients in east-Asian countries and 20% of patients in western countries1. EGFR tyrosine kinase inhibitor (TKIs) are highly effective for tumors with EGFR mutations and resistance mechanisms to these compounds have been well documented: the most frequent being the acquisition of a secondary mutation in EGFR (T790M)2, followed by amplification of the hepatocyte growth factor receptor (MET) gene3 and mutations in BRAF and PIK3CA genes4,5. Histological transformation from LUAD to SCLC occurs in up to 15% of cases with acquired resistance to first and second generation EGFR TKIs5. Histological plasticity as a mechanism of resistance is becoming increasingly prominent as other resistant mechanisms can now be successfully targeted: MET-inhibitors are employed for MET-amplified tumours and 3rd generation EGFR TKIs are used to overcome resistance driven by the EGFR T790M muation6. Importantly, the 3rd generation EGFR TKI osimertinib was approved by the FDA in 2018 and thus, cases of treatment-induced SCLC transformation may increase in prominence as other mechanisms are targeted. Currently, conventional platinum doublet chemotherapy is the standard of care for patients with treatment-induced SCLC as well as de novo SCLC. Unfortunately, this treatment often produces an incomplete and non-durable response followed by inevitable relapse within months, leading to poor patient outcomes7. Thus, this mechanism of resistance will represent a major barrier towards the success of 3rd generation TKIs and new strategies to prevent this lineage shift or to treat SCLC transformed tumors are urgently needed.

      Despite the increasing clinical importance of LUAD to SCLC transformation, the biological pathways regulating this process are poorly understood. Since the first description in 20068, numerous studies have aimed to characterize the molecular changes that drive transformation in the context of drug resistance. Assessment of clinical samples has revealed that EGFR-mutant tumors universally lose EGFR protein expression upon SCLC transformation, despite still harboring EGFR mutations that confirms their clonal origin9. Furthermore, the mutation spectrum of these transformed cases often resemble de novo SCLC, containing inactivation of the tumor suppressors RB and p53 in nearly all cases9. This mirrors neuroendocrine transformation that occurs in prostate adenocarcinoma, where loss of RB/p53 are known to upregulate the reprogramming transcription factor SOX2, driving lineage plasticity and resistance upon anti-androgen therapy10. Furthermore, loss of RB and inactivation of p53 are required to reprogram a normal cell of epithelial lineage to a neuroendocrine lineage, and when combined with expression of myristoylated AKT1 and overexpression of MYC and BCL2, leads to the development of lethal SCLC in vivo11. Inactivation of p53 and RB also leads to the development of SCLC in transgenic mouse models, even when targeted in specifically to type-II airway epithelial cells, the putative cell of origin for EGFR-mutant LUAD12. Together, these studies highlight the essential role for these tumor suppressor genes in reprograming transcriptional profiles and chromatin accessibility in facilitating neuroendocrine lineage transformation.

      However, accumulating experimental evidence has demonstrated that while necessary, dual inactivation of RB and p53 is not sufficient to cause SCLC lineage transformation in EGFR-mutated LUAD, suggesting that additional factors are required9. MYC amplification and PIK3CA mutation have been proposed to potentially cooperate with RB/p53 loss to facilitate transformation13, and specific epigenetic regulators may also provide the appropriate context for lineage reprograming to occur. Despite this, no in vitro or in vivo models of SCLC transformation in EGFR TKI resistance have been developed, making it difficult to comprehensively explore the molecular events driving this lineage shift. Interestingly, there are clear differences between LUAD and SCLC regarding EGFR expression and gene alterations in MAPK pathway including EGFR/KRAS mutations: EGFR is usually not expressed14 and EGFR/KRAS mutations are extremely rare in SCLC15; in contrast, EGFR/KRAS play crucial roles in LUAD biology, including regulating differentiation in addition to prolferation16. To date, however, no clear explanation has been given for these differences. We have recently shown that activation of MAPK signaling in SCLC leads to suppression of the neuroendocrine phenotype - including downregulation of the transcription factors NEUROD1, INSM1, BRN2 and ASCL1 - and transformation to a NSCLC-like state17. Using this model system, we have begun to elucidate the key transcription factors and epigenetic changes that drive SCLC to NSCLC transformation in the hope that the same processes will also be involved in the clinically relevant scenario: SCLC transformation from EGFR mutant LUAD during TKI resistance. We suggest that only EGFR-mutant LUADs that do not reactivate MAPK signaling through secondary EGFR mutations or alterations in parallel kinase pathways (ie. MET) during development of TKI resistance will be able to undergo SCLC lineage transformation, and that RB/p53 loss and epigenetic plasticity provide the permissive context for which this transformation can occur. Greater understanding of lineage transformation in LUAD will provide important insights in terms of managing outcomes of patients undergoing targeted therapy and offer new avenues towards treatment of TKI resistant tumors.

      References:

      1. Dearden S et al. Ann Oncol 2013;24:2371-6.

      2. Kobayashi S et al. NEJM 2005;352:786-92.

      3. Bean J et al. PNAS 2007;104:20932-7.

      4. Ohashi K et al. PNAS 2012;109:E2127-33.

      5. Sequist LV et al. Sci Transl Med 2011;3:75ra26.

      6. Mok TS et al. NEJM 2017;376:629-40.

      7. Roca E et al. Cancer Treat Rev 2017;59:117-22.

      8. Zakowski MF et al. NEJM 2006;355:213-5.

      9. Niederst MJ et al. Nat Commun 2015;6:6377.

      10. Mu P et al. Science 2017;355: 84-8.

      11. Park et al. Science. 2018;362:91-95.

      12. Sutherland KD et al. Cancer Cell 2011;19:754-64

      13. Lee JK et al. J Clin Oncol. 2017;35:3065-3074.

      14. Gamou S et al. Cancer Res 1987;47:2668-73.

      15. Cristea S et al. J Thorac Oncol 2016;11:1233-41.

      16. Byers LA et al. Cancer Discov 2012;2:798-811.

      17. Y. Inoue and W. Lockwood. J Thorac Oncol 2018;13:S433–S434.

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      ES11.03 - Immunotherapy and Endogenous Retroviruses in Small-Cell Lung Cancer (Now Available) (ID 3213)

      15:15 - 16:45  |  Presenting Author(s): Israel Canadas

      • Abstract
      • Presentation
      • Slides

      Abstract

      Introduction: Tumor cell heterogeneity is a key determinant of cancer progression and drug resistance, which is often mediated by

      mesenchymal cell subpopulations. While these subclones can secrete growth factors, chemokines and cytokines, the immune signaling

      networks that fuel this pro-tumorigenic state remain incompletely defined. Elucidating what underlies this state would provide insights into

      tumor biology and inform clinical strategies to improve anti-cancer therapies.

      Methods: Because of their well-defined nature, we used the phenotypically distinct H69M and H69AR Small Cell Lung Cancer (SCLC)

      mesenchymal subclones to uncover a novel mechanism of dysregulated innate immune signaling as compared with parental neuroendocrine

      H69 cells. Analysis of gene signatures across TCGA and CCLE databases, functional studies in additional cell lines, and ex vivo testing of

      patient-derived organotypic tumor spheroids (PDOTS) were conducted to determine the broader relevance across human cancers.

      Results: We discovered a novel epigenetically regulated subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in

      mesenchymal cancer subpopulations. Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3’UTRs of

      certain interferon-inducible genes and silenced by EZH2. De-repression of these loci resulted in dsRNA generation following IFNγ exposure

      due to bi-directional transcription from the STAT1-activated gene promoter and the 5’ LTR of the antisense ERV. We found that dsRNA sensing

      preferentially by MAVS fuels activation of TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction across

      specific human tumors and cell lines is tightly associated with downregulation of chromatin modifying enzymes, including EZH2, a

      mesenchymal AXL positive cell state, and B2M and MHC class 1 antigen expression. SPARCS high tumors were marked by immune infiltration,

      but also exhibited multiple features of tumor

      immune suppression. IFNγ treatment of PDOTS with de-repressed SPARCS markedly enhanced CXCL10 production and sensitized them to

      PD-1 blockade.

      Conclusions: Together, these data unveil a novel subclass of ERVs whose de-repression triggers pathologic innate immune signaling in cancer,

      with potentially important implications for cancer immunotherapy.

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      ES11.04 - Mechanisms for Resistance to TKI and ICI (Now Available) (ID 3214)

      15:15 - 16:45  |  Presenting Author(s): Katerina Politi

      • Abstract
      • Presentation
      • Slides

      Abstract

      Targeted therapies and immunotherapies have transformed the treatment landscape for lung cancer over the past 15 years. These therapies are effective in subsets of patients, however, acquired resistance is an impediment to cures. In the case of targeted therapies, acquired resistance occurs in all cases although new generations of targeted therapies delay inevitable relapse. Upon treatment with immune checkpoint inhibitors, data suggest that acquired resistance occurs in ~50% of cases following an initial response to the therapies. However, studies of acquired resistance to these immunotherapies are limited and the exact frequency remains to be determined. Therefore understanding the mechanisms of acquired resistance to targeted therapies and immunotherapies is of critical importance to developing new therapeutic strategies to overcome and prevent the emergence of drug resistance.

      EGFR mutant lung cancer is a paradigm for the use of targeted therapies in this disease. Tyrosine kinase inhibitors (TKIs) are the first line of treatment for EGFR mutant lung cancer and are effective in 70-80% of cases. Acquired resistance to first and second generation inhibitors, like erlotinib, gefitinib and afatinib, most frequently is the result of a secondary mutation in EGFR, EGFR T790M. Third generation TKIs that can inhibit the activity of EGFR T790M-containing mutants were recently developed and one of these, osimertinib, is now approved for the first- and second-line treatment of EGFR mutant lung cancer and is increasingly used in the clinic. Even with osimertinib, acquired resistance occurs and there is a need to understand the mechanisms of resistance to this TKI. We will review current knowledge of acquired resistance to osimertinib and discuss new findings from studies in genetically engineered mouse models, patient-derived xenografts, patient specimens and cell line models.

      In contrast to the extensive knowledge of the mechanisms of acquired resistance to TKIs, very little is known about acquired resistance to immune checkpoint inhibitors. In melanoma, lung cancer and colon cancer, defects in antigen processing and presentation have emerged as a mechanism of acquired resistance to these agents. Defects in this pathway can occur in different ways including loss of specific neoantigens and genetic loss or downregulation of essential components of the pathway like b2-microglobulin. In the presentation, we will discuss known mechanisms of acquired resistance to immune checkpoint inhibitors and new approaches and models that we and others are developing to study this problem.

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      ES11.05 - MSK-IMPACT, a Hospital Based Genetic Screening Using FDA-Approved NGS System (Now Available) (ID 3215)

      15:15 - 16:45  |  Presenting Author(s): Alexander Drilon

      • Abstract
      • Presentation
      • Slides

      Abstract

      A variety of actionable genomic signatures are found across different cancer types. These signatures have been associated with clinical benefit from a variety of therapeutics, including targeted therapy and immunotherapy. MSK-IMPACT is a broad, hybrid capture-based next-genereation sequencing platform that is capable of detecting sequence mutations, small insertions and deletions, copy number alterations, and select structural rearrangements. The assay has been validated and approved for clinical use by the New York State Department of Health Clinical Laboratory Evaluation Program. Furthermore, the assay has received authorization by the United States Food and Drug Authority. Comprehensive profiling of various cancers with assays such as MSK-IMPACT has advanced genomic medicine by increasing the identification of patients for whom matched therapies may be appropriate, elucidating putative resistance mechanisms, and identifying novel, potentiallly actionable signatures.

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      ES11.06 - Toxicology of Tobacco and Metabolites, and Impact on Cancer (Now Available) (ID 3216)

      15:15 - 16:45  |  Presenting Author(s): Maciej L. Goniewicz

      • Abstract
      • Presentation
      • Slides

      Abstract

      Tobacco smoke is a significant source of exposure to toxic compounds among active smokers and those exposed to secondhand smoke (SHS). Over 7000 chemicals have been identified in tobacco smoke, including 69 known carcinogens. Characterizing human exposure to tobacco smoke constituents is important for public health efforts aimed at reducing exposure to these chemicals. Tobacco smoke exposure can be assessed through biomonitoring, i.e., by measuring the concentration of a toxicant or its metabolites in human physiological fluids. Biomarkers, ideally unique to a toxic mixture such as tobacco smoke, are useful for exposure assessment and for source apportionment. Nicotine, its metabolites, and the tobacco-specific nitrosamine (TSNA) metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) are the most specific of the commonly used biomarkers for tobacco smoke exposure. Carbon monoxide, metabolites of volatile organic compounds (VOCs), and polycyclic aromatic hydrocarbons (PAHs) metabolites, are also useful biomarkers, but they have sources other than tobacco smoke. Levels of these biomarkers are generally elevated in smokers as compared to nonsmokers, but specificity may be inadequate to measure SHS exposure. In general, biomarker studies can demonstrate internal exposure to toxic constituents due to tobacco product use and can be used to assess relative harm of modified-risk tobacco products. Epidemiologic studies directly support a link between exposure to tobacco-specific toxicants and subsequent risk for cancer in smokers of conventional cigarettes as well as lifelong never-smokers.

      Nicotine metabolites and total nicotine equivalents (sum of nicotine, cotinine, 3ʹ-hydroxycotinine, and their glucuronides), which can be measured in urine, blood or saliva, represent approximately 73%–96% of the nicotine dose and provide a superb indicator of nicotine uptake. Although nicotine was one of the first biomarkers to be used for assessing exposure to cigarette smoke, its short half-life (t1/2=~2 h) and variable rate of metabolism led to the use of cotinine and other nicotine metabolites as biomarkers of nicotine exposure. Cotinine is the major metabolite of nicotine, and its longer elimination half-time (t1/2=16–18 h) makes it a good biomarker for nicotine uptake in various biological fluids and tissues. The nicotine metabolite ratio (ratio of 3ʹ-hydroxycotinine to cotinine) in plasma is an excellent phenotypic indicator of hepatic CYP2A6 activity in smokers and can be used as a measure of individual risk for addiction.

      Tobacco-specific nitrosamines (TSNAs) include the potent lung carcinogen NNK and the oral cavity and esophageal carcinogen N′-nitrosonornicotine (NNN) and are—as indicated by their common name—regarded as completely specific to tobacco. Consequently, these compounds and their metabolites are among the most important biomarkers for monitoring tobacco exposure and evaluating cancer risk in tobacco users. NNAL is a metabolite of NNK and itself is a carcinogen. A key benefit of NNAL assays is the compound’s elimination half-time ( t1/2 of 10–18 days), which is longer than other tobacco biomarkers. The main disadvantage is that the urinary concentration of NNAL is many times lower than that of cotinine, so the assay is more technically challenging and expensive to perform. Measurements of NNAL typically require extensive sample preparation and fewer laboratories can reliably measure NNAL than cotinine or nicotine.

      Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants formed from incomplete combustion of organic matter and use of combustible tobacco products results in substantial exposure to those chemicals. Over 500 PAHs and their alkyl derivatives have been identified in tobacco smoke. Some PAHs induce tumors in animals and are carcinogenic to humans. For example, benzo[a]pyrene induces malignant lesions in animal studies. Urinary concentrations of PAH metabolites, specifically monohydroxylated PAHs, have been used as biomarkers of human exposure to PAHs including naphthalene, fluorene, phenanthrene and pyrene. The PAH exposure profiles for tobacco smoke may differ from other sources, and it may be possible to identify PAH biomarkers that are more selective for tobacco smoke than others.

      Volatile organic compounds (VOCs) are a diverse group of chemicals that are abundant in tobacco product emissions and in the polluted atmosphere. Many VOCs are formed by incomplete combustion of organic materials, and tobacco is not the only source of exposure. Although VOCs are also present in foods and beverages, the levels of many VOCs and VOC metabolites are elevated in smokers’ urine compared with nonsmokers. Several VOCs in tobacco smoke, including acrolein, benzene, and 1,3-butadiene, can cause cardiovascular and lung damage. 1,3-butadiene is also a human carcinogen and benzene is a human carcinogen known to cause leukemia. A number of harmful VOCs and their metabolites can be measured in human blood, urine, and breath and those biomarkers serve as a surrogate measure for tobacco smoke exposure.

      While tobacco-specific biomarkers are useful for interim assessments of exposure, there are several sources of variation to consider when interpreting such data. These include frequency and intensity of tobacco use product type, inter- and intra-individual variability, biomarker/chemical half-life, and variability in lab methods. Differences in carcinogen exposure from different cigarette products could contribute to differences in smoking-associated cancer incidence. Due to the introduction of new tobacco-derived products and the development of novel ways to modify and use conventional tobacco products, biomarker studies can be used to assess relative harm of modified-risk tobacco products. For example, short-term observational studies have shown reduction in biomarker levels for VOCs, TSNAs, and PAHs in cigarette smokers who switched to e-cigarettes, smokeless or heated tobacco products. This suite of biomarkers has the potential to provide objective data on levels of nicotine as well as selected important carcinogens and toxicants that may be associated with use of novel tobacco products.

      Selected Biomarkers of Exposure to Tobacco Products
      Toxicant Group Tobacco Constituents Biomarkers Clinical Relevance
      Nicotine Metabolites Nicotine Cotinine Addictive chemical
      Tobacco Specific Nitrosamines (TSNAs) 4-methylnitrosamino)-4-(3-pyridyl)-1-butanon (NNK) 4-methylnitrosaminol)-4-(3-pyridyl)-1-butanol (NNAL) Carcinogen
      Polycyclic Aromatic Hydrocarbons (PAHs) Naphthalene and Pyrene 2-Napthol and 1-Hydroxypyrene Possible human carcinogens
      Volatile Organic Compounds (VOCs) Acrylonitrile, acrolein, acrylamide CYMA, CEMA, AAMA Probable human carcinogens

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    ES20 - Strategies for Cancer Patients to Have Optimal Outcomes (ID 23)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Prevention and Tobacco Control
    • Presentations: 5
    • Now Available
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      ES20.01 - Tobacco Cessation After Cancer Diagnosis: Declaration from IASLC (Now Available) (ID 3267)

      14:00 - 15:30  |  Presenting Author(s): Jacek Jassem

      • Abstract
      • Presentation
      • Slides

      Abstract

      Tobacco Cessation After Cancer Diagnosis: Declaration from IASLC

      Tobacco use is a well established cause of cancer, contributing to about 1 in 3 cancer deaths annually. Whereas detrimental effects of smoking are well recognized, the harms of continued smoking after a cancer diagnosis are undervalued (1). Smoking by cancer patients and survivors causes adverse treatment outcomes, including increased overall mortality, cancer related mortality and risk for second primary cancer, and considerably increases cancer treatment toxicity (2,3). The clinical effects of smoking after a cancer diagnosis has a substantial effect on increased cancer treatment costs (4). Smoking cessation after a cancer diagnosis can improve cancer treatment outcomes (1), but most cancer patients who smoke at the time of diagnosis persist in a smoking habit during long term follow-up (5). Unfortunately, oncologists often do not work with their patients to quit, and do not provide tobacco cessation assistance for continuing tobacco users (6,7). Large analyses of IASLC members demonstrate that although most oncologists recognize that smoking causes adverse outcomes, approximately 90% ask about tobacco use and 80% advise patients to quit, only few offer assistance with quitting (8). There is a clear and unmet need to address tobacco use in patients with cancer. The diagnosis of cancer is “the teachable moment”, allowing health care professionals the best opportunity to discuss with patients their lifestyle habits, including nicotine addiction (9). An enhanced focus on smoking cessation at the time of a cancer diagnosis and its active promotion may increase patients’ motivation to quit. All patients should be screened for tobacco use and advised on the benefits of tobacco cessation. In patients who continue smoking after diagnosis of cancer evidence-based tobacco cessation assistance should be routinely and integrally incorporated into multidisciplinary cancer care. Smoking status should be a required data element for all prospective clinical studies, and clinical trials of patients with cancer should be designed to determine the most effective tobacco cessation interventions (10). Recognizing the critical importance of smoking cessation to increase the efficacy of cancer treatment, these postulates will be a subject of IASLC Declaration presented at the 20th World Conference On Lung Cancer in Barcelona.

      References:

      1. Warren GW, Simmons VN. Tobacco Use and the Cancer Patient. In: Lawrence TL. editor. DeVita, Hellman, and Rosenberg's Cancer: Principles and Practice of Oncology, 11th ed. Philadelphia, PA: Lippincott, Williams, & Wilkins, 2018.

      2. National Center for Chronic Disease Prevention and Health Promotion (US) Office on Smoking and Health. The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General. Atlanta, GA: Centers for Disease Control and Prevention, 2014.

      3. Jassem J. Tobacco smoking after diagnosis of cancer: clinical aspects. Transl Lung Cancer Res 2019. doi: 10.21037/tlcr.2019.04.01

      4. Warren GW, Cartmell KB, Garrett-Mayer E, et al. Attributable failure of first-line cancer treatment and incremental costs associated with smoking by patients with cancer. JAMA Netw Open 2019;2:e191703.

      5. Westmaas JL, Newton CC, Stevens VL, et al. Does a recent cancer diagnosis predict smoking cessation? An analysis from a large prospective US cohort. J Clin Oncol. 2015;33:1647-52.

      6. Burke L, Miller LA, Saad A, et al. Smoking behaviors among cancer survivors: an observational clinical study. J Oncol Pract 2009; 5: 6-9.

      7. Warren GW, Marshall JR, Cummings KM, et al. Addressing tobacco use in patients with cancer: a survey of American Society of Clinical Oncology members. J Oncol Pract 2013; 9: 258-62.

      8. Warren GW, Marshall JR, Cummings KM, et al. Practice patterns and perceptions of thoracic oncology providers on tobacco use and cessation in cancer patients. J Thorac Oncol. 2013;8:543-8.

      9. Gritz ER, Fingeret MC, Vidrine DJ et al. Successes and failures of the teachable moment: smoking cessation in cancer patients. Cancer. 2006 Jan 1;106:17-27.

      10. Toll BA, Brandon TH, Gritz ER, et al. Assessing tobacco use by cancer patients and facilitating cessation: An American Association for Cancer Research Policy Statement. Clin Cancer Res 2013; 19: 1941-8.

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      ES20.02 - Why It Matters for Patients to Quit - What We’ve Done (Now Available) (ID 3263)

      14:00 - 15:30  |  Presenting Author(s): Abhishek Shankar

      • Abstract
      • Presentation
      • Slides

      Abstract

      Smoking after a cancer diagnosis causes adverse outcomes including increasing overall mortality, cancer specific mortality, and risk for second primary cancer. Continued smoking is also associated with increased toxicity from cancer treatment. The best method to prevent the adverse effects of smoking is to assist patients with quitting. However, large surveys consistently demonstrate that while most providers ask about tobacco use and advise patients to quit, most oncologists unfortunately do not provide assistance. Predictive barriers to providing assistance with quitting include a lack of time, education, and resources. Continued smoking after a diagnosis can result in substantial added cancer treatment costs, which can be used to justify resources to assist patients with quitting. Methods to assist patients include counseling and pharmacotherapy. Considering in person or phone based approaches to cessation support is important to implement effective and sustainable changes within each practice setting. As approaches are implemented, significant opportunity exists to increase the efficiency of smoking cessation in cancer care. Additional opportunities exist for identifying optimal cancer treatment strategies for cancer patients who smoke. The key to realizing the clinical and financial benefits of addressing tobacco use in cancer care is the systemic incorporation of standardized approaches to identifying tobacco use, providing assistance for patients to quit, and tracking tobacco use after diagnosis in combination with monitoring clinical outcomes.”

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      ES20.03 - Tobacco Control Integration in Cancer Care: The Canadian Experience (Now Available) (ID 3264)

      14:00 - 15:30  |  Presenting Author(s): William K. Evans  |  Author(s): Rebecca Truscott, Erin Cameron, Caitlyn Timmings, Mohammad Haque, Michelle Halligan, Sargam Rana, Deb Keen, Linda Rabeneck

      • Abstract
      • Presentation
      • Slides

      Abstract

      The evidence that smoking cessation improves outcomes for cancer patients is irrefutable. Continued smoking after a diagnosis of cancer can increase all-cause and cancer-specific mortality, result in increased adverse treatment effects and cause a higher incidence of recurrence and second malignancies (1,2).

      In 2011, Cancer Care Ontario (CCO) noted the potential benefits of smoking cessation in two seminal papers (3,4) and established a Steering Committee to create an implementation framework for a provincial smoking cessation initiative. The framework provided guidance on standard program elements, optional regional initiatives and central administrative support (5). Required elements included screening of all new ambulatory cancer patients using a standardized tobacco screening question to identify current and recent smokers (smoked within past six months); appointment of regional smoking cessation Champions; training for healthcare providers on the health benefits of smoking cessation for cancer patients; referral of patients willing to accept help in quitting; and submission of performance metric data.

      Optional elements of the framework were the intensity of the regional smoking cessation intervention and location of smoking cessation services (cancer centre or host hospital vs external provider).

      Central administrative support included a secretariat within the division of Prevention and Cancer Control, and a central database within Analytics and Informatics.

      Patients were to be screened for smoking status by a nurse or physician using the 5As (ask, advise, assess, assist, arrange) model of smoking cessation. The screening question asked is “Have you used any form of tobacco in the last six months?” To assess a patient’s willingness to quit, the question asked is “Are you interested in learning about what is available to help you avoid smoking/using tobacco in the future?” Centres were to develop an inventory of regional smoking cessation resources. Potential resources included the Canadian Cancer Society’s Smokers’ Helpline – a quit line accessible by phone, web and text-based messages (6), trained pharmacists and family physicians, public health units and hospital and community-based smoking cessation clinics.

      In 2016, based on the Ontario initiative, the Canadian Partnership Against Cancer (CPAC) offered funding to all provinces to plan, implement or evaluate smoking cessation initiatives within cancer centres. Seven provinces and two territories made submissions in response to CPAC’s request for proposals, leading to multiple new efforts within cancer agencies across Canada to assist cancer patients to stop smoking (7). Cancer Care Ontario used funding from CPAC to implement educational initiatives for both providers and patients (e.g., development of posters, multilingual brochures and videos), and to conduct a survey to determine best implementation processes. Monthly teleconferences with the regional Champions and annual face-to-face meetings to review progress and celebrate successes were critical success factors.

      Other factors that contributed to a successful implementation were strong leadership from the Steering Committee (now Advisory Committee), commitment from CCO executive and clinical leadership and the use of performance metrics and performance management. The initial five key performance metrics were: 1) proportion of ambulatory cancer patients screened for smoking status; 2) proportion of those screened who were current or recent smokers; 3) proportion of smokers advised to quit smoking; 4) proportion of those advised to quit who were recommended a referral to smoking cessation services; and 5) proportion of those offered a referral who accepted a referral. Two metrics (tobacco use screening and accepted a referral) are reviewed on a quarterly basis by senior CCO executives with the regional cancer centre leaders in order to drive change. Targets are set and performance metrics on smoking cessation are used, amongst others, to determine the overall ranking of a cancer centre within the province of Ontario.

      Most of the 14 regional cancer centres are achieving the target of 75% of new ambulatory cancer patients screened for tobacco use but fall below the target of 25% for acceptance of a cessation referral. This poor performance led to the adoption of an “opt-out” approach in which patients are automatically referred to smoking cessation services unless they specifically refuse.

      It is critical that busy oncologists not be overburdened, and that other frontline staff assume responsibility for implementing the smoking cessation program. “Scripts” can communicate to patients that the physician wants them to stop smoking in order to get the best results from treatment. Using 3As (ask, advise, act) also minimizes the burden on staff.

      CPAC has disseminated these learnings across Canada and engaged all 10 provinces and three territories in a 2019-21 funding initiative requiring an evaluation plan with 15 quality indicators. Already, a 10% increase in the level of implementation of evidence-based tobacco cessation programs within ambulatory cancer settings across Canada has occurred (56% adoption in 2017/18; 66% adoption in 2018/19).

      The approaches to smoking cessation vary by jurisdiction (7,) but the culture within cancer centres is evolving with a growing realization that it is never too late for a cancer patient to stop smoking, and acceptance that smoking cessation must be integrated into cancer treatment for it to be truly considered quality cancer care.

      References:

      Toll BA, Brandon TH, Gritz ER et al. AACR subcommittee on tobacco and Cancer. Assessing tobacco use by cancer patients and facilitating cessation: an American Association for Cancer Research policy statement. Cancer Clin Cancer Res 2013; 19:1941 – 1948.

      Health consequences of smoking – 50 years of progress: a report of the Surgeon General, 2014. Available at http://www.surgeongeneral.gov/library/reports/50-years-of-progress/

      Parson A, Daley A, Begh R, Aveyard P. Influence of smoking cessation after diagnosis of early stage lung cancer on prognosis: systematic review of observational studies with meta-analysis. BMJ 2010; 340: b5569

      Browman GP, Wong G, Hodson I et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 1993; 328:159 – 76.

      Evans WK, Truscott R, Cameron E, et al. Lessons learned implementing a province-wide smoking cessation initiative in Ontario’s cancer centres. Curr Oncol 2017 Jun; (3): 185 – 190.

      Get help to quit smoking - Canadian Cancer Society. Available at: https://www.cancer.ca/en/support-and-services/support-services/quit-smoking/?region=on

      Integrating Tobacco Cessation + Relapse Prevention to Improve Quality of Cancer Care. Available at: https://content.cancerview.ca/download/cv/prevention_and_screening/tobacco_cessation/documents/integrating_tobacco_cessation_relapse_prevention_one_pager_en_frpdf?attachment=0

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      ES20.04 - Tobacco Control Integration in Cancer Care: The Jordan Experience (Now Available) (ID 3265)

      14:00 - 15:30  |  Presenting Author(s): Feras Ibrahim Hawari

      • Abstract
      • Presentation
      • Slides

      Abstract

      Tobacco Control Integration in Cancer Care: The Jordan Experience

      Tobacco control is an integral component of any action plan that aims to reduce cancer incidence and mortality. Efforts at King Hussein Cancer Center, the only comprehensive cancer center in Jordan and the region, started 10 years ago. We sought to address the tobacco epidemic in Jordan on multiple fronts. In Jordan, tobacco prevalence exceeds 60%. About 50% of patients presenting with a cancer diagnosis are smokers. Integrating tobacco control in general and tobacco dependence treatment in patients suffering from cancer is pivotal. Smoking in patients with cancer has been shown to impact cancer treatment, increase complications from cancer treatment, increase cancer recurrence, increase the odds of development of secondary malignancies and eventually decrease overall long-term survival. Throughout the last 10 years our tobacco dependence tretament program grew in services and scope. The program addressed three major components required for tobacco control in cancer patients: First, patient-centered clinical tobacco dependence treatment service. Second, tobacco dependence treatment training and education for health-care providers. Third, research that addresses tobacco dependence in cancer patients. Our program provides 6 smoking cessation clinics every week dedicated mainly to our cancer patients. We have managed to address training needs for our staff by establishing a tobacco treatment specialist training program, the first ever to be accredited by The Council for Tobacco Treatment Training Programs outside the USA. We studied outcomes of our treatment program and developed means to improve referral to smoking cessation clinics as well as improve the abstinence of our patients. In addition, we studied knowledge, attitude and perception of our health care providers working at our institution; a step especially important in a country where significant numbers of health care providers are smokers. Finally, we studied the impact of our tobacco dependence treatment program on the survival of our patients. Understanding the impact of smoking cessation on short-term survival of patients with cancer (2 years) highlights the importance of integrating such programs as part of the acute treatment phase of these patients. Cancer registry and smoking cessation clinic data for cancer patients diagnosed between 2012 and 2016 were analyzed. Approximately 19% of cancer patients were seen at the smoking cessation clinic. In a sub-sample of 2,387 patients, a significant two-year survival advantage was observed for smokers who had visited the smoking cessation clinic and confirmed that they had not smoked on at least two of their 3, 6 or 12-month follow-up visits (HR 2.8, 95% confidence interval [CI] = 1.7–4.5) relative to those who never went to the smoking cessation clinic. Those at the smoking cessation clinic who were abstinent at only one follow-up point also exhibited a survival advantage (non-abstainers at the smoking cessation had comparable survival to those who were not seen at the clinic).

      In conclusion, tobacco control in patients with cancer has an important role in the outcome and survival of these patients and must be integrated in their short and long-term plan of care.

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      ES20.05 - Tobacco Control in Indonesia (Now Available) (ID 3266)

      14:00 - 15:30  |  Presenting Author(s): Sita Andarini

      • Abstract
      • Presentation
      • Slides

      Abstract

      Tobacco Control in Indonesia

      Indonesia is the largest archipelago country of more than 17,000 islands over 5,200 km width, with population over 260 million makes it fourth most populated country in the world. As the largest economy in South East Asia, and member of G20 country, Indonesia’s economy growth is second fastest growing economy after China. A changing in socioeconomic profile of Indonesia is in paralel with increase prevalence of tobacco smoking. Current data showed prevalence of current adult male tobacco smoking is 64.9% which predicted to increase to 79% in the year of 2030, while youth male prevalence of current tobacco use is 23.0% and current cigarette smoking is 21.4%. This number is highest for daily smoking rate in male, and two third Indonesian women are regularly exposed to second-hand tobacco smoke.

      Indonesia’s life expectancy increased between 1990 and 2016 at 8 years to 71.7 years (7.4 years for male and 8.7 years for female). Double health burden due to mix of communicable and noncommunicable diseases. Of all proportional mortality, 35% are cardiovascular diseases, 12% cancer, 6% chronic respiratory diseases, 21% communicable, maternal, perinatal and nutritional conditions, 6% injuries, 6% diabetes. Noncommunicable disease are estimated to responsible for 73% of all death in Indonesia. The increasing leading causes of DALYs in 2017 as compared to 1990 are ischaemic heart disease, cerebrovascular diseases, diabetes, COPD, lung cancer. Tobacco listed as fourth risk factor of cause of death after high systolic blood pressure, dietary risks, high fasting plasma glucose.

      Tobacco control remains contradictionary within the country, despite strong national tobacco control program and government law implementation, Indonesia has yet to sign the WHO Framework Convention on Tobacco Control.

      National tobacco control program in Indonesia were transformed into specific national government objectives in tobacco control, such as national agency of technical unit for tobacco control, through MPOWER activities. Monitor tobacco use and prevention policies were implemented in Indonesian Law Article 26/2009 for Health and translated in Goverment Ordinant Article 109/2012 for the Security and Restriction of Addictive Substance of Tobacco and other several Presidential Decrees and Ministerial Decrees. Protect people from tobacco smoke were implemented in Ministerial Decree, and Provincional Decree for for Tobacco Smoke Free policy. Offer help to quit tobacco use were included in Ministerial of Health Decree and implemented in National Smoking Cessation Program. Warn about the dangers of tobacco were translated in Ministrerial Decrees Article 56/2017 for tobacco health effect warning in tobacco products and pictorial warning of tobacco smoke. Enforce bans on tobacco advertising, promotion and sponsorship were implemented through Indonesian Broadcasting Law Article 46 Clause 3B prohibits promotion of addictive substances, and Raise taxes on tobacco were implemented in Ministry of Finance Decree article 222/2017 regarding using, monitoring and evaluation of tobacco tax income. Moreover, Presidential Decree article 44/2016 and Ministry of Industry Decree Article 64/2014 for Regulation and Control of tobacco industry.

      Tobacco and related indutries argued against tobacco control policy by mentioning largescale effects of tobacco industry for Indonesian economy, and controlling tobacco industry will create massive unemployment, and economic crisis. Ministry of Industry of Republic Indonesia mentioned that tobacco industry creates 5.98 million employments, in which 4.28 million in manufacture and distribution, and 1.7 million people working in tobacco farming. In 2018, export rate of tobacco as cigarettes and cigar were 931.6 million USD, increasing 2.98% as compared to 2017. Tobacco company links closely to small medium enterprises as the tobacco company’s social responsibility (CSR) program. One CSR program as retail community, was founded in 34 provinces, 408 cities which included 60,000 small business retail. Other tobacco related industry's CSR are including sports, youth and creative activities nationwide.

      Since 1968, Indonesia National Health insurance system was only implemented for formal sector, individual, civil servants, police and military member, but, since 2014, Indonesian Government launched Universal Health System called Jaminan Kesehatan Nasional (JKN) for all Indonesian. In 2017 approximately 180.7 million people are insured through JKN, 70% of total population and planned to reach 95% target in 2019. While tobacco industry tax income were IDR 153 trillion (approximately USD 10.9 billion) in the year of 2018, tobacco related lost due to early death and disease were IDR 4,200 trillion (one third of national GDP), and economy related lost due to tobacco consumption were approximately IDR 596 trillion. This should be bear in mind, that amount of tax income from tobacco company is incomparable to high burden loss due to tobacco related morbidity and mortality.

      References:

      Mboi N, Surbakti IM, Trihandini I, Elyazar I, Smith KH, Ali PB et al. On the road to universal health care in Indonesia, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2018;392:581-91.

      Xi B, Liang Y, Liu Y, Yan Y, Zhao M, Ma C, Bovet P. Tobacco use and second-hand smoke exposure in young adolescents aged 12-15 years: data from 68 low-income and middle-income countries. Lancet Glob Health 2016:4:e795-805.

      World Health Organization – Noncommunicable Diseases (NCD) Country Profiles, 2018.

      Cited from Indonesian Ministry of Industry press release. http://www.kemenperin.go.id/artikel/17257/Kontribusi-Besar-Industri-Hasil-Tembakau-Bagi-Ekonomi-Nasional

      Agustina R, Dartanto T, Sitompul R, Susiloretni KA, Suparmi, Achadi EL et al. Universal health coverage in Indonesia: concept, progress, and challenges. Lancet 2019;393(10166):75-102.

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    ES25 - Liquid Biopsy (ID 27)

    • Event: WCLC 2019
    • Type: Educational Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 4
    • Now Available
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      ES25.01 - Liquid Biopsy: State of the Science (Now Available) (ID 3287)

      14:30 - 16:00  |  Presenting Author(s): Eloisa Jantus-Lewintre

      • Abstract
      • Presentation
      • Slides

      Abstract

      I. The present.

      Molecular diagnosis in cancer certainly requires the analysis of a tumor biopsy. However, in lung cancer, there is still a 20- 30% of tissue failure rates for tumor genotyping in routine pathological samples. As a consequence, liquid biopsy (LB) has emerged as a valid alternative source of information for the analysis of tumor specific alterations. LB refers to specimens obtained from body fluid such as blood, urine, saliva, cerebrospinal fluid, among others.

      In the complex matrix represented by blood, the main clinical developments have focused on the analysis of: i) circulating tumor DNA (ctDNA), which represents a small part of cell free circulating DNA released from tumor cells and, ii) circulating tumor cells (CTCs), defined as disseminated cancer cells in the bloodstream. Each of these materials offers unique opportunities to test different biomarkers and to analyze characteristics of the tumors.

      The advantages of the use of blood samples are clear: i) it is a minimally invasive way to get relevant tumor information, ii) serial samples can be obtained capturing tumor evolution in real time, iii) LB abrogates the limitations associated with tumor heterogeneity, since nucleic acids or tumor cells present in circulation recapitulate the information belonging from different tumor locations (primary tumor and metastases), iv) the development of new sensitive assays for analyses of ctDNA and CTCs allow the assessment of minimal residual disease and v) the costs of LB analysis are comparable with other molecular biology techniques already used in the clinical setting in addition to the reduced risks of complications associated with tissue biopsy. All these factors accelerated the implantation of LB in the clinical practice in oncology in several scenarios, especially in lung cancer.

      I.1.Lung Cancer. Clinical applications of liquid biopsies.

      At present, LB is no longer a promise but a reality allowing better treatment selection, real-time monitoring of lung cancer patients and early detection of acquired resistances. Figure 1 highlights the biological basis of LB as a source for biomarkers analysis and key clinical applications in lung cancer.

      •Personalized therapeutics/ Resistance detection: regarding the detection of tumor-associated genetic alterations in LB samples, there are a lot of scientific data demonstrating similar response rates to targeted therapies than the obtained in tissue biopsies. In particular, in the context of NSCLC patients with progressive or recurrent disease during treatment with TKIs, the IASLC guidelines suggest the use of LB-first algorithm to detect resistance mechanism.

      For those lung cancer patients receiving immune-based therapeutic treatments, recent data show that assessment of tumor mutational burden in plasma (bTMB) correlated with the values found in tissue and predicts efficacy of immune-checkpoint inhibitors.

      •Detection of minimal residual disease: Persistent detection of ctDNA or CTCs after local therapy or after adjuvant treatments was found associated with poor clinical outcome. In this particular clinical setting it is important to highlight that sensitivity of the methods used for ctDNA or CTCs evaluation really matters.

      •Real-time monitoring of disease: this is one of the most interesting application of LB, since tissue biopsies are intrinsically unable to capture tumor heterogeneity while ctDNA can comprehensively recapitulates clonal evolution over time, allowing to early detect and track the emergency of resistance mutations.

      II. The future.

      Current assays for LB analysis do not meet all the needs required for the fully implementation of the Precision Oncology. There is still room for improvement to reach its maximum informative potential. Hopefully, studies on exosomes, platelets, cfRNAs, metabolites, will help to have a more integrative picture of tumor status at each time it is evaluated.

      One of the clinical applications in which LB is called to play a key role is in the screening and early detection of lung cancer. In this regard, there are some interesting data coming from multiparametric (DNA and protein) plasma analysis. However, caution is required since there are still some important issues, such as clonal hematopoiesis, that need to be further considered.

      Another important challenge for LB is standardization. It is necessary to cross-validate platforms, standardize pre-analytical issues, compare sensitivity of different methodological approaches and also to work in the harmonization of bioinformatic tools for data analysis.

      It is clear that in the near future, tests based on the analysis of "liquid biopsies" will be more generalized, offering complementary information to tissue biopsies and providing valuable information to early diagnose lung cancer, to detect molecular progressions even prior to radiographic or clinical progression and as a source for real-time treatment monitoring.

      References

      Alix-Panabières C, Pantel K. Clinical Applications of Circulating Tumor Cells and Circulating Tumor DNA as Liquid Biopsy. Cancer Discov. 2016;6(5): 479-91.

      Bardelli A, Pantel K. Liquid Biopsies, What We Do Not Know (Yet). Cancer Cell. 2017; 31(2):172-179.

      Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24

      Calabuig-Fariñas S, Jantus-Lewintre E, Herreros-Pomares A, Camps C. Circulating tumor cells versus circulating tumor DNA in lung cancer-which one will win? Transl Lung Cancer Res. 2016; 5(5):466-482

      Heitzer E, Haque IS, Roberts CE, Speicher MR. Current and future perspectives of liquid biopsies in genomics-driven oncology. Nat Rev Genet. 2019;20(2):71-88.

      Pantel K, Alix-Panabières C. Liquid biopsy: Potential and challenges. Mol Oncol. 2016; 10(3):371-3.

      Rossi G, Ignatiadis M. Promises and Pitfalls of Using Liquid Biopsy for Precision Medicine. Cancer Res. 2019;79(11):2798-2804.

      Siravegna G, Marsoni S, Siena S, Bardelli A. Integrating liquid biopsies into the management of cancer. Nat Rev Clin Oncol. 2017;14(9):531-.548

      figure 1.png

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      ES25.02 - Liquid Biopsy: Utility for Surveillance in Early Stage (Now Available) (ID 3288)

      14:30 - 16:00  |  Presenting Author(s): Lecia Sequist

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      ES25.03 - Leveraging the Quantitative Nature of Cfdna Genotyping for Lung Cancer Care (Now Available) (ID 3289)

      14:30 - 16:00  |  Presenting Author(s): Cloud P Paweletz

      • Abstract
      • Presentation
      • Slides

      Abstract

      Nearly 70 years after the discovery of free-floating DNA in the blood, also known as cell free DNA (cfDNA) (1), plasma genotyping of cfDNA is transforming cancer care with promise in non-invasive genotyping, early diagnosis, and disease prognostication by detection of minimal residual disease (MRD). At present the most widespread use of cfDNA in lung cancer is detection of mutations in EGFR and KRAS or re-arrangements in ALKand ROS1 in the metastatic setting. In fact, the only FDA approved liquid biopsy test among all cancers is Roche’s Cobas plasma EGFR mutation test for non-small cell lung cancer. (NSCLC) (2), while many diagnostic companies have developed PCR or next generation sequencing (NGS) laboratory developed tests that are commonly reimbursed by payors in house. Next-generation sequencing (NGS) permits broader inquiries, allowing assessment of the mutation status of thousands to millions of bases.

      The use of cfDNA in early cancers is confounded by the fact that early detection demands ultra-sensitive assays of low abundant biological markers. As proof of concept Bettegowda et al. performed digital PCR on cfDNA of 640 cancer patients of varying cancer type and stage. Intriguingly they found that rates of tumor DNA differed by tissue of origin, and 47% of stage I cancers and 55% of stage II cancers had detectable circulating tumor DNA (ctDNA) (3). An observation that as we and others have confirmed is a main source for false negatives (4). At present, NGS efforts are focused either on targeted approaches using either barcoded targeted amplicon (TAmSeq) or hybrid capture approaches (CAPP-Seq) covering 10Mb to 50Mb at reported sensitivities of 0.01% to 0.50% for fit for purpose build NGS assays. However, pushing assay sensitivity increases false positives.

      Recently, we and other have found that false positives are reported in many commercial assays and are routinely attributed to ‘tumor heterogeneity’ . These can be attributed to DNA shed from normal cells, including germline variants or non-cancerous somatic variants from clonal hematopoiesis (CH) (5-8). The latter is particularly challenging because CH can involve cancer-associated genes (e.g. TP53, JAK2, KRAS). To limit false positives and to investigate the common link between cancer-related mutations within the blood and underlying malignancies broad sequencing of cfDNA should also detect other cancer-related mutations, such as inactivating mutations in tumor suppressors and include assaying of the patients blood cells to filterout germlines. Thus, deep and broad sequencing could provide sensitivity needed to detect low levels of cfDNA alterations in early stage patients. Indeed, Abbosh et al. perform multi region whole-exome sequencing of early-stage NSCLC tumors to show an abundance of clonal mutations in these tumors (9). Abbosh and colleagues provide an intriguing solution to this issue by requiring the detection of two or more SNVs for the determination of the presence of cancer.In this presentation we present factors affecting ultras sensitive assays with particular emphasis on interpretation of commercial tests and future use of cfDNA assays in early cancers.

      1. Mandel P and Metais P. Les acides nucleiques du plasma sanguin chez l’homme [in French]. C R Seances Soc Biol Fil 1948;142:241-243.

      2.Center for Drug Evaluation and Research. Approved Drugs - cobas EGFR Mutation Test v2 [Internet]. U S Food and Drug Administration Home Page. Center for Drug Evaluation and Research; Available from: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm504540.htm

      3.Bettegowda C, Sausen M, Leary R, Kinde I, Agrawal N, Bartlett B, et al. Detection of Circulating Tumor DNA in Early and Late Stage Human Malignancies. Science Translational Medicine 2014;16:224ra24.

      4. Oxnard GR, Thress KS, Alden RS, et al: Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer. Journal of Clinical Oncology 34:3375–3382, 2016

      5.Hu Y, Ulrich BC, Supplee J, et al: False-Positive Plasma Genotyping Due to Clonal Hematopoiesis. Clin Cancer Res 24:4437-4443, 2018

      6.Hu Y, Alden RS, Odegaard JI, et al: Discrimination of Germline EGFR T790M Mutations in Plasma Cell-Free DNA Allows Study of Prevalence Across 31,414 Cancer Patients. Clin Cancer Res 23:7351-7359, 2017

      7.Slavin TP, Banks KC, Chudova D, et al: Identification of Incidental Germline Mutations in Patients with Advanced Solid Tumors Who Underwent Cell-Free Circulating Tumor DNA Sequencing. Journal of Clinical Oncology 36:3459-3465, 2018

      8.Oxnard GR, Tara M, Earl H, et al. Genome-wide sequencing for early stage lung cancer detection from plasma cell-free DNA (cfDNA): The Circulating Cancer Genome Atlas (CCGA) study. Journal of Clinical Oncology : LBA8501-LBA8501, 2018

      9.Abbosh C, Birkbak NJ, Wilson GA, Jamal-Hanjani M, Constantin T, Salari R, et al. Phylogenetic ctDNA Analysis Depicts Early Stage Lung Cancer Evolution. Nature 2017;545:446-451.

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      ES25.04 - Liquid Biopsy: Utility for Early Detection (Now Available) (ID 3290)

      14:30 - 16:00  |  Presenting Author(s): Ana Vivancos

      • Abstract
      • Presentation
      • Slides

      Abstract

      Personalized treatment according to molecular profile is standard of care in advanced NSCLC patients. Epidermal Growth Factor Receptor (EGFR) activating mutations predict sensitivity to first- and second-generation anti-EGFR tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). However, obtaining a tissue biopsy remains a limitation in NSCLC patients. Liquid biopsy is a non-invasive method that allows the detection and quantification of tumor somatic mutations in plasma, although around 20% of all tumors don’t appear to shed DNA into the bloodstream. Here, we aimed to correlate the presence and amounts of ctDNA in plasma of NSCLC patients with several clinical parameters, as well as obtaining serial data on non-shedding patients throughout their course of illness.

      We collected 280 serial blood samples of 40 patients with NSCLC diagnosis harboring EGFR sensitizing mutations in their tumor biopsy. Extracted ctDNA was tested for five common EGFR mutations (exon 19 deletion, L858R, L861Q, T790M and C797S) by highly sensitive and quantitative Droplet Digital PCR (ddPCRTM; Bio-Rad), at a limit of detection between 0.1-0.5% and quantified the percentage of mutant alleles of EGFR. Of these patients, 16 provided one plasma sample (32%) and the other 34 (68%) provided multiple blood collections with an average of 5 follow-up plasma samples. All patients received targeted TKI therapy before or during the study. Lines of treatment, Progression free survival (PFS) and overall survival (OS) were annotated for each patient in the cohort.

      Out of the 40 patients evaluated, we detected presence of baseline ctDNA in 32 patients (80%). Such parameter was independent of the sensitizing mutation; tumors harboring exon 19 or exon 21 mutation tend to equally shed DNA into the bloodstream (78% and 80%, respectively). After a median follow up of 36.1 months, and immature survival data, the PFS and OS are higher among patients with baseline ctDNA positive compared to patients without ctDNA detected: 22 months vs. 13.6 months and 35 vs. 24 months, respectively. T790M and C797S resistance mutations were detected at different prevalences, depending on the TKI treatment regimen, and were always subclonal in plasma as compared to the clonal EGFR mutation (indel 19/L858R). We observed that, for the whole period analyzed in non-shedding patients, ctDNA was never detected.

      In our series, sensitizing EGFR mutations in plasma were identified in 80% of the patients by ddPCR. Acquired resistance mutations in EGFR appeared to be subclonal, which might impact detection in liquid biopsy. Shedding is a complex biological entity that warrants further research in order to improve our understanding on its impact in prognosis.

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    IBS05 - Lung Cancer Genetics to Beat Lung Cancer (Ticketed Session) (ID 36)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Biology
    • Presentations: 2
    • Now Available
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      IBS05.01 - KRAS Mutant Lung Cancer (Now Available) (ID 3328)

      07:00 - 08:00  |  Presenting Author(s): Pasi A Jänne

      • Abstract
      • Presentation
      • Slides

      Abstract

      KRASmutations are the most common oncogenic alteration in Caucasian patients with advanced non-small cell lung cancer (NSCLC), detected in approximately 25% of patients with adenocarcinoma. Although KRASmutations were discovered over 30 years ago, no approved targeted therapies exist for KRASmutant NSCLC. KRASmutations occur most commonly in codon 12 and less frequently in codons 13 and 61. The development of KRAS mutant lung cancer is most closely associated with a history of current or former smoking although KRASmutations can also occur in up to 15% of never smokers who develop lung cancer (1). While KRAS G12C mutations are the predominant mutation subtype in smokers, G12D mutations are the most common subtype of KRAS mutations in never smokers.


      Until recently, no direct targeted therapies existed for KRASmutant lung cancers and the therapeutic efforts have mostly focused on targeting downstream effector pathways including the MAPK and PI3K/AKT pathways. MEK inhibitors have limited single agent activity (response rates 10-20%) and initial enthusiasm from a randomized phase II trial of selumetinib/docetaxel vs. docetaxel suggested a potential benefit of adding chemotherapy to a MEK inhibitor (2). However, the initial findings could not be reproduced in a larger randomized phase III trial (3). The CDK4/6 inhibitor abemaciclib has also been evaluated as a single agent in KRASmutant lung cancer based on both preclinical data and as a result of the phase I trial which demonstrated a differential benefit in patients with KRASmutant NSCLC (4). However, a phase III trial, randomizing previously treated KRASmutant NSCLC to either abemaciclib or erlotinib failed to demonstrate an improvement in overall survival.

      It has increasingly been recognized that not all KRASmutant cancers are the same. Not only are there a variety of allelic variants of KRAS, there several subtypes of co-mutations within KRAS mutant cancers (5). Approximately 30% of KRASmutant tumors harbor a concomitant alteration in TP53 which another 30% harbor concomitant mutations in LKB1/STK11. Mutations in LKB1/STK11most commonly result in loss of function of the LKB1/STK11protein(5,6). Immune checkpoint blockade (ICB), administered as a single agent or in combination with chemotherapy, is an effective therapy in lung cancer (7). While strategies to identify biomarker to predict optimal response to ICB are diverse, LKB1/STK11mutations are associated with lack of response to both single agent ICB or when administered together with combination chemotherapy. Ongoing efforts are focusing on understanding the mechanistic basis for the lack of response to ICB in LKB1/STK11mutant tumors and levering this understanding to develop new strategies to enhance responsiveness of this subset of NSCLC to ICB.

      New therapeutic approaches to target KRAS are rapidly entering the clinic. These include inhibitors or SHP2, SOS1 and the direct inhibitors of KRAS G12C. Novel structural insights into into the KRAS protein helped identify a unique allosteric site formed in the presence of the G12C mutation. These insights led to the identification of potential drugs that could occupy this pocket and covalently bind KRAS G12C (8). Multiple companies are now developing KRAS G12C inhibitors including Mirati Therapeutics (MRTX849) and Amgen (AMG510). Encouraging early clinical signs of efficacy have been observed. Over the next few years, clinical data will emerge on the efficacy of direct KRAS G12C inhibitors, the impact of concomitant genomic alterations, the mechanisms of acquired resistance as well as combination treatment strategies. In addition, continued studies of KRAS biology and new therapeutic studies will also hopefully lead to new treatments for patients with non-G12C KRASmutations.

      References

      1. Riely GJ, Kris MG, Rosenbaum D, Marks J, Li A, Chitale DA, et al.Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma. Clin Cancer Res 2008;14(18):5731-4 doi 14/18/5731 [pii]

      10.1158/1078-0432.CCR-08-0646.

      2. Janne PA, Shaw AT, Pereira JR, Jeannin G, Vansteenkiste J, Barrios C, et al.Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study. Lancet Oncol 2013;14(1):38-47 doi 10.1016/S1470-2045(12)70489-8.

      3. Jänne PA, van den Heuvel MM, Barlesi F, Cobo M, Mazieres J, Crinò L, et al.Selumetinib Plus Docetaxel Compared With Docetaxel Alone and Progression-Free Survival in Patients With KRAS-Mutant Advanced Non–Small Cell Lung Cancer: The SELECT-1 Randomized Clinical Trial. Jama 2017;317(18):1844-53.

      4. Patnaik A, Rosen LS, Tolaney SM, Tolcher AW, Goldman JW, Gandhi L, et al.Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Cancer Discov 2016;6(7):740-53 doi 10.1158/2159-8290.CD-16-0095.

      5. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al.Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455(7216):1069-75.

      6. Skoulidis F, Byers LA, Diao L, Papadimitrakopoulou VA, Tong P, Izzo J, et al.Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities. Cancer Discov 2015;5(8):860-77 doi 10.1158/2159-8290.CD-14-1236.

      7. Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al.STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS-Mutant Lung Adenocarcinoma. Cancer Discov 2018;8(7):822-35 doi 10.1158/2159-8290.CD-18-0099.

      8. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503(7477):548-51 doi 10.1038/nature12796.

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      IBS05.02 - Functional Genomic Approaches to Identify Novel Therapeutic Targets in Lung Cancer (Now Available) (ID 3329)

      07:00 - 08:00  |  Presenting Author(s): Tao Zou  |  Author(s): Matthew Meyerson

      • Abstract
      • Presentation
      • Slides

      Abstract

      Despite the discovery and availability of targeted therapies and immunotherapies, lung cancer remains the leading cause of cancer death worldwide. Importantly, most lung cancer patients are not eligible for targeted therapies because their tumors lack an actionable genomic alteration. Moreover, immunotherapy-based regimens fail to induce treatment responses in a substantial proportion of lung cancer patients (1-3). Therefore, the identification of novel therapeutic modalities remains critical to improving outcomes in lung cancer care.

      Lung cancer cells may harbor specific genomic or functional alterations that render them vulnerable to particular genetic perturbations (4,5). Discovery of these synthetic lethal interactions may provide opportunities to develop novel classes of therapeutics for this disease. Through systematic analysis of genome-scale loss-of-function datasets (6,7), we identify adenosine deaminase acting on RNA (ADAR or ADAR1) as an essential gene for the survival of a subset of lung cancer cell lines (8). ADAR1-dependent cell lines display increased expression of interferon-stimulated genes. Moreover, activation of type I interferon signaling in the context of ADAR1 deficiency can induce cell lethality in non-ADAR1-dependent cell lines. ADAR deletion causes activation of the cytoplasmic double-stranded RNA sensor, protein kinase R (PKR). Disruption of PKR signaling, through inactivation of PKR or overexpression of either a wild-type or catalytically inactive mutant version of ADAR1, partially rescues cell lethality after ADAR1 loss, suggesting that both catalytic and non-enzymatic functions of ADAR1 may contribute to preventing PKR-mediated cell lethality. Taken together, these data nominate ADAR1 as a potential therapeutic target in lung cancers displaying elevated interferon-stimulated gene expression and underscore the ability of functional genomic approaches to uncover novel genetic vulnerabilities in lung cancer.

      References

      1. Gandhi L, Rodriguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018;378:2078-92

      2. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med 2018;379:2040-51

      3. Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33

      4. Oike T, Ogiwara H, Tominaga Y, Ito K, Ando O, Tsuta K, et al. A synthetic lethality-based strategy to treat cancers harboring a genetic deficiency in the chromatin remodeling factor BRG1. Cancer Res 2013;73:5508-18

      5. Zhou Z, Patel M, Ng N, Hsieh MH, Orth AP, Walker JR, et al. Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening. BMC Cancer 2014;14:944

      6. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G, Cowley GS, et al. Defining a Cancer Dependency Map. Cell 2017;170:564-76 e16

      7. Aguirre AJ, Meyers RM, Weir BA, Vazquez F, Zhang CZ, Ben-David U, et al. Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 2016;6:914-29

      8. Gannon HS, Zou T, Kiessling MK, Gao GF, Cai D, Choi PS, et al. Identification of ADAR1 adenosine deaminase dependency in a subset of cancer cells. Nat Commun 2018;9:5450

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    IBS15 - Biology and Genetics in ICI Treatments (Ticketed Session) (ID 46)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Biology
    • Presentations: 2
    • Now Available
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      IBS15.01 - Current Status of IO in Lung Cancer (Now Available) (ID 3360)

      07:00 - 08:00  |  Presenting Author(s): Scott Gettinger

      • Abstract
      • Presentation
      • Slides

      Abstract

      Only a decade ago, lung cancer was largely considered a non-immunogenic tumor. The focus of most clinical efforts at the time was development of molecularly targeted agents in hopes to personalize the systemic treatment of lung cancer. Although much has been accomplished over the last 15 years, with regulatory approvals of several targeted agents for EGFR, ALK, ROS1, BRAF and NTRK driven tumors, and emerging targeted therapies for other molecularly defined cohorts (e.g. MET, RET, HER2 driven tumors), the majority of patients with lung cancer do not have readily targetable molecular alterations. Arguably, the most impactful advance in the systemic treatment of lung cancer over the last several decades has been the appreciation and utilization of immunotherapy to attack and control typical lung cancer. Indeed, five- year survival rates from the first phase I trials of programmed death (PD)-1 inhibitor trials (BMS-003 and KEYNOTE-001) in patients with pre-treated advanced non-small cell lung cancer (NSCLC) are an unprecedented 16% (n=578, median duration of response 17 - 39 months), with five- year survival rate from one trial (KEYNOTE-001) evaluating chemo naive advanced lung cancer patients of 23% (n=101, median duration of response 17 months) (ref: PMID 29570421, 31154919). Based on subsequent randomized clinical trials, PD-1 axis inhibitor therapy has become standard first line therapy for the majority of patients with advanced NSCLC (those without readily targetable tumor molecular alterations), either alone (pembrolizumab) if tumor PD- ligand 1 (L1) expression is high (> 50%), or with standard platinum doublet chemotherapy if tumor PD-L1 expression is low/ negative/ unknown (pembrolizumab regardless of NSCLC histology; atezolizumab for non-squamous NSCLC) (ref: PMID 30620668, 29658856, 30280635, 2986395). PD-1 axis inhibitor therapy with durvalumab is additionally approved as consolidation therapy for patients with locally advanced NSCLC after receiving definitive concurrent chemoradiation without progression (ref: PMID 30280658). PD-1 axis inhibitor therapy has also shown activity in advanced small cell lung cancer (SCLC), with regulatory approvals of atezolizumab combined with first line etoposide/ platinum chemotherapy, and nivolumab or pembrolizumab as 3rd line therapy (in practice, nivolumab is often combined with ipilimumab after failure of chemotherapy as endorsed by the National Comprehensive Cancer Network) (ref: PMID 30280641, 27269741). Several phase III immunotherapy lung cancer studies are ongoing in the adjuvant and metastatic setting, with additional regulatory approvals anticipated in the coming years.

      Despite the success with PD-1 axis inhibitors, and tremendous impact on treatment paradigms for lung cancer, most treated patients do not clearly benefit from therapy, and most of those who do respond will ultimately develop resistance with recurrence/ progression of their cancer. Little is known about mechanisms of resistance, and coordinated translational efforts across cancer centers will be required to understand both acquired and primary resistance (to date, we are only aware of two published reports describing potential mechanisms of acquired resistance to PD-1 axis inhibitors in lung cancer; one implicating acquired loss of beta-2 microglobulin with resultant lack of MHC1 expression, the other, loss of tumor specific neoantigens through elimination of tumor subclones or chromosomal loss of truncal alterations ) (ref: PMID: 28031159, 29025772). Currently, several trials are evaluating novel immunotherapeutic agents, including other immune checkpoint inhibitors, costimulatory agonists, vaccines, oncolytic viruses and cellular therapies. In most of these trials, patients are not selected by unique molecular/ immunologic characteristics of their tumor. Rather, empiric combinations of therapy (often including a PD-1 axis inhibitor) are generally trialed with tumor biopsies to help understand mechanisms of response and resistance.

      In clinical practice, a handful of unanswered questions repeatedly surface when treating lung cancer patients with immunotherapy. These include:

      What is the optimal duration of PD-1 axis inhibitor therapy? Although there is little data to guide us here, we generally consider treatment holiday after 2 years of therapy without progression. However, PD-1 axis therapy can be continued indefinitely as was done in most registrational trials.

      What is the role of immunotherapy in never smokers and those with targetable molecular alterations driving their disease? There remains pessimism about use of immunotherapy in these populations, with the belief that tumors in such patients are less immunogenic (lower mutational burden with less neoantigens). However, there are limited numbers of patients who do respond, and efforts are underway to understand these responses. Novel immunotherapeutic approaches are also being developed. Currently, many thoracic oncologists will reserve PD-1 axis inhibitor therapy until no other standard targeted therapies (or trials evaluating novel targeted therapy) or chemotherapy remain.

      When should we concede that a patient’s tumor is primarily resistant to PD-1 axis inhibitor therapy. i.e., how much time on therapy should be allowed to exclude delayed response or pseudo-progression. Generally, if a patient’s performance status has not deteriorated at the first tumor assessment on immunotherapy (6-8 weeks), many thoracic oncologists will continue therapy for another 6 weeks. If assessment at that time shows further progression, therapy is discontinued.

      Should immunotherapy ever be continued with addition of other systemic therapy on progression of disease? Generally, this is not recommended, unless a patient is having a mixed response or acquired resistance with oligo-progressive disease. That said, there is some rationale here, as PD-L1 may be induced in tumors by subsequent therapy.

      Is there any role for consolidation durvalumab in patients with locally advanced NSCLC after concurrent chemoradiation followed by lung resection? The PACIFIC trial leading to approval of consolidation durvalumab did not include such patients; currently, durvalumab is not indicated after surgery.

      Should salvage nivolumab combined with ipilimumab be considered in patients with extensive stage small cell lung cancer after progression on standard chemotherapy plus/ minus atezolizumab. Although nivolumab plus ipilimumab is not approved for use in the United States as salvage therapy for SCLC, it is occasionally prescribed as endorsed by the NCCN. It is unclear if the combination would have any activity in a patient who failed prior atezolizumab in combination with etoposide/ platinum.

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      IBS15.02 - Determinants of Response to ICI (Now Available) (ID 3361)

      07:00 - 08:00  |  Presenting Author(s): Fred R. Hirsch

      • Abstract
      • Presentation
      • Slides

      Abstract

      PREDICTIVE BIOMARKERS FOR IMMUNOTHERAPY IN LUNG CANCER

      Fred R. Hirsch, MD, PhD. Professor of Medicine and Executive Director, Center for Thoracic Oncology, The Tisch Cancer Institute, Mount Sinai Health System, NY, NY. USA

      While great promise has emerged with the development of immunotherapy (IT) in lung cancer, we are still struggling with how to select the right treatment to the right patients and how to select the patients, who will benefit from IT. Only 20-30 % of the patients with NSCLC will have a clear benefit from IT compared to chemotherapy alone, and the challenge is to select those patients.

      PD-L1 protein expression demonstrated by immunohistochemistry (IHC) has been pursuit as primary selection biomarker in the clinical trial development. However, the major challenge for evaluation of PD-L1 and top compare the results from one study to another was the use of different antibodies/assays and processing by the different companies. A comparison of the different PD-L1 assays was performed in the “PD-L1 Blueprint Project”, and three antibodies/assays was found to be performing similarly and could be interchangeable (1,2). While higher PD-L1 expression seems to be associated with gradually increased outcome of IT, a tumor proportion score (TPS) ≥ 50% seems to be useful in the choice of IT (e.g. pembrolizumab) monotherapy versus IT plus chemotherapy (CT). The results (PFS/OS) of IT monotherapy for patients with high PD-L1 expression is not significantly different than for IT+CT, although not directly compared, while for patients with tumors having lower PD-L1 expression, the combination of IT+CT seems better (3, 4). Thus, the predictive role of PD-L1 expression might be different between IT alone and IT+CT. The prognostic role of PD-L1 (e. g. association to outcome without any therapy) is still not clear with conflicting reported outcomes in the literature.

      Tumor mutation burden (TMB) has in some clinical trials demonstrated to be of predictive value, both based on tissue and plasma (5, 6, 7). In several studies it has been shown that the patient population with high TMB has little overlap with the patient population with high PD-L1 expression (6). Prospective clinical trials arer today performed evaluating plasma TMB as predictive biomarker (b-FIRST). However, also challenges related to TMB reports occur; different assay platforms have been used in different clinical trials, different definitions (e. g cut-offs) have been applied in the definition of high TMB vs low TMB, and also for TMB an comparison of results /assays seems to be needed. Such comparison studies are on-going both in the US (i.e. Friends of Cancer) and in Europe.

      On this stage, it is not clear whether TMB can replace PD-L1 IHC in treatment decisions; who will benefit from IT or not? Some studies (i.e. CheckMate 227) (8), indicate also that the two predictive assays are not “competing” but complementary. It has been shown that for patients having tumors with low (≤1%)- or no PD-L1 expression, but high TMB a treatment option of combined therapy with nivolumab+ ipilumumab seems justified. There are also conflicting results reported on the prognostic role of TMB associated to no systemic therapy or predictive role associated to chemotherapy alone.

      Other candidate biomarkers are under investigations and will be discussed.

      REFERENCES:

      Hirsch FR et al. J Thorac Oncol 2017 (2): 208-222

      Tsao MS et al: J Thorac Oncol 2018 (9): 1302-1311

      Gandhi L et al; N Engl J Med 2018 378(22): 2078-2092

      Reck M et al; N Engl J Med 2016 375(19): 1823-1833

      Carbone DP et a;; N Engl J Med 2017 376(25): 2415-2426

      Gandara DR et al. Nat Med 2018 (9): 1441-1448

      Samstein RM et al; Nat Genet 2019 (2): 202-206

      Hellman MD et al; N Engl J Med 2018 378(22): 2093-2114

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    IBS26 - Treatment Techniques for Localized Therapy in Malignant Pleural Mesothelioma (Ticketed Session) (ID 57)

    • Event: WCLC 2019
    • Type: Interactive Breakfast Session
    • Track: Mesothelioma
    • Presentations: 3
    • Now Available
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      IBS26.01 - Treatment Planning for Pleural Imrt (Imprint) (Now Available) (ID 3395)

      07:00 - 08:00  |  Presenting Author(s): Andreas Rimner

      • Abstract
      • Presentation
      • Slides

      Abstract

      We have developed an Intensity-modulated pleural radiation therapy (IMPRINT) technique targeting the entire hemithoracic pleural space including the diaphragm that simultaneously spares the ipsilateral lung, heart, liver, kidneys and abdominal contents was developed.1 It provides an opportunity for safer, less toxic treatments and increased efficacy by enabling higher radiation doses to the tumor target due to a much higher level of dosimetric control and certainty leading to better target coverage than conventional radiation techniques.2 IMPRINT became technically necessary to deliver adjuvant radiation due to the increased use of lung-sparing surgical techniques such as pleurectomy/decortication (P/D) for malignant pleural mesothelioma. Here we describe the contouring and treatment planning aspects for IMPRINT and potential pitfalls.

      Since developing this technique the clinical delivery of IMPRINT has been shown to be safe and feasible. Our first report in 36 MPM patients with 2 intact lungs showed that hemithoracic adjuvant IMPRINT (50.4 Gy in 28 fractions) could be delivered with a 20% (n=7) ≥ grade 3 pneumonitis risk; 1 patient had grade 5 pneumonitis.1 The median survival in resectable patients was 26 months. A tomotherapy technique was published with similar toxicity outcomes (20% ≥ grade 2 pneumonitis, one fatal case of pneumonitis).3 These encouraging results have led to a 2-institution phase II trial of trimodality therapy using induction chemotherapy with cisplatin and pemetrexed, lung-sparing P/D, and adjuvant hemithoracic IMPRINT.4 Twenty-seven patients were treated and 29.6% developed radiation pneumonitis (6 grade 2; 2 grade 3). Median progression-free and overall survival was 12.4 and 23.7 months, respectively. In resectable MPM patients who received chemotherapy and IMPRINT, 2-year OS was very promising at 59%. A review of the outcomes of trimodality therapy including IMPRINT demonstrated a median OS of 20 months from the start of RT.5

      Based on these findings a multi-institutional phase II study is ongoing to demonstrate the safety and exportability of IMPRINT to 5 institutions (clinicaltrials.gov: NCT00715611). All patients’ treatment contours and plans are centrally reviewed and revised for uniformity. This will be followed by NRG LU-006, a randomized phase III study of P/D, chemotherapy +/- adjuvant IMPRINT which is planned to open in the fall of 2019.

      Target delineation of the entire pleural space is a challenging task. The higher precision of IMRT delivery requires detailed knowledge of the intrathoracic anatomy, incorporation of all diagnostic imaging tools available, pathologic findings at the time of surgery, assessment of the respiratory tumor motion using a 4D scan, and image-guided treatment delivery. A systematic review of failure patterns in 67 patients identified areas at significant risk for local failures emphasizing the need for optimization of radiation targeting and experience with this complex radiation technique.6 Increasing experience over time led to fewer marginal failures and decreased toxicity, suggesting the improvement in target delineation and RT planning. Emergence of multiple pleural nodules and pleural thickening were identified as the most common features of local recurrences.7 We have developed a contouring atlas for target delineation for IMPRINT that will be presented.

      Treatment planning is similarly complex and requires significant experience. Typically fixed-beam angle IMRT is delivered with six to nine coplanar 6 MV beams equispaced over 200-240 degrees around the ipsilateral hemithorax were used. More recently, rotational techniques such as volumetric arc therapy or tomotherapy have been shown to allow for even more effective sparing of organs at risk.3,8 Strict normal tissue constraints need to be applied to avoid serious toxicities, foremost radiation pneumonitis. Most recently we identified an association of radiation dose to the heart and overall survival that has led to incorporation of new dosimetric planning constraints.9 Details about dosimetric constraints will be presented.

      1. Rosenzweig KE, Zauderer MG, Laser B, et al: Pleural intensity-modulated radiotherapy for malignant pleural mesothelioma. International Journal of Radiation Oncology Biology Physics 83:1278-1283, 2012

      2. Krayenbuehl J, Dimmerling P, Ciernik IF, et al: Clinical outcome of postoperative highly conformal versus 3D conformal radiotherapy in patients with malignant pleural mesothelioma. Radiat Oncol 9:32, 2014

      3. Minatel E, Trovo M, Bearz A, et al: Radical Radiation Therapy After Lung-Sparing Surgery for Malignant Pleural Mesothelioma: Survival, Pattern of Failure, and Prognostic Factors. Int J Radiat Oncol Biol Phys 93:606-13, 2015

      4. Rimner A, Zauderer MG, Gomez DR, et al: Phase II Study of Hemithoracic Intensity-Modulated Pleural Radiation Therapy (IMPRINT) As Part of Lung-Sparing Multimodality Therapy in Patients With Malignant Pleural Mesothelioma. J Clin Oncol 34:2761-8, 2016

      5. Shaikh F, Zauderer MG, von Reibnitz D, et al: Improved Outcomes with Modern Lung-Sparing Trimodality Therapy in Patients with Malignant Pleural Mesothelioma. J Thorac Oncol 12:993-1000, 2017

      6. Rimner A, Spratt DE, Zauderer MG, et al: Failure patterns after hemithoracic pleural intensity modulated radiation therapy for malignant pleural mesothelioma. Int J Radiat Oncol Biol Phys 90:394-401, 2014

      7. Halpenny D, Raj M, Rimner A, et al: Computed tomography features of local pleural recurrence in patients with malignant pleural mesothelioma treated with intensity-modulated pleural radiation therapy. Eur Radiol, 2019

      8. Dumane V, Rimner A, Yorke ED, et al: Volumetric-modulated arc therapy for malignant pleural mesothelioma after pleurectomy/decortication. Applied Radiation Oncology 5:24-33, 2016

      9. Yorke ED, Jackson A, Kuo LC, et al: Heart Dosimetry is Correlated with Risk of Radiation Pneumonitis after Lung-Sparing Hemithoracic Pleural IMRT for Malignant Pleural Mesothelioma. Int J Radiat Oncol Biol Phys, 2017

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      IBS26.02 - Role of Extrapleural Pneumonectomy Compared to Pleurectomy Decortication: When and How? (Now Available) (ID 3396)

      07:00 - 08:00  |  Presenting Author(s): Walter Weder

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      IBS26.03 - Surgical Technique of Pleurectomy/Decortication (Now Available) (ID 3397)

      07:00 - 08:00  |  Presenting Author(s): David Waller

      • Abstract
      • Presentation
      • Slides

      Abstract

      Lung sparing radical surgery by (extended) pleurectomy decortication has become for many high volume units the surgical approach of choice rather than extrapleural pneumonectomy. However, the persuasive benefits of reduced postoperative mortality must not lead to compromise of the basic intent to obtain macroscopic complete resection of the malignant pleural mesothelioma. While it is naïve to intend to obtain a R0 resection (because of the anatomical relations of the pleura) a R2 resection should be considered a failure of surgical selection or technique. In this presentation I will consider the salient points in a stepwise fashion of the operation that I have learned over a 20 year experience of over 500 such procedures and illustrate each step with images or operative video sequences.

      1.Anaesthetic requirements – double lumen intubation under general anaesthesia with single lung intubation is a prerequisite. Epidural analgesia is desirable as the extent of pleurectomy does not facilitate paravertebral catheter placement. Preoperative insertion of a large bore oesophageal bougie facilitates intraoperative dissection around the oesophagus reducing the risk of inadvertent injury.

      2.Exposure – a standard posterolateral thoracotomy through the 6th intercostal space dividing just the latissimus dorsi is usually sufficient. Particularly bulky tumours in either the apex or base should be approached using a two level thoracotomy via the 4th and 8th intercostal spaces.

      3.Dissection- in general the mode of dissection is by digital mobilization having found the correct tissue plane by sharp incision. I use electrocautery to divide most tissues.

      Parietal pleurectomy – I begin with the parietal dissection to confirm resectability from the chest wall. Limited chest wall resection of up to 3 ribs is acceptable but larger defects are usually associated with poor prognosis and are not justified by the increased postoperative morbidity. I continue the parietal pleurectomy down to the diaphragm to determine whether phrenectomy can be avoided but then the phrenic nerve must be preserved. The parietal pleurectomy is continued from the apex down to the azygos vein or aortic arch and then over the oesophagus onto the hilum and down to the diaphragm.

      Visceral pleurectomy – Whilst the parietal pleura can be incised over its lateral aspect I prefer to follow the main bronchus down to the pleural reflection. Then open the space beneath it by sharp dissection and then develop the subpleural plane by digital , blunt dissection across each lobe separately. A prior pleurodesis helps in this process as the fused pleural sheet can then be opened by electrocautery down onto a double gloved finger which protects the underlying lung. The stripping of the fused pleural sheet of tumour from the underlying lung parenchyma should continue in two directions away from and towards the oblique fissure. This action is best performed using a swab as a gentle abrasive putting pressure on the pleural sheet rather than the lung. Meticulous technique is imperative to reduce parenchymal damage which will reduce postoperative air leak and hence hospital stay. I find positive pressure ventilation of the underlying lung to be beneficial in providing counter-traction for the pleurectomy. It also allows for early identification and closure of parenchymal tears and sources of air leak.

      Lung resection – there are commonly areas of parenchymal adhesion or frank invasion at the peripheries of the lung at the medial aspect of the upper lobes (particularly the lingula) and the diaphragmatic surface of the lower lobe. Rather than persist in trying to preserve all lung parenchyma at the expense of air leak I have a low threshold for stapled excision of these peripheral strips of lung. Lobectomy is very rarely indicated.

      Pericardiectomy – I prefer to err on the side of resection rather than preservation of the pericardium to ensure macroscopic complete resection (MCR).

      Phrenectomy – Preservation of the diaphragm muscle whilst ensuring MCR is only applicable in the earliest stage lowest volume tumour. Over enthusiastic blunt dissection of a non-existent tissue plane may damage the underlying muscle and increases the risk of postoperative dysfunction or even herniation. As above I prefer to err on the side of resection to ensure MCR. This may require near total phrenectomy in higher volume tumours with dissection into perinephric fat in the most bulky. We have not found that this aggressive policy towards phrenectomy increase intra-abdominal disease progression, the “seeding” theory.

      Lymph node dissection – as with non small cell lung cancer the importance of accurate intraoperative nodal staging cannot be overemphasized. However, there is not as yet a formally described systematic method. I do adopt the standard method as for lung cancer resection but also, noting the different lymph node drainage of mesothelioma, incorporate dissection of the internal mammary, periphrenic and intercostal (where visible) nodes.

      4.Reconstruction

      Pericardium – an absorbable mesh is used to create a non restrictive “sling” to prevent postoperative cardiac herniation. A few interrupted sutures into the pericardial resection margin are used whilst carefully observing for any haemodynamic compromise (particularly on the left) from a patch that is too tight.

      Diaphragm – I prefer a bio-absorbable material to potentially reduce the risk of persistent perioperative pleural sepsis. Secure, non-absorbable interrupted sutures are inserted into the diaphragmatic resection margin over the posterior and medial aspects. This may require direct insertion into chest wall if no diaphragm remains. Anteriorly, the patch is fixed with interrupted pericostal (non-buttressed) nonabsorbable sutures.

      5.Closure

      Prior to closure in standard fashion careful attention is paid to aerostasis with suture closure of leaks and spraying of aerosolized tissue sealant over the lung surface. Meticulous haemostasis is imperative aided by the local application of haemostatic patches to the parietal surface. Prophylactic clipping of the thoracic duct is advisable to reduce the risk of postoperative chylothorax.

      6. Postoperative

      To reduce the problem of persistent postoperative air leak , 3 large bore intercostal drains are connected to suction to bring the lung surface to the rib cage and the patient is extubated as soon as possible to reduce the damaging effects of positive pressure ventilation.

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    MA03 - Clinomics and Genomics (ID 119)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
    • Now Available
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      MA03.01 - The Impact of Early Steroids on Clinical Outcomes in Patients with Advanced NSCLC Treated with Immune Checkpoint Inhibitors- A Cancerlinq Cohort (Now Available) (ID 2807)

      10:30 - 12:00  |  Presenting Author(s): Nathan Pennell  |  Author(s): Pradnya Dinkar Patil, Xuefei Jia, Brian Hobbs

      • Abstract
      • Presentation
      • Slides

      Background

      Immune checkpoint inhibitors (ICIs) have changed the treatment paradigm for patients with NSCLC, however only a fraction of patients have objective responses to these agents. Identifying clinical factors that influence efficacy of ICIs is crucial for optimal patient selection for treatment. Since ICIs produce anti-tumor responses by reinvigorating cytotoxic effector T cells, one can surmise that patients who receive steroids within a short interval of initiating ICIs will have less robust anti-tumor responses. Clinical trials usually exclude patients receiving steroids for this reason. In clinical practice, patients with NSCLC often receive corticosteroids for various indications such as brain metastases, appetite stimulation, autoimmune disorders, or COPD. By analyzing data obtained from a large real world cohort of patients with NSCLC, we aim to study the impact of early steroids (within 30 days) on clinical outcomes in patients with advanced NSCLC treated with ICIs.

      Method

      Using the Cancerlinq Discovery Database which consists of data aggregated from the electronic medical records of oncology practices, 11,143 patients with advanced NSCLC treated with ICIs were identified. Of these, 1581 patients were prescribed or administered ≥ 10 mg of prednisone or equivalent corticosteroid dose within the first 30 days of initiating ICIs. To account for prognostic heterogeneity within the population, we created matched cohorts of patients that exhibited similar prognostic clinical characteristics such as age (using 65 years as a cutoff) and gender. Association between time on treatment with ICIs and early steroid use was evaluated using the Student’s t-test. Overall survival (OS) was estimated using the Kaplan-Meier method and analyzed using the Cox proportional-hazards model.

      Result

      The cohort consisted of a predominantly white population (53.4%), with a median age of 76 years and a slight male predominance (54.9%). The median time on ICI treatment was 3.8 months. Patients who received steroids within the first 30 days had a shorter time on treatment- median of 3.36 months vs 3.86 months for those without steroid use (p= 0.023). Early steroid use was also associated with significantly worse overall survival [HR 1.16, 95% CI (1.05, 1.28) p<0.002].

      Figure: Kaplan-Meier survival analyses of patients with NSCLC treated with ICIs according to early steroid use

      p1.png

      Conclusion

      The use of ≥ 10 mg of prednisone equivalent corticosteroid dose within 30 days of initiating ICIs was associated with shorter time on treatment and worse overall survival in this large real world cohort of NSCLC patients. It is prudent that clinicians judiciously prescribe corticosteroids upon initiation of ICIs.

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      MA03.02 - Genetic Variants in ERAP1 and NCF2 in the MHC Class I Related Genes Are Associated with Non-Small Cell Lung Cancer Survival (Now Available) (ID 1491)

      10:30 - 12:00  |  Presenting Author(s): Sen Yang  |  Author(s): Qingyi Wei, David C Christiani, Qiming Wang

      • Abstract
      • Presentation
      • Slides

      Background

      Adaptive immunity, particularly the presence of tumor-infiltrating CD8+ T cells, is crucial in the control of tumor cells and preventing overall cancer progression. However, the process of CD8+ T cells recognizing and killing tumor cells depends on the expression of MHC class I (MHCI) complex presented on tumor cell surface.

      Method

      In the present study, we performed a two-phase analysis of two independently published genome-wide association studies (GWASs) to evaluate associations between genetic variants in the MHCI-related gene-set and overall survival (OS) of patients with non-small cell lung cancer (NSCLC). In the discovery GWAS dataset, we performed multivariate Cox proportional hazards regression with Bayesian false-discovery probability for multiple test corrections and evaluated associations between 9,718 single-nucleotide polymorphisms (SNPs) in 102 genes and survival of 1,185 NSCLC patients. After validation in another GWAS dataset, we performed linkage disequilibrium, function prediction and a multivariate stepwise Cox proportional hazards regression analysis.

      Result

      We found that two independent, potentially functional SNPs in two genes (ERAP1 rs469783 T>C and NCF2 rs10911362 C>T) were significantly associated with NSCLC survival, and their meta‐analysis showed an adjusted hazards ratio (HR) of 0.83 [95% confidence interval (CI) =0.77–0.89] and P meta =  8.2×10-7; 1.31 (1.06-1.73) and P meta = 0.0009; respectively. A genetic score of unfavorable genotypes of these two SNPs revealed a decreased OS in a dose–response manner (P trend < 0.0001). Further expression quantitative trait loci (eQTL) analysis showed significant associations between the genotypes and mRNA expression levels. Furthermore, the expression levels of these genes in tumor and normal tissues were different and had an effect on patient survival as well.pdf转图片- 老版.jpgpdf转图片- 老版11.jpg

      Conclusion

      Taken together, the genetic variant of the ERAP1 rs469783 and NCF2 rs10911362 from the MHCI pathway genes may be a promising predictor of survival in NSCLC patients via ERAP1 and NCF2 expression alteration.

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      MA03.03 - CEA and CYFRA 21-1 as Prognostic Biomarkers of Benefit from Nivolumab and as a Tool in Treatment Monitoring in Advanced NSCLC (Now Available) (ID 1370)

      10:30 - 12:00  |  Presenting Author(s): Filippo Gustavo Dall'Olio  |  Author(s): Francesca Abbati, Francesco Facchinetti, Francesco Gelsomino, Barbara Melotti, Maria Massucci, Sebastiano Buti, Michele Veneziani, marcello Tiseo, Andrea Ardizzoni

      • Abstract
      • Presentation
      • Slides

      Background

      To assess the role of pre-therapy levels of Carcinoembryonic antigen (CEA) and Cytokeratin-19 Fragments (CYFRA 21-1) as prognostic marker in advanced NSCLC patients treated with nivolumab, and their change as an early predictor of treatment outcome.

      Method

      This is a retrospective cohort study including all patients with stage IIIB – IV NSCLC who received nivolumab after first-line chemotherapy in 2 Italian institutions. Median Overall Survival (OS), Overall Response Rate (ORR), Disease Control Rate (DCR) and Time to Treatment Failure (TTF) were chosen as endpoints.

      Result

      100 patients were included. Cyfra 21-1 > ULN resulted correlated with OS (FIG.1A) both in univariate (HR 2.77, 95% CI 1.53 – 5.30, p 0.001) and multivariate analysis (HR 2.72, 95% CI 1.44 – 5.16, p 0.002). The only other factor correlated with OS in multivariate was ECOG PS (0-1 vs 2) (HR 5.46, 95% CI 3.07 – 9.91, p< 0.001) (Table 1).

      ECOG PS (0-1 vs 2) and CYFRA 21-1 (≤ 3.5 vs > 3.5) where combined to create a prognostic score (FIG.1B). Median OS was 23.9 months for patients without risk factors, 6.3 months with one (HR 2.75, 95% CI 1.40 – 5.40 p 0.003) and 1.3 months with 2 risk factors (HR 14.50, 95% CI 6.35 – 33.09, p< 0.001).

      Early 20% reduction after 3rd cycle was correlated with OS for CEA, HR 0.05 (95% CI 0.01–0.41), p 0,003 and borderline for CYFRA 21-1, HR 0.29 (95% CI 0.09 – 1.01), p 0.052. (FIG.1C-1D)imm per abstr.jpg.

      Univariate

      Multivariate

      Covariate

      HR (95% CI)

      P value

      HR (95%CI)

      P value

      ECOG PS 2 vs 0-1

      5.40 (3.21 – 9.09)

      < 0.001

      5.46 (3.07 – 9.91)

      < 0.001

      Cyfra > vs ≤ ULN

      2.77 (1.53 – 5.03)

      0.001

      2.72 (1.44 – 5.16)

      0.002

      Liver metastasis yes vs no

      2.19 (1.26 – 3.78)

      0.005

      0.102

      Neutrophil/lymphocyte ratio ≥ 4 vs < 4

      1.99 (1.23 – 3.20)

      0.005

      0.105

      KRAS mutated vs wild type*

      0.39 (0.21 – 0.74 )

      0.004

      0.262

      Bone metastasis yes vs no

      1.75 (1.10 – 2.79)

      0.018

      0.362

      Response to previous therapy yes vs no

      0.51 (0.29 – 0.91)

      0.023

      0.376

      CEA > vs ≤ ULN

      1.41 (0.88 – 2-25)

      0.150

      0.418

      Stage IV vs IIIB

      1.63 (0.75 – 3.54)

      0.22

      0.449

      Squamous vs non squamous

      0.79 (0.48 – 1.28)

      0.334

      0.689

      Smoker vs never smoker

      0.88 (0.65 – 1.18)

      0.386

      0.694

      Second-line vs third or more

      0.94 (0.60 – 1.47)

      0.77

      0.843

      Brain metastasis yes vs no

      1.16 (0.66 – 2.04)

      0.603

      0.594

      Conclusion

      Our data suggests that Cyfra 21-1 pre-therapy assessment, both alone and in combination with other factors in a prognostic/predictive score, may provide clinicians with further information on the prognosis of patients treated with nivolumab.

      CEA and CYFRA 21-1 repeated measures could be useful as an early surrogate marker of clinical benefit.

      Further analysis are warranted to confirm these findings.

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      MA03.04 - Discussant - MA03.01, MA03.02, MA03.03 (Now Available) (ID 3723)

      10:30 - 12:00  |  Presenting Author(s): Nathan Pennell

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA03.05 - BRAF Mutations Are Associated with Increased Benefit from PD1/PDL1 Blockade Compared with Other Oncogenic Drivers in Non-Small Cell Lung Cancer (Now Available) (ID 1472)

      10:30 - 12:00  |  Presenting Author(s): Marcelo Vailati Negrao  |  Author(s): Ferdinandos Skoulidis, Meagan Montesion, Katja Schulze, Ilze Bara, Vincent Shen, Sylvia Hu, Yasir Elamin, Xiuning Le, Michael E Goldberg, Chang-Jiun Wu, Jianhua Zhang, David S Barreto, Waree Rinsurongkawong, George R Simon, Jack Roth, Stephen Swisher, Jack Lee, Anne Tsao, Vassiliki A Papadimitrakopoulou, Don Lynn Gibbons, Bonnie Glisson, Vincent A Miller, Brian Alexander, Garrett M Frampton, Lee A Albacker, David S Shames, Jianjun Zhang, John Victor Heymach

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1/PD-L1 immune checkpoint blockade (ICB) has revolutionized the treatment of non-small cell lung cancer (NSCLC), but only a minority of patients achieve durable clinical benefit. Although classic EGFR/ALK alterations are correlated with ICB resistance, it is unknown if patients with other molecular subtypes of NSCLC also derive poorer outcomes from ICB. We investigated if there are oncogene-driven NSCLC associated with higher response rates (RR) and progression-free survival (PFS) to ICB.

      Method

      Two independent retrospective cohorts of oncogene-driven NSCLC treated with ICB monotherapy were analyzed for clinical outcome: MD Anderson (MDACC) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (FH-CGDB). PD-L1 expression (Dako 22C3 - FoundationCore) and tumor mutational burden (TMB - FoundationCore; TCGA and MSK-IMPACT – cbioportal.org) were compared across distinct molecular subtypes of NSCLC to determine differences in clinical outcome.

      Result

      Among five oncogene defined groups from the MDACC cohort, BRAF-mutant NSCLC had the highest response rate (RR) (RECIST 1.1) (P<0.01) and PFS (P<0.01) when treated with ICB (Table). These differences remained significant after adjusting for PD-L1 expression. Classic EGFR and HER-2 mutant NSCLC had the lowest RR and PFS (Table). Similar results were observed in the independent FH-CGDB cohort where BRAF-mutant NSCLC had longer real-world (rw) PFS and OS to ICB monotherapy (Table). PD-L1 expression (tumor score ≥1% and ≥50%) and TMB were higher in BRAF-mutant NSCLC compared to EGFR and HER-2 (P<0.01). BRAF V600E NSCLC had lower TMB compared to non-V600E (5.9 vs 13.7 mut/Mb, P<0.01), but both had high PD-L1 expression (≥1%: 72% vs 61%; ≥50%: 42% vs 32%).

      KRAS

      BRAF

      Classic EGFR

      EGFR exon 20

      HER2

      MDACC cohort

      Patients – N

      87

      10 (V600E 3 / non-V600E 7)

      28

      25

      15

      RR – %

      24.3

      62.5

      4.5b

      10b

      8.3

      Median PFS – mo (95% CI)

      2.76

      (2.23-3.30)

      7.37 (not estimable)a

      1.78 (1.18-2.37)

      2.73 (1.71-3.75)

      1.88 (1.63-2.12)

      FH-CGDB

      Patients – N

      503

      68 (V600E 32 / non-V600E 36)

      52

      42

      25

      Median rwPFS -

      mo (95% CI)

      3.55

      (3.15-4.24)

      6.0

      (2.89-11.6)

      2.17b

      (1.77-2.63)

      2.66b

      (2.23-5.13)

      1.87b (1.31-4.34)

      Median rwOS – mo (95% CI)

      10.28

      (8.51-12.02)

      16.07

      (8.64-NA)

      5.29b

      (3.25-17.68)

      9.89b

      (3.68-20.86)

      10.81

      (4.17-NA)

      FoundationCore cohort – N

      NA

      188 (V600E 74 / non-V600E 114)

      386

      96

      57

      TMB – mean (mut/Mb)

      NA

      10.6a

      3.7

      3.8

      5.8

      PD-L1 TPS ≥ 50% (%)

      NA

      36a

      19

      23

      16

      a: P<0.01 vs all groups; b: P<0.05 for pairwise comparison vs BRAF.

      Conclusion

      NSCLCs with BRAF mutations are associated with increased benefit from ICB when compared to tumors harboring other targetable oncogenic drivers. Oncogene driver mutations are associated with distinct patterns of TMB and PD-L1 expression. These findings highlight the importance of developing mutation-specific clinical trials in NSCLC.

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      MA03.06 - Efficacy Results of Selective AXL Inhibitor Bemcentinib with Pembrolizumab Following Chemotherapy in Patients with NSCLC (Now Available) (ID 2271)

      10:30 - 12:00  |  Presenting Author(s): Enriqueta Felip  |  Author(s): Paal Brunsvig, Åslaug Helland, Nuria Viñolas, Santiago Ponce Aix, Enric Carcereny, Manuel Dómine, Jose Manuel Trigo Perez, Edurne Arriola, Rosario Garcia Campelo, James Spicer, Jonathan Robert Thompson, Ana Laura Ortega Granados, Robert J. Holt, Dominic Smethurst, James B. Lorens, Muhammad Shoaib, Abdul Siddiqui, Julia Schoelermann, Katherine Lorens, Emmett V. Schmidt, Michael Jon Chisamore, Matthew Krebs

      • Abstract
      • Presentation
      • Slides

      Background

      The RTK AXL is implicated in epithelial-to-mesenchymal transition, negative regulation of anti-tumour immunity and resistance to multiple therapies including immune checkpoint inhibitors.

      Bemcentinib (BGB324) is a first-in-class, oral, highly selective and potent AXL inhibitor which has been demonstrated to enhance anti-PD1 therapy.

      Method

      This phase II trial (Cohort A, NCT03184571) enrolled 48 advanced lung adenocarcinoma patients with progression on or after no more than one prior line of platinum-based chemotherapy. Patients with EGFR/ALK mutations were included in this study and must have progressed on or after at least one standard targeted therapy. The primary endpoint was ORR according to RECIST v1.1. Additional endpoints included efficacy according to biomarker expression, DCR, PFS, OS, and safety. Tumour biopsies were analysed for PD-L1 expression (22C3 pharmDx), AXL by IHC, and infiltrating immune cells.

      Result

      As of April 2019, the trial was fully recruited: median age 65 (range 39-82) yrs, 61% male, 76% smokers or ex-smokers.

      At time of writing, a total of 210 treatment cycles had been completed by all patients. 17 patients were ongoing.

      17 of 32 biomarker-evaluable patients (53%) were PD-L1 negative, 13 (41%) had TPS 1-49%, and 2 (6%) had TPS >50%. Of 28 biomarker-evaluable patients, 14 (50%) expressed AXL on their tumours.

      Among patients who had at least 1 evaluable on-treatment scan: 5 responses were observed in 13 AXL positive patients (38%), and 7 in 30 patients with TPS 0-49% (23%). There were 10 responses observed among 34 evaluable patients overall (29%).

      In Stage 1, two of the 4 AXL positive responses are ongoing; mDoR is not mature in the AXL positive patients. mPFS was 5.9 mo in AXL positive patients (n=10, 3.0-NR) and 4.0 mo (95% CI 1.9-NR) overall (n=24). mOS was not mature.

      The most common TRAEs (occurring in >10% of patient in both stages) were transaminase increases (34%), asthenia/fatigue (30%), diarrhoea (26%), nausea (13%), anaemia (11%), decreased appetite (11%), and pruritus (11%). All cases of transaminase increase were reversible and resolved with concomitant administration of systemic corticosteroids and interruption of study treatments.

      Conclusion

      Patients had predominantly low or no PD-L1 expression; approximately half were AXL positive. The combination of bemcentinib and pembrolizumab was well tolerated and showed promising efficacy in previously treated IO-naïve NSCLC patients, particularly in those with AXL positive disease, including PD-L1 negative patients. Mature ORR for both stages, as well as 12-month OS for stage 1 will be presented at the meeting.

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      MA03.07 - First-Line Atezolizumab Chemoimmunotherapy in Advanced Non-Squamous NSCLC Patients Harboring EGFR/ALK Genetic Alterations (Now Available) (ID 1163)

      10:30 - 12:00  |  Presenting Author(s): Kyaw Zin Thein  |  Author(s): Nusrat Jahan, Aung Myint Tun, Anita Sultan, Sriman Swarup, Francis Mogollon-Duffo, Rachana Yendala, Miguel Quirch, Thura Win Htut, Nicholas D’cunha, Shabnam Rehman, Fred Hardwicke, Sanjay Awasthi, Lukman Tijani

      • Abstract
      • Presentation
      • Slides

      Background

      Management of advanced non-squamous non-small cell lung cancer (NSCLC) is an area in dire need of therapeutic innovation. In recent years, multiple randomized clinical trials (RCT) have combined atezolizumab, programmed death ligand 1 (PDL-1) antibody, with chemotherapy as first-line treatment of advanced non-squamous NSCLC. In patients with EGFR/ ALK genetic alterations, PDL-1 or programmed death receptor 1 (PD-1) inhibitors monotherapy previously failed to demonstrate survival benefits compared to standard chemotherapy. The purpose of our study is to explore the efficacy of atezolizumab in combination with chemotherapy for first-line treatment of advanced non-squamous NSCLC harboring EGFR or ALK genetic alterations.

      Method

      We conducted a comprehensive literature search using PUBMED, MEDLINE, EMBASE databases and meeting abstracts from inception through March 2019. RCTs utilizing first-line atezolizumab combination regimen in patients with advanced non-squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied.

      Result

      3 RCTs (IMpower – 130, 132 and 150) including 2101 patients with advanced non-squamous NSCLC were eligible. The study arm used standard chemotherapy regimens in combination with atezolizumab while control arm used only standard chemotherapy regimens. The randomization ratio was 2:1 in IMpower130 study and 2:1 in other studies. The I2statistic for heterogeneity was 0, suggesting homogeneity among RCTs. 1949 patients were EGFR/ ALK wild type and 152 patients from Impower 130 and 150 were positive for EGFR/ ALK genetic alterations. The pooled HR for PFS was statistically significant at 0.62 (95% CI: 0.56- 0.69; P < 0.0001) in patients with EGFR or ALK genetic alterations, favoring first-line atezolizumab chemoimmunotherapy regimen. In the EGFR/ ALK wild type population, the pooled HR for PFS was 0.63 (95% CI: 0.43 to 0.94; P = 0.02).

      Conclusion

      Our meta-analysis demonstrated that atezolizumab in combination with chemotherapy significantly improved progression-free survival compared to standard chemotherapy in patients with advanced non-squamous NSCLC, regardless of the presence or absence of EGFR/ ALK genetic alterations.

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      MA03.08 - Discussant - MA03.05. MA03.06, MA03.07 (Now Available) (ID 3724)

      10:30 - 12:00  |  Presenting Author(s): Myung-Ju Ahn

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA03.09 - Dramatic Responses to Immune Checkpoint Inhibitors in MET Exon 14 Skipping Mutation (METex14mut) Non Small Cell Lung Cancers (Now Available) (ID 1621)

      10:30 - 12:00  |  Presenting Author(s): Marie Mayenga  |  Author(s): Isabelle Monnet, Marie-Ange Massiani, Jean-Baptiste Assié, Laure Tabeze, Sylvie Friard, Severine Fraboulet, Anne-Cécile Metivier, Christos Chouaid, Leila Zemoura, Elisabeth Longchampt, Samia Melaabi, Louis-Jean Couderc, Helene Doubre

      • Abstract
      • Presentation
      • Slides

      Background

      METex14 mutations occur in 2-3% of Non-Small-Cell Lung Cancers (NSCLC), with a higher prevalence in patients aged over 70-years-old, non-smokers.and women. Crizotinib, a MET-inhibitor, allows remarkable, but often short, tumor responses. Immune Checkpoint Inhibitors (ICIs) have become pivotal treatments in NSCLC but seem less efficient in non-smokers and in case of oncogenic addiction. We report durable strong responses in four non-smoker women (A, B, C, D) and two smokers (E, F) treated by ICIs in a second-line setting for NSCLC harboring METex14 mut.

      Method

      We studied the clinical and biological characteristics and the tumor response after ICIs for each patient. The complete DNA sequencing of the tumor was available after the beginning of ICIs (explaining why crizotinib was not proposed in second line). PDL1 expression on tumor cells was evaluated by antibody clone E1L3N (Cell signaling Technology).

      Result

      Table 1 summarizes patient and tumor characteristics, and the evolution during ICIs : Nivolumab for all patients except E (pembrolizumab). There were neither EGFR, BRAF, KRAS mutations, nor ALK or ROS translocations (except minority KRAS mutation for C). No concurrent MET amplification was found.

      tableau.jpeg

      Partial or complete response was rapidly (2 months) obtained in five patients, while pseudo-progression was first observed in D. After a grade 3 diarrhea and diabetic ketoacidosis, ICI was stopped in A but the reintroduction one year later did not cause any toxicity. The tolerance was excellent for the 5 other patients. Response was maintained from 16 to 40 months and treatment is ongoing in four patients. C stopped ICI after 26 months (Complete response on PETscan). B had an isolated bone progression after 7 months of ICI which benefited from a local radiotherapy. After almost 2 years of ICI, a multisite progression occurred and crizotinib was proposed.

      Conclusion

      ICIs should be discussed in the treatment of METex14 mut NSCLC.

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      MA03.10 - Prospective Evaluation of a Prognostic Clinico-Molecular Score (DEMo) to Predict Outcome of Advanced NSCLC Patients Treated with Immunotherapy (Now Available) (ID 1378)

      10:30 - 12:00  |  Presenting Author(s): Arsela Prelaj  |  Author(s): Claudia Proto, Giuseppe Lo Russo, Diego Signorelli, Roberto Ferrara, Mavis Mensah, Giulia Galli, Alessandro De Toma, Giovanni Randon, Filippo Pagani, MARTA Brambilla, Benedetta Trevisan, Monica Ganzinelli, Nicoletta Zilembo, Filippo Guglielmo Maria De Braud, VALTER Torri, Marina Chiara Garassino, Gabriella Sozzi, Mattia Boeri

      • Abstract
      • Presentation
      • Slides

      Background

      We have already reported three different molecular (MSC: plasma miRNA-signature classifier, Boeri, Clin Cancer Res 2019) and clinico-biochemical scores (DiMaio: Di Maio, EJC 2010; EPSILoN: Ann.Onco 2018 supp) able to differently predict prognosis in advanced non-small cell lung cancer (aNSCLC) patients treated with immunotherapy (IO). Exploiting the ability of each test we developed a combined clinico-biological composite score called DEMo (DiMaio EPSILoN MSC). Objective of the study is to prospectively evaluate the prognostic value of DEMo in aNSCLC patients treated with IO.

      Method

      We enrolled 127 consecutive aNSCLC patients treated with IO in first (n=37) and further-lines (n=90) at Istituto Nazionale dei Tumori, Milan. All patients had complete clinico-laboratoristic data necessary for both scores: DiMaio (ECOG-PS, sex, histology, stage, uses of platinum-based therapy at first-line and response to first-line) and EPSILoN (ECOG-PS, Smoke, Liver, LDH, NLRatio). MSC was prospectively evaluated in plasma samples collected prior starting IO and the risk level were assessed. Progression-free survival (PFS) and overall survival (OS) in strata of MSC/DiMaio/EPSILoN alone or DEMo and overall response rate (ORR), were considered as endpoints. Kaplan Meier were used to generate survival curves and Cox hazard model were employed to perform multivariate analyses.

      Result

      In multivariate analyses, adjusted for age, sex, pack/year and ECOG-PS, patients with high MSC and high DiMaio and EPSILoN scores reported a lower PFS (MSC: HR 1.72 CI95% 1.06 – 2.77, p=0.027; DiMaio: HR 2.63 CI95% 1.40 – 5.00, p=0.002; EPSILoN: HR 2.17 CI95% 1.16 – 4.16, p=0.014) and OS (MSC: HR 2.17 CI95% 1.29 – 3.70, p=0.003; DiMaio: HR 3.57 CI95% 1.66 – 7.69, p=0.001; EPSILoN: HR 2.50 CI95% 1.15 – 5.26, p=0.020). DEMo stratified patients into four risk groups according to the presence of 3–2–1–0 bad markers (High MSC/DiMaio/EPSILoN or none). Groups had 0%–0%–32.2%–53.3% 1-year PFS (p<0.0001) and 4.4%– 19.4% – 66.9% – 75.4% 1-year OS (p<0.0001). We further compared 0/1 to 2/3 combined groups. At the multivariate Cox model group 2/3 had a mPFS 1.9 vs 9.4 mo compared to group 0/1 (HR 3.70 CI95% 2.08 – 6.67, p<0.0001) and mOS 4.1 vs 22.4 mo (HR 4.76 CI95% 2.56 – 9.10, p<0.0001). Regarding ORR, DEMo group 0/1 had a 3.86 (CI95% 1.76-8.47) fold higher probability to respond compare to 2/3 group (p=0.0007).

      Conclusion

      DEMo composite biomarker is able to predict better prognosis compared to each single score and can be a useful tool for guiding IO treatment choices. In particular, DEMo allowed a good selection for those patients who are less likely to benefit from IO.

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      MA03.11 - Chemotherapy After PD-1 Inhibitors Versus Chemotherapy Alone in Patients with Non–Small Cell Lung Cancer (WJOG10217L) (Now Available) (ID 409)

      10:30 - 12:00  |  Presenting Author(s): Hirotsugu Kenmotsu  |  Author(s): Eriko Miyawaki, Ryoji Kato, Hidetoshi Hayashi, Yasutaka Chiba, Junichi Shimizu, Tomohiro Ozaki, Daichi Fujimoto, Ryo Toyozawa, Yuki Akazawa, Motoyasu Okuno, Sayako Morikawa, Tatsuo Ohira, Taishi Harada, Ryota Ushio, Akihito Kubo, Toshiyuki Harada, Nozomu Kimura, Hiroyuki Yamaguchi, Kazuo Nishikawa, Nobuyuki Yamamoto, Kazuhiko Nakagawa

      • Abstract
      • Presentation
      • Slides

      Background

      Studies have suggested that chemotherapy after immune checkpoint inhibitors may confer an improved response in patients with non–small cell lung cancer (NSCLC). However, potential selection bias in such studies has not been addressed. We therefore applied propensity score analysis to investigate the efficacy of subsequent chemotherapy after PD-1 inhibitors (CAP) compared with chemotherapy alone.

      Method

      We conducted a multicenter retrospective cohort study for patients with advanced or recurrent NSCLC who were treated at 47 institutions across Japan between 1 April 2014 and 31 July 2017 with chemotherapy (docetaxel with or without ramucirumab; S-1; or pemetrexed) either after PD-1 inhibitor therapy (CAP cohort) or alone (control cohort). The primary end point was objective response rate (ORR). Inverse probability weighting (IPW) was applied to adjust for potential confounding factors, including age, sex, smoking status, performance status, histology, EGFR or ALK genetic alterations, brain metastasis, and recurrence after curative radiotherapy.

      Result

      A total of 1439 patients (243 and 1196 in the CAP and control cohorts, respectively) was available for unadjusted analysis. Several baseline characteristics—including age, histology, EGFR or ALK alterations, and brain metastasis—differed significantly between the two cohorts. After adjustment for patient characteristics with the IPW method, ORR was 18.9% for the CAP cohort and 10.8% for the control cohort (ORR ratio, 1.75; 95% confidence interval [CI], 1.25–2.45; P = .001). Median PFS was 3.5 and 2.6 months for the CAP and control cohorts, respectively (hazard ratio [HR], 0.862; 95% CI, 0.743–0.998; P = .048). The PFS rate at 3, 6, and 12 months was 53.3%, 28.5%, and 4.6%, respectively, for the CAP cohort, and 44.3%, 19.7%, and 6.1% for the control cohort. Median OS was 9.8 months for the CAP cohort and 10.3 months for the control cohort (HR, 0.979; 95% CI, 0.813–1.179; P = .822).

      Conclusion

      After adjustment for selection bias using propensity score–weighted analysis, CAP showed a significantly higher ORR and longer PFS compared with chemotherapy alone, with the primary end point of ORR being achieved. However, these results did not translate into an OS advantage, and no PFS benefit was apparent at 12 months despite the improvement observed at 3 and 6 months. Our findings suggest that prior administration of PD-1 inhibitors may result in a synergistic antitumor effect with subsequent chemotherapy, but that such an effect is transient. CAP therefore does not appear to achieve durable tumor control or confer a lasting survival benefit.

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      MA03.12 - Discussant - MA03.09, MA03.10, MA03.11 (Now Available) (ID 3725)

      10:30 - 12:00  |  Presenting Author(s): HOWARD WEST

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 12
    • Now Available
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      MA06.01 - Mediastinal Lymph Node Dissection (MLND) v Systematic Sampling (SS) v Neither (NN) in Population-Based Cohort (Now Available) (ID 2974)

      13:30 - 15:00  |  Presenting Author(s): Meredith Ray  |  Author(s): Nicholas Faris, Carrie Fehnel, Cheryl Houston-Harris, Olawale Akinbobola, Philip Ojeabulu, Matthew P Smeltzer, Ray Osarogiagbon

      • Abstract
      • Presentation
      • Slides

      Background

      American College of Surgeons’ Oncology Group (ACOSOG) Z0030 revealed similar survival after MLND v SS for early-stage non-small cell lung cancer (NSCLC), but a recent meta-analysis of 1,980 patients in 5 randomized controlled trials from 1989-2007 suggested superior survival after MLND, raising doubts about Z0030 findings. We compared survival of patients with MLND v SS v NN in a population-based cohort.

      Method

      All resections for NSCLC in all institutions within 4 contiguous United States Hospital Referral Regions from 2009-2018 stratified by ACOSOG Z0030 nodal examination criteria into MLND (stations 2R,4R, 7, 8, 9 and 10R for right-side resections; 4L, 5, 6, 7, 8, 9, and 10L for left-sided), SS (minimum of 4R, 7, and 10R on the right and 5,6,7 and 10L on the left, but MLND definition not met), and NN (neither MLND nor SS ).

      Using appropriate statistical tests, we compared demographic and clinical characteristics, perioperative complication rates and survival, adjusting survival for extent of resection, histology, age, race, sex and insurance.

      Result

      2118 patients met Z0030 eligibility criteria (clinical T1/2,N0/non-hilar N1,M0): 15% had MLND, 15% SS, 69% NN. The distribution of age, race, insurance was similar, but 54% v 51% v 43% of MLND v SS v NN, were female (p=.0002). Use of preoperative PET-CT scans was similar (p=.5797), but invasive staging was used in 21% v 19% v 28% (p<.01), Although the distribution of clinical T,N and aggregate stage was similar (p>.05), 10% of the patients who met neither MLND nor SS criteria had no lymph nodes examined (pathologic NX). The median (interquartile range) number of mediastinal lymph nodes examined was 8(6-12), 5(4-8), 2 (0-5) (p<.001); hilar/intrapulmonary nodes 5(2-9), 6(3-10), 3(1-7) (p<.001). Postoperative complication rates were similar, including rates of cardiac arrhythmia, chylothorax and ICU re-admission. ICU length of stay (LOS) was 1(1-2) days in all groups, hospital LOS was 5(3-7), 5(3-8), 6(4-10) days. The 30-day mortality rate was 4% for all groups. Unadjusted hazard ratio (HR) was 0.80 (0.56-1.10, p=1.664) between MLND and SS; adjusted (a)HR 0.81 (0.58-1.138, p=0.2273). Survival of MLND and SS patients was significantly better than NN (Figure): aHR 0.62(0.48-0.81, p=0.0004) for MLND v NN; aHR 0.76 (0.60-0.98, p=0.0304) for SS v NN.

      figure acosog.png

      Conclusion

      ACOSOG systematic nodal dissection was achievable and safe in a ‘real-world,’ population-based cohort. SS was associated with similar survival to MLND in early-stage NSCLC, corroborating Z0030 findings. However, the majority of resections did not attain either criteria, with significantly worse survival.

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      MA06.02 - NSCLC Surgery Outcomes Between Facility Types and Association with Guideline Directed Surgical Quality of Care Metrics  (Now Available) (ID 2245)

      13:30 - 15:00  |  Presenting Author(s): David E. Gerber  |  Author(s): Mitchell Von Itzstein, Rong Lu, Yang Xie

      • Abstract
      • Presentation
      • Slides

      Background

      Non-small cell lung cancer (NSCLC) treatment outcomes differ between facility types. Surgical outcome differences may be related to modifiable factors and likelihood of receiving guideline centered care, which could be improved with new policy initiatives. We therefore analyzed the National Cancer Database (NCDB), to determine the variables related to different outcomes between facility types.

      Method

      The NCDB is a cancer registry curated by the Commission on Cancer that captures demographic and clinical data for an estimated 80% of NSCLC patients in the United States. A retrospective analysis of the NCDB was performed from 2004-2013 for Stage 1, 2 and 3a NSCLC patients treated with surgery. We compared overall survival between academic comprehensive cancer programs (ACAD) and community cancer programs (CCP) and four surgical quality metrics; lobectomy or greater vs sublobectomy, positive vs negative margin status, whether regional lymph node (LN) surgery was performed and number of nodes removed (less that 10 or equal to or greater than 10), in addition to 16 other demographic and clinical variables known to affect NSCLC survival. Kaplan-Meier estimates, log-rank test, multivariate Cox proportional hazard models and propensity score matching were used to evaluate survival differences while adjusting the effects of covariates. Quality of matching was checked using Wilcoxon rank sign test, chi-square test, and multivariate logistic regression models.

      Result

      The total cohort was 75,976 patients. After propensity matching for clinical and demographic variables, median overall survival (OS) for Stage 1, 2 and 3a was 76, 51 and 36 months for ACAD and 67, 43 and 32 months for CCP respectively (p<0.002 for all). Overall, selection of lobectomy or greater was the same between facility types (p=0.645), but ACAD were more likely to have negative margins (92.3% vs 89.8%, p<0.00001), perform LN dissection (89.5% vs 84.3%%, p<0.00001) and remove greater than 10 LN (37.4% vs 23.1%%, p<0.00001). After contrast matching for the surgical quality metrics, OS for Stage 1, 2 and 3a was 73, 49 and 34 months for ACAD and 67, 43 and 32 months at CCP respectively, with a non-significant P value for Stage 3a sub-cohort. Analysis revealed that the four key surgical quality measures explained 38% of the OS difference in median survival (p<0.00001).

      Conclusion

      In this large cohort of Stage 1, 2 and 3a NSCLC patients treated surgically, OS was higher at ACAD compared to CCP, which was in part explained by differences in surgical quality metrics. In the era of discussions of nationalized healthcare, policymakers will need to consider the differential treatment outcomes at different centers and consider consolidating treatment for NSCLC at high performing centers or improving the quality care measures of low performing centers.

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      MA06.03 - Poor Pulmonary Function Does Not Define “Medical Inoperability”:  Short and Long Term Results of a Matched Lung Cancer Cohort (Now Available) (ID 2846)

      13:30 - 15:00  |  Presenting Author(s): Brendon M Stiles  |  Author(s): Adam N Sholi, Mohamed K Kamel, Abu Nasar, Ajita Naik, Sebron Harrison, Benjamin Lee, Jeffrey L Port, Nasser K Altorki

      • Abstract
      • Presentation
      • Slides

      Background

      Patients with suboptimal pulmonary function tests (PFTs) are often denied surgery for NSCLC. However, there is no consensus definition of compromised lung function. This study compared morbidity and survival following surgery in patients with preoperative %predicted FEV1or DLCO <50% (Low-Group) versus those with both values >50%(High-Group).

      Method

      A prospectively-maintained database was reviewed for patients undergoing surgery for NSCLC between 1990–2019. Propensity matching (1:2) was performed based on age, gender, histology, pathologic stage, and comorbidity index. Overall survival (OS) was estimated using Kaplan-Meier analysis and multivariable analysis identified predictors of survival.

      Result

      Among 2982 patients with PFT data, 372(12.5%) had FEV1or DLCO <50%. We matched 321 patients with FEV1or DLCO <50% to 637 patients with both PFTs >50%. No significant differences were observed in perioperative complications(Table) or 30-day mortality between Low and High groups (0.3% vs. 0.6%, p=0.668). The Low group more frequently underwent sublobar resection (41% vs. 22%, p<0.001). Median follow-up was 41 months, and median, 3-, and 5-year OS for the Low and High groups was 118 vs.148 months, 79% vs. 82%, and 70% vs. 74%, respectively (p=0.003). Patients with both FEV1and DLCO <50% (n=44) had a median survival of 109 months and 3- and 5-year OS of 77% and 71%. Multivariable analysis identified advanced age (HR=1.03, CI 1.01–1.05), higher clinical stage (HR=1.85, CI 1.22–2.82), and earlier year of surgery (HR=1.06, CI 1.01–1.12) as predictors of poor survival, but not FEV1or DLCO <50% (p=0.672). Among the Low group only, advanced age (HR=1.05, CI 1.02–1.07) and sublobar resection (HR=1.60, CI 1.04–2.45) predicted worse OS.

      pfttable.png

      Conclusion

      Patients with decreased lung function have comparable perioperative outcomes to patients with normal lung function and experience excellent long-term survival. “Medical inoperability” should therefore be determined by surgeons and not by pulmonary function alone.

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      MA06.04 - Discussant - MA06.01, MA06.02, MA06.03 (Now Available) (ID 3736)

      13:30 - 15:00  |  Presenting Author(s): Daniel J Boffa

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA06.05 - Predictive Performance of Quantitative Metabolic Metrics of FDG-PET/CT on Survival and the Effect of Adjuvant Chemotherapy in Lung Cancer (Now Available) (ID 1294)

      13:30 - 15:00  |  Presenting Author(s): Yojiro Makino  |  Author(s): Yoshihisa Shimada, Sachio Maehara, Hagiwara Masaru, Masatoshi Kakihana, Naohiro Kajiwara, Tatsuo Ohira, Norihiko Ikeda

      • Abstract
      • Presentation
      • Slides

      Background

      Growing evidence suggests metabolic metrics of tumors, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on FDG-PET/CT, reflect the malignancy of early-staged lung cancer. We aimed to investigate the role of metabolic metrics in predicting prognosis and response to adjuvant chemotherapy in pathological stage I (the 7th Edition of TNM Staging of Lung Cancer) lung adenocarcinoma (p-I Ad).

      Method

      The study included 452 patients with p-I Ad who underwent FDG-PET/CT followed by complete resection between July 2012 and December 2017. In this study, MTV is defined as the total tumor volume with an SUV > 2.5 while TLG is calculated as mean of SUV x MTV. The three metabolic metrics measured by a three-dimensional workstation and clinico-pathological factors were analyzed to identify the factors associated with unfavorable overall survival (OS) and recurrence-free survival (RFS). We assessed whether the metabolic metrics were associated with response to oral adjuvant chemotherapy with uracil-tegafur (AC with UFT) in patients with p-I Ad amenable to the treatment.

      Result

      All the three metabolic metrics were significantly correlated with unfavorable OS and RFS on univariate analyses (SUVmax; p=0.047 / p<0.001, MTV2.5; p=0.003 / p<0.001, TLG2.5; p=0.005 / p<0.001). On multivariate analyses, smoking status (p=0.043), the value of serum CEA (p < 0.001), and SUVmax (p=0.001) were independent determinants for poorer RFS while gender (p=0.013) and MTV2.5 (p=0.028) were independent significant factors for unfavorable OS. The receiver operating characteristic areas under the curves for SUVmax, MTV2.5, and TLG2.5 relevant to recurrence were 0.901, 0.849, and 0.872, respectively. Among 239 patients who fitted the criteria of AC with UFT (p-IA > 2cm or p-IB), 80 patients (33.4%) received the treatment (250 mg of tegafur per square meter of body-surface area per day). Although the administration of AC with UFT did not significantly affect RFS and OS (p=0.411 and 0.753), patients with TLG2.5 > 12.8, which value corresponded to the cut-off level, who were not given AC with UFT exhibited worse RFS than those who received the treatment (5-year RFS rate of 72.1% vs. 92.7%; p=0.041).figure.png

      Conclusion

      Metabolic metrics on FDG-PET/CT such as SUVmax, MTV, and TLG enable us to estimate survival outcomes and the effectiveness of AC with UFT in patients with p-I Ad. Patients with metabolically active tumors should be considered high risk, and this information can be useful for the selection of appropriate therapeutic strategy including AC with UFT.

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      MA06.06 - A Phase III Study of Adjuvant Chemotherapy in Patients with Completely Resected, Node-Negative Non-Small Cell Lung Cancer  (Now Available) (ID 285)

      13:30 - 15:00  |  Presenting Author(s): Hideo Kunitoh  |  Author(s): Hiroyuki Sakurai, Masahiro Tsuboi, Masashi Wakabayashi, Morihito Okada, Kenji Suzuki, Norihiko Ikeda, Makoto Takahama, Mitsuhiro Takenoyama, Yasuhisa Ohde, Katsuo Yoshiya, Isao Matsumoto, Motohiro Yamashita, Takashi Marutsuka, Hiroshi Date, Toru Hasumi, Yoshinori Yamashita, Norihito Okumura, Shun-ichi Watanabe, Hisao Asamura

      • Abstract
      • Presentation
      • Slides

      Background

      Post-operative UFT (tegafur/uracil) has been shown to prolong survival of Japanese patients with completely resected, p-stage I (T1> 2 cm) non-small cell lung cancer (NSCLC). This trial, the Japan Clinical Oncology Group (JCOG) 0707, aimed at estimating the efficacy of S-1 (tegafur/gimeracil/oteracil) compared to UFT as adjuvant therapy in this population.

      Method

      Eligible patients had received complete resection with lymph node dissection for p-stage I (T1-2N0M0, T1> 2 cm, by 5thEdition UICC TNM) NSCLC, within 56 days of enrollment. Patients were randomized to receive: oral UFT 250mg/m2/day for 2 years (Arm A), or oral S-1 80mg/m2/day for 2 weeks and 1 week rest, for 1 year (Arm B). The initial primary endpoint was overall survival (OS). Based upon the monitoring in Jun. 2013, which showed the combined OS of the 2 arms better than expected (4-year OS of 91.6% vs. presumed 5-year OS of 70-76.5%), it was judged to be underpowered. The study protocol was amended so that the primary endpoint is relapse-free survival (RFS). With the calculated sample size of 960, this study would detect the superiority of Arm B over Arm A with power 80% and one-sided type I error of 0.05, assuming the 5-year RFS of 75% in Arm A and the hazard ratio of 0.75.

      Result

      From Nov. 2008 to Dec. 2013, 963 patients were enrolled (Arm A : 482, Arm B : 481): median age 66 (range: 33 to 80), male 58%, adenocarcinoma 80%, p-T1/T2 46%/54%. Only 2 received pneumonectomy. >Grade 3 toxicities (hematologic/nonhematologic) were observed in 15.9 (1.5/14.7) % in Arm A, and in 14.9 (3.6/12.1) % in Arm B, respectively. 60.0% of the patients in Arm A and 54.7% of them in Arm B completed the protocol treatment (p=0.10). There were 4 cases of deaths during protocol treatment, probably of cardio-vascular origin, with 1 in Arm A and 3 in Arm B. At the data cut-off of Dec. 2018, the hazard ratio (HR, Arm B vs. Arm A) of RFS was 1.06 (95% confidence interval (C.I.): 0.82-1.36), showing no superiority of S-1 over UFT. The HR of OS was 1.10 (95% C.I.: 0.81-1.50). The 5-year RFS/OS rates were 79.4%/88.8% in Arm A and 79.5%/89.7% in Arm B, respectively. Pre-specified subset analyses for gender, age, smoking, stage, tumor side, lymph node dissection area, pleural invasion and histology revealed no remarkable results; S-1 arm was not superior to UFT arm in each analysis. Of the 77 and 85 OS events for Arm A/Arm B, 45 each (58%/53%, respectively) were due to the NSCLC. During the follow-up period, secondary malignancy was observed in 85 (17.8%) and 84 (17.8%) in Arm A and Arm B, respectively.

      Conclusion

      Post-operative adjuvant therapy with oral S-1 was not superior to that with UFT in stage I (T>2 cm) NSCLC after complete resection. UFT remains standard in this population. Future investigation should incorporate identification of high-risk population for recurrence, since survival of each arm was so good with substantial number of OS events due to other causes of deaths in this trial.

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      MA06.07 - E1505: Adjuvant Chemotherapy +/- Bevacizumab for Early Stage NSCLC: Updated Chemotherapy Subset Analysis (Now Available) (ID 2885)

      13:30 - 15:00  |  Presenting Author(s): Heather A Wakelee  |  Author(s): Suzanne E Dahlberg, Steven M Keller, William J Tester, Seena C Aisner, Jan M. Rothman, Jyoti D Patel, Robert Delaune, Sean R McDermott, Atif Shafqat, Roman Perez-Soler, Andrew E Chapman, Samer S Kasbari, Anne M Traynor, Tracey L Evans, Leora Horn, Stephen L Graziano, David R Gandara, Alex A Adjei, Charles A Butts, Natasha B Leighl, Suresh S Ramalingam, Joan H Schiller

      • Abstract
      • Presentation
      • Slides

      Background

      Adjuvant chemotherapy (chemo) for resected early stage NSCLC provides modest survival benefit with limited comparison data between regimens. From this trial we previously reported that adding bevacizumab (B) to adjuvant chemo failed to improve either disease free survival (DFS) or overall survival (OS). Here we update outcomes by chemotherapy regimen with an additional 30 months of follow-up.

      Method

      Enrolled patients with resected early stage NSCLC, stratified by stage, histology, sex, and chemo option, were randomized 1:1 to chemo alone or with B (15 mg/kg every 3 weeks for up to 1 year). Chemo consisted of a planned 4 cycles of every 3 week cisplatin with either vinorelbine (V), docetaxel (D), gemcitabine (G) or pemetrexed (P).

      Result

      From July 2007 to September 2013, 1501 patients were enrolled with this distribution of chemo: V 25.0%, D 22.9%, G 18.9% and P 33.2%. P was added in 2009 and restricted to non-squamous (NSq) pts. Chemo regimen was chosen (not randomized). Arms were well balanced for known prognostic factors; 28% had Sq histology. Median f/up per chemo group is: V 83.5 months(m); D 89.9m; G 87.8m; P 71.9m. In pooled analysis DFS differed by histology ranging from 29.9m(G)-43.5m(V) for NSq and 59.4m(V)-77.3m(G) for Sq. OS also differed by histology ranging from 80m(D)-98.8m(P) for NSq and 98m(G)-119m(V) for Sq. A non-significant decline in both DFS and OS was seen when B was added to D or V regimens, regardless of histology. Conversely, the addition of B to P improved both DFS (HR 0.74, p= .00994) and OS (HR 0.65, p= .00368). We thus compared outcomes across non-B regimens and though numerical differences were seen in median DFS and OS, these failed to reach statistical significance. Toxicity details were presented previously.

      Conclusion

      B did not improve OS when added to adjuvant chemo for patients with surgically resected early stage NSCLC, though variable DFS and OS outcomes by chemotherapy regimen have emerged with longer-term follow-up. These include a significant positive improvement in DFS and OS with B combined with P and trends of worse outcomes when B was added to other regimens. Ongoing molecular analysis of samples will hopefully elucidate the etiology of these differences.

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      MA06.08 - Discussant - MA06.05, MA06.06, MA06.07 (Now Available) (ID 3737)

      13:30 - 15:00  |  Presenting Author(s): Jordi Remon

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA06.09 - Timing of Driver Mutation Development and the Genetic Evolution of Semi-Solid Lung Nodules into Early NSCLC (Now Available) (ID 2980)

      13:30 - 15:00  |  Presenting Author(s): Gavitt A Woodard  |  Author(s): Vivianne Ding, Il-Jin Kim, Kirk Jones, Gordon Chavez, Greg Haro, Johannes Kratz, Michael J. Mann, Julia Rotow, Collin M Blakely, David M Jablons

      • Abstract
      • Presentation
      • Slides

      Background

      The genetic changes that drive the appearance of a ground glass opacity and subsequent development of an invasive solid component within a semi-solid lesion (SSL) are not well understood. Biomarkers that predict the transition to invasive cancer are needed to determine when ground glass lesions will evolve into invasive cancer.

      Method

      From a prospective database 65 patients with surgically resected SSL between 2011-2018 were identified. Clinical characteristics and disease free survival was compared between SSL and 155 stage I adenocarcinomas resected during the same time period. Paraffin tissue blocks were obtained from 22 of the SSL and areas of normal lung (NL) ground glass (GG) and solid (S) tumor were identified and microdissected separately from within the same lesion. Next generation sequencing (NGS) was performed on DNA extracted from 19 nineteen matched GG and S samples on twenty-five common lung cancer driver mutations. Affymetrix microarray of over 48,000 transcripts was performed on S, GG, and NL samples from eight patients with SSL.

      Result

      No patients with a resected SSL has recurred to date with significant differences in 5-year disease free survival verses stage I adenocarcinomas from the same time period (100% vs 80.9%, log-rank p-value 0.007). Driver mutations in the solid component of SSL were EGFR mutation (43%; L858R 26% and exon 19 deletion 11%), KRAS mutation (21%), and no mutation identified (42%). All driver mutations present in S component of SSL were also identified in GG regions of the same lesion with very similar gene expression profiles. Only 32 transcripts were significantly different between GG and S areas of the same tumor. The greatest difference observed between GG and S portions of the same tumor was significantly higher expression of secreted phosphoprotein 1 (SPP1) in the invasive solid portion suggesting that SPP1 may serve as a biomarker of invasive potential.

      Conclusion

      This is the first study to examine the systems genetics of mutations and gene expression from the microenvironments of solid and ground glass areas within the same tumor. Mutations are present in the ground glass portion of a semi-solid tumor suggesting early development of driver mutations. Increased expression of SPP1 emerged as the most promising biomarker of invasive potential of a semi-solid lesion. In other studies SPP1 has been shown to correlate with poor prognosis and is a biomarker that warrants further study.

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      MA06.10 - Stereotactic Ablative Radiotherapy in the Management of Synchronous Early Stage Non-Small Cell Lung Cancers (Now Available) (ID 1924)

      13:30 - 15:00  |  Presenting Author(s): Zeina Ayoub  |  Author(s): Eric D Brooks, James W Welsh, Aileen Chen, Saumil Gandhi, John Victor Heymach, Ara A Vaporciyan, Joe Y Chang

      • Abstract
      • Presentation
      • Slides

      Background

      The aim of the study is to evaluate the efficacy and patterns of failure of early stage synchronous non-small cell lung cancer (NSCLC) treated with stereotactic ablative radiotherapy (SABR).

      Method

      Patients with synchronous NSCLC who received SABR (50 grays in 4 fractions or 70 grays in 10 fractions) to at least one lesion were reviewed. Synchronous lesions were defined as multiple ipsilateral or contralateral intrapulmonary lesions diagnosed within 6 months.

      Result

      Out of a total of 912 patients treated with SABR for early stage NSCLC between 2005 and 2015, 82 (9%) had synchronous disease. The median age was 70 years and 34 (41.5 %) patients were males. The median diameter was 2.1 cm (Interquartile range (IQR) 1.6-3 cm) for index lesions and 1.5 cm (IQR 1.1-2.2 cm) for second lesions. At a median follow-up time of 58 months, the 1, 3 and 5-year progression-free survival (PFS) rates were 85.4%, 47.3% and 28.5%, respectively; the corresponding overall survival rates were 95.1%, 66.9% and 52.4% and the 1, 3 and 5-year local recurrence (LR)-free survival rates were 97.3%, 79.6% and 70.8%, respectively. Among the 39 (47.6%) patients with disease progression, intralobal LR was the first site of failure in 15 (18.3%) patients, with a total of 19 local recurrences out of 169 (11.2%) thoracic lesions. Isolated regional recurrence occurred in 3 (3.7%) patients, and distant failure in 221 (25.6%) patients. On multivariate analysis, factors associated with improved PFS were an improved ECOG PS score (HR 10.786; 95% CI 2.845-40.902; p-value <0.001), DLCO (HR 0.947; 95% CI 0.903-0.994; p-value 0.026) and an index lesion pathology of adenocarcinoma (HR 0.167; 95% CI 0.033-0.841; p-value 0.030). Only the ECOG PS score maintained significance (HR 6.165; 95% CI 2.081-18.263; p-value 0.001) on multivariate analysis for OS. No association was found between the use of chemotherapy as part of the initial management strategy and survival outcomes. Similarly, no difference in outcomes was observed whether all lesions were treated with SABR compared to SABR and other modalities.

      Conclusion

      SABR achieves promising long-term survival and tumor control rates and may be a potential curative treatment for synchronous early stage NSCLC. Our data indicates that patients presenting with synchronous NSCLC lesions can be approached as having two separate primary lung tumors, and be offered definitive local therapy with aims of cure.

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      MA06.12 - Discussant - MA06.09, MA06.10, MA06.11 (Now Available) (ID 3738)

      13:30 - 15:00  |  Presenting Author(s): Samina Park

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA06.13 - Tsuguo Naruke Lectureship Award for Surgery (Now Available) (ID 3901)

      13:30 - 15:00  |  Presenting Author(s): Raja Flores

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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    MS14 - Molecular Subsets and Novel Targeted Approaches to Small Cell and Neuroendocrine Cancers (ID 77)

    • Event: WCLC 2019
    • Type: Mini Symposium
    • Track: Small Cell Lung Cancer/NET
    • Presentations: 5
    • Now Available
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      MS14.01 - Molecular Subsets of Neuroendocrine Tumors (Now Available) (ID 3519)

      11:30 - 13:00  |  Presenting Author(s): Christine Lee Hann

      • Abstract
      • Presentation
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      Abstract

      Small cell lung cancer (SCLC) is an aggressive tumor with one of the highest case-fatality rates among cancer. Clinically SCLC is hallmarked by early metastatic behavior and rapid development of therapeutic resistance. Over the past decades multiple research teams have used genomic, epigenomic, transcriptomic and proteomic approaches to further characterize SCLC. Long considered a relatively homogeneous tumor, these data have led to a deeper understanding of SCLC biology and support the concept that there are distinct biologic subsets of SCLC. Complementary work using patient-derived xenografts and genetically engineered mouse models have validated some of this data and these models serve as platforms for novel therapeutic development. These studies support translational efforts in SCLC focused on distinct vulnerabilities in subsets of this disease and the development of predictive biomarkers.

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      MS14.02 - Subclonal Architecture and Genomic Evolution of SCLC (Now Available) (ID 3520)

      11:30 - 13:00  |  Presenting Author(s): Jinghui Wang

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      Abstract

      Small cell lung cancer (SCLC) accounts for 15-20% of all of lung cancer worldwide and it is a highly aggressive and rapidly progressive tumor with rapid growth speed and strongly associated with smoking. SCLC is divided to limited disease and extensive disease. The staging systems for SCLC are Veterans Administration scheme (VA), the AJCC TNM staging systemand NCCN staging, among of these VA is most commonly used. In recent several decades, chemotherapy combined radiotherapy is the main treatment for SCLC. The overall survival (OS) in patients with limited disease-SCLC and extensive disease were 15-18 months and 10-12 months, respectively. Immunotherapy is becoming a promising treatment for SCLC nowadays.

      Targeted therapy based on genotyping in non-small cell lung cancer is a main treatment. However, targeted therapy in SCLC is not successful and studies on the genomic evolution of SCLC are rare. ctDNA (circulating cell-free tumor DNA) is a good tool for monitoring the genomic changing in patients with malignant tumors, especially for monitoring acquired resistance of targeted therapy. ctDNA and CTCs are useful for genomic evolution of cancer. However, isolation and identification of CTCs are not satisfied in lung cancer, though there are more CTCs in small call lung cancer because of tumor cells are more easily to shed to blood stream in SCLC. ctDNA can provide more accurate genomic landscape of SCLC through overcome heterogeneity.

      We conducted a study that aimed to explore the genomic structure and gene evolution pattern of SCLC using next-generation sequencing and who had been followed by dynamic samples after chemotherapy or/and radiotherapy. We found that TP53 and RB1 are the most common mutations in SCLC, and NOTCH1-4, CREBBP, EG300, MYC, MYCL1, and MYCN are also frequently mutated genes and copy number alterations. We also compared the tissue and blood ctNDA genome and we found that a majority of mutations detected in tumor DNA were also detected in paired ctDNA samples suggesting ctDNA sequencing is sensitive and reliable for detecting mutations in SCLC patients. We used the average VAF (Variant allelic frequencies) of mutations from the major clones as a surrogate for overall ctDNA level. We found higher median ctDNA level was associated with shorter progression-free survival (PFS) and overall survival (OS). Dynamic ctDNA levels are correlated with tumor measurements on imaging suggesting that ctDNA sequencing has the potential for monitoring the clinical course of SCLC. The genomic profiles derived from pre-treatment ctDNA to the genomic profiles from ctDNA at different time points during treatment from post-treatment plasma samples available. Some new mutations that were not exist in pre-treatment blood samples.

      Immunotherapy is an important method for lung cancer. PD-L1 expression and tumor mutation burden (TMB) are two common predictors for immunotherapy. In our cohort, tumor mutation burden is not higher based on the large gene panel. PD-L1 expression is about more than 10% in SCLC. The treatment for SCLC is still highly challenging. TMB based on ctDNA is worth further investigation on predicting SCLC immunotherapy. A previous study showed that SCLC with high TMB had a better response to checkpoint inhibitors. Shedding of ctDNA is a complicated process affected by many factors. With the technique development and increasing understanding of tumor biology, the genome of SCLC will be a useful tool for guiding the treatment and predicting the prognosis of SCLC in the future.

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      MS14.03 - Targeting Transcription (Including Lurbinectedin) (Now Available) (ID 3521)

      11:30 - 13:00  |  Presenting Author(s): Manuel Cobo

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      Abstract not provided

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      MS14.04 - Targeting DNA Damage and Repair (Now Available) (ID 3522)

      11:30 - 13:00  |  Presenting Author(s): Charles M Rudin

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      Abstract

      Genomic profiling of small cell lung cancer has revealed nearly universal inactivation of the key tumor suppressor genes TP53 and RB1. Loss of these critical regulators of cell cycle entry and DNA damage response together results in selective sensitivity to DNA damaging agents, inhibitors of DNA damage repair, and inhibitors of the remaining late phase cell cycle checkpoints. Multiple preclinical studies and recent clinical data nominate these pathways as potential synthetic lethal vulnerabilities in small cell lung cancer. Recent study has also demonstrated that targeting DNA damage response can activate the anti-tumor immunity and potentiate the response of immune checkpoint blockade antibodies. This talk will review these recent studies, focusing on opportunities and future directions in investigational therapy for patients with small cell lung cancer.

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      MS14.05 - DLL3 Targeting Agents (Now Available) (ID 3523)

      11:30 - 13:00  |  Presenting Author(s): John T Poirier

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      Abstract

      Delta-like ligand 3 (DLL3) is a single-pass transmembrane Notch ligand that interacts with full-length, unprocessed NOTCH1 in the Golgi apparatus, inhibiting the pathway in cis. DLL3 is selectively overexpressed in the subtype of small cell lung cancer (SCLC) driven by the transcription factor ASCL1 (SCLC-A) that accounts for ~70% percent of SCLC diagnoses (95% CI [60 – 79])1. In one study immunoreactivity was observed in 1,040/1,363 (70.4%) of SCLC specimens, consistent with this incidence2. Overexpression of DLL3 leads to low-level cell surface expression of the protein on the order of 10,000 proteins per cell while expression in normal tissues is restricted to intracellular compartments: the same study demonstrated only low to moderate cytoplasmic or nuclear immunoreactivity in normal adult tissues3. High expression of DLL3 has also been reported in low-grade glioma4,5, neuroendocrine prostate6, and occasionally in other cancer types when neuroendocrine features are present7,8. The exquisitely selective expression of surface DLL3 on cancer cells presents an attractive target for a variety of therapeutic strategies.

      Rovalpituzumab teserine (Rova-T; SC16LD6.5) is an antibody drug conjugate consisting of a monoclonal antibody targeting DLL3, a cathepsin-cleavable linker, and a pyrrolobenzodiazepine (PBD) warhead4. The first-in-human clinical trial of Rova-T in recurrent SCLC demonstrated
      encouraging activity despite often severe side-effects attributable to the PBD warhead9; however, the phase 2 TRINITY study showed a disappointing 16% objective response rate while reporting a similar toxicity profile (NCT02674568). Subsequently, the phase 3 TAHOE study was halted due to shorter overall survival in the treatment arm. An active phase 3 trial of Rova-T in the maintenance setting (MERU) is ongoing (NCT03033511).

      Other DLL3-targeting therapies under active investigation include the bispecific T cell engager (BiTE) AMG 757 (NCT03319940), and a chimeric antigen receptor CAR-T AMG119 (NCT03392064). These agents have shown significant anti-tumor activity in preclinical models of SCLC; however, AMG 119 required direct delivery of the engineered T cells for activity. AMG 757 was therefore the more potent of the two strategies in preclinical models and may therefore be better suited to overcome known barriers to CAR-T activity in solid tumors.

      Alternative strategies remain under exploration including the use of 89Zr-SC16, a PET radiotracer, for in vivo imaging and as a companion diagnostic to optimize the selection of patients for treatment with DLL3-directed therapeutic agents. 89Zr-labeled-SC16 antibody successfully delineated normal tissue from subcutaneous and orthotopic SCLC tumor xenografts. Radiotracer accumulation in tumors was directly correlated with the degree of DLL3 expression and, also correlated with response to SC16LD6.5 therapy in SCLC patient–derived xenograft models.

      1 Rudin, C. M. et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer 19, 289-297, doi:10.1038/s41568-019-0133-9 (2019).
      2 Huang, R. S. P. et al. Delta-like Protein 3 Prevalence in Small Cell Lung Cancer and DLL3 (SP347) Assay Characteristics. Arch Pathol Lab Med, doi:10.5858/arpa.2018-0497-OA (2019).
      3 Sharma, S. K. et al. Non-invasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer. Cancer Res, doi:10.1158/0008-5472.CAN-17-0299 (2017).
      4 Saunders, L. R. et al. A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo. Sci Transl Med 7, 302ra136, doi:10.1126/scitranslmed.aac9459 (2015).
      5 Spino, M. et al. Cell Surface Notch Ligand DLL3 is a Therapeutic Target in Isocitrate Dehydrogenase-mutant Glioma. Clin Cancer Res 25, 1261-1271, doi:10.1158/1078-0432.CCR-18-2312 (2019).
      6 Puca, L. et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med 11, doi:10.1126/scitranslmed.aav0891 (2019).
      7 Koshkin, V. S. et al. Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target. Clin Cancer Res 25, 210-221, doi:10.1158/1078-0432.CCR-18-1278 (2019).
      8 Ding, X., Li, F. & Zhang, L. Knockdown of Delta-like 3 restricts lipopolysaccharide-induced inflammation, migration and invasion of A2058 melanoma cells via blocking Twist1-mediated epithelial-mesenchymal transition. Life Sci 226, 149-155, doi:10.1016/j.lfs.2019.04.024 (2019).
      9 Rudin, C. M. et al. Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study. Lancet Oncol 18, 42-51, doi:10.1016/S1470-2045(16)30565-4 (2017).

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