Scientific Program

Filter Results:

  • +

    PL 03 - Immunology in Lung Cancer Update 2017

    • Type: Plenary Session
    • Track: Immunology and Immunotherapy
    • +

      PL 03.03 - Blueprint 2: PD-L1 Immunohistochemistry Comparability Study in Real-Life, Clinical Samples

      08:15 - 09:45  |  Presenting Author(s): Ming Sound Tsao  |  Author(s): Keith M Kerr, Yasushi Yatabe, Fred R. Hirsch

      • Abstract

      Abstract:
      PD-L1 immunohistochemistry (IHC) has been established as companion or complementary diagnostic assays, each having been developed as a predictive biomarker for specific anti-PD-1/PD-L1 immunotherapies.[1] The Blueprint phase 1 was conducted as a feasibility study to assess the staining (analytical) comparability of four PD-L1 IHC assays (22C3, 28-8, SP142, and SP263) that were developed for their respective immune checkpoint inhibitor therapies.[2] Without correlation with treatment outcome, the study also assessed the putative diagnostic performance of these assays through comparisons of PD-L1 status classification above and below selected expression cutoffs associated with the clinical use of various assays. Serial sections from paraffin blocks of 39 resected non-small cell lung cancers (NSCLC) were stained using assays that were used in the clinical trials, and three experts in interpreting the four respective assays independently assessed the percentages of tumor and immune cells staining positive at any intensity. The results demonstrated that three PD-L1 assays (28-8, 22C3, SP263) showed comparable analytical performance for assessment of PD-L1 expression on tumor cells, while the SP-142 PD-L1 assay appeared to stain less tumor cells compared to the other assays.[2] In contrast, all assays stained tumor infiltrating immune cells, but with poor concordance between assays. The phase 1 study had several limitations: (1) samples were obtained from a commercial source and did not necessarily reflect the real-world samples tested clinically, and (2) the number of pathologists involved in the scoring was small. In addition, a fifth PD-L1 assay (73-10) has since been developed as a potential biomarker for avelumab (EMD Serono/Merck KGaA/Pfizer). The goals of Blueprint phase 2 are: (1) to validate the assay comparability results obtained in Blueprint phase 1 study using real world clinical lung cancer samples and all five clinically used PD-L1 assays (28-8, 22C3, SP142, SP263, and 73-10), (2) to assess the comparability and heterogeneity of PD-L1 assay results in surgical tumor resection, core needle and FNA samples prepared from same tumor, and (3) to assess the concordance of PD-L1 scoring by pathologists from around the world using standard light microscopy vs. digital images accessed by a web-based system. In blueprint phase 2A, 18 participating pathologists, with respective institutional research ethics board approval, contributed unstained serial sections from altogether 81 lung cancer cases that came through routine clinical practice. These included 40 adenocarcinomas, 25 squamous cell carcinomas, 5 poorly differentiated non-small cell carcinoma and 11 small cell carcinomas. The cases included resected tumor (n=20), core/bronchial biopsies (n=20), tumor positive lymph node biopsy/resection (n=20) and cytology cell block (n=21) samples. In blueprint phase 2B, 9 pathologists prepared from 30 freshly resected NSCLC specimens, paraffin blocks of matched resection, core needle and fine needle aspiration samples. Each slide set of 81 cases from phase 2A were stained with the FDA-cleared (28-8, 22C3, SP142) or clinical trial (SP263 and 73-10) PD-L1 assays, in a CLIA-approved immunohistochemistry laboratory. The slides were scored by 24 experienced pulmonary pathologists (IASLC Pathology committee Blueprint phase 2 members),[4] all having received group training on scoring the PD-L1 IHC on tumor and immune cells. PD-L1 stained tumor cells were scored as continuous number (0% to 100%), and placed into 1 of 7 categories (<1%, 1-4%, 5-9%, 10-24%, 25-49%, 50-79%, 80-100%). These categories represent cut-offs that have been used in various immune checkpoint inhibitor trials. All assays were also scored for immune cell PD-L1 staining based on the scoring system developed for the SP-142 assay. As only one set of glass slides is available for each assay, each pathologist was randomly assigned to conduct the scoring using microscope (2 glass assays) or by web-based digital images (3 digital assays). The inter-assay concordance of PD-L1 staining on tumor cells and tumor infiltrating immune cells will be assessed using the mean scores from all pathologists. The large sample size scores should provide more reliable data on their analytical comparability. Inter-pathologist concordance results should provide evidence on reliability of scoring with different cut-points. Importantly, the above concordance results across different sample types should also provide insights on potential variability and feasibility in PD-L1 scoring across different sample types, especially cytology samples. This may then allow for a broad implementation strategy on PD-L1 testing in clinical practice. The results of phase 2A will be presented at the meeting.IASLC Pathology Committee Blueprint phase 2 members: Mary-Beth Beasley, Alain Borczuk, Johan Botling, Lukas Bubendorf, Gang Chen, Lucian Chirieac, Teh-Ying Chou, Jin-Haeng Chung, Sanja Dacic, Fred R. Hirsch, Keith M. Kerr, Mari Mino-Kenudson, Sylvie Lantuejoul, Andre Moreira, Andrew Nicholson, Masayuki Noguchi, Guiseppe Pelosi, Claudia Poleri, Prudence Russell, Jennifer Sauter, Erik Thunnissen, William D. Travis, Ming S. Tsao, Ignacio Wistuba, Murry Wynes, Yasushi Yatabe, Hui Yu. References: IASLC ATLAS of PD-L1 Immunohistochemistry Testing in Lung Cancer. M.S.Tsao, K.M. Kerr, Y. Yatabe, S. Dacic, F.R. Hirsch (Editors), International Association for Study of Lung Cancer (IASLC) Press, 2017 Hirsch FR, McElhinny A, Stanforth D, et al. PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the "Blueprint PD-L1 IHC Assay Comparison Project". J Thorac Oncol. 2017 Feb;12(2):208-222. Feng Z, Schlichting M, Helwig C, et al. Comparative study of two PD-L1 expression assays in patients with non-small cell lung cancer (NSCLC). J Clin Oncol 35, 2017 (suppl; abstr e20581)

  • +

    P3.01 - Advanced NSCLC

    • Type: Poster Session with Presenters Present
    • Track: Advanced NSCLC
    • Moderators:
    • +

      P3.01-019 - Canadian Multicentre Validation Study of Plasma Circulating Tumour DNA for Epidermal Growth Factor (EGFR) T790M Testing

      09:30 - 16:00  |  Presenting Author(s): Ming Sound Tsao  |  Author(s): T. Zhang, P.K. Cheema, J. Laskin, A. Karsan, T. Barnes, G. Liu, S. Owen, J. Rothenstein, R. Burkes, M. Iqbal, A. Spatz, I. Izevbaye, L.V. Kempen, S. Kamel-Reid, Natasha B Leighl

      • Abstract

      Background:
      Plasma detection of EGFR T790M mutations in circulating tumour DNA (ctDNA) of advanced lung cancer patients with acquired resistance to EGFR tyrosine kinase inhibitor (TKI) has been proposed as alternative to tumor re-biopsy. This national validation study across Canadian centres aimed to establish the sensitivity and specificity of plasma detection of T790M as a clinical test using digital droplet (dd)PCR and next generation sequencing (NGS) assays.

      Method:
      Canadian patients at 7 centres undergoing screening for ASTRIS (NCT02474355) were invited to participate in this companion blood-based study. Patients with acquired resistance to EGFR TKI consented to collection of blood samples and demographic data. Samples were analysed using ddPCR and/or NGS platforms available at 4 molecular diagnostic laboratories across Canada. Concordance between the results of plasma T790M assayed in these 4 laboratories with reference tissue/plasma testing conducted for ASTRIS was assessed.

      Result:
      63 patients participated; the median age was 64 years (range 31-87), 69%(40/58) were Asian; 55%(33/60) were male. All patients received prior EGFR TKI, 17%(10/60) also received prior chemotherapy. Reference testing for EGFR T790M for ASTRIS eligibility identified positive T790M(+) results for 31(49%), negative(-) for 30(48%) and indeterminate(i) results for 2(3%) patients. One laboratory tested all 63 patient samples using both ddPCR and NGS (Oncomine Lung cfDNA assay), another laboratory tested 18 samples using ddPCR and NextSeq, a third tested 10 samples using ddPCR and COBAS EGFRv2, and a fourth tested 6 samples using Ion Torrent PGM. A total of 188 tests were performed including 91 by ddPCR, 87 NGS and 10 COBAS assays. Combining test results for each patient, 60%(38/63) of patient plasma samples were T790M+, 23(37%) were T790M-, and 2(3%) were inconclusive. Of 31 patients with reference T790M+ results from ASTRIS, 23(74%) had T790M detected in plasma, 6(19%) did not (T790M-), and 2(7%) had indeterminate (T790Mi) plasma results. For 30 patients with T790M- reference results from ASTRIS, 13(43%) had plasma T790M+ and 17 plasma T790M- results. The 2 patients with T790Mi by reference testing both had T790M+ results from plasma. Altogether, 47%(15/32) of patients deemed to have T790M-/i tumours by reference testing were found to have T790M+ results by plasma in this multicentre study. Combining results from both tissue and plasma testing, 73%(46/63) of study patients had T790M+ results.

      Conclusion:
      Plasma ctDNA testing in this multicentre Canadian study identified a significant number of additional patients eligible for osimertinib therapy beyond routine biopsy tissue testing for EGFR T790M.

    • +

      P3.01-062 - The Perceived Value of Avoiding Biopsy: Patients' Willingness to Pay for Circulating Tumour DNA T790M Testing

      09:30 - 16:00  |  Presenting Author(s): Tristan Alexandra Barnes  |  Author(s): J. Laskin, P.K. Cheema, G. Liu, M. Iqbal, J. Rothenstein, R. Burkes, S. Owen, D. Laurence, I. Carvalhana, L. Markin, L. Wong, N. Perera-Low, M. Sawczak, Ming Sound Tsao, Natasha B Leighl

      • Abstract

      Background:
      Plasma detection of circulating tumour DNA (ctDNA) with T790M mutation in the context of EGFR tyrosine kinase resistance has been shown to have high concordance with tissue biopsy specimens. In a public healthcare system, patients’ perceived value of a test and willingness to pay can inform policy decisions regarding implementation and funding of a novel technology.

      Method:
      As part of screening for the ASTRIS clinical trial (NCT02474355), Canadian patients were invited to participate in a national validation study of blood-based ctDNA T790M testing. Eligible patients had acquired resistance to EGFR TKI and consented to collection of blood samples, demographic data, and completion of a structured interview measuring their perceived value of blood-based ctDNA testing as an alternative to tumour biopsy. They were asked about their willingness to pay for testing using both open-ended and iterative bidding approaches. The study was supported by a grant from AstraZeneca.

      Result:
      60 patients were accrued to the study. Median age of the cohort is 64 years (range 31-87); 69% are Asian (40/58); 55% (33/60) are male. All patients had received prior EGFR kinase inhibitor treatment, with 67% (45/60) receiving gefitinib. 17% of patients also received chemotherapy (10/60). A median of 1 prior line of therapy had been received (range 1-6). All patients preferred to have the blood test over repeat tumour biopsy. Patients estimated a mean reasonable price to pay for the test of $954; median $300 (range 0-10,000; IQR 150-800). Patients were personally willing to pay a mean of $281; median $100 (range 0-2500; IQR 33-350).

      Conclusion:
      In a public health system that covers the cost of standard diagnostic tests, Canadian patients indicated a willingness to pay out of pocket for peripheral blood detection of ctT790M. Patients have high perceived value of ctDNA and prefer it to tumor biopsy.

  • +

    P3.02 - Biology/Pathology

    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Moderators:
    • +

      P3.02-097c - Detection of the EGFR P.(T790M) Mutation by Different Methods: A Small Comparison Case Study

      09:30 - 16:00  |  Presenting Author(s): Hangjun Wang  |  Author(s): A. Spatz, M.L. Aguirre, J. Agulnik, V. Cohen, D. Small, C. Pepe, L. Sakr, G. Kasymjanova, A.Y. Wang, S. Owen, Ming Sound Tsao, L.V. Kempen

      • Abstract

      Background:
      About 50-60% of non-small cell lung cancer (NSCLC) patients with a Tyrosine Kinase Inhibitor (TKI) sensitizing EGFR mutation can develop therapy resistance via the acquisition of the additional p.(T790M) mutation. The identification of this group of patients is important because they can be treated with a 3[rd] line TKI: Osimertinib. Analysis of plasma samples has become a minimally invasive alternative to repeat tissue biopsy for the detection of the EGFR p.(T790M) mutation. The mutation can be detected in plasma and tissue by various methods including the FDA approved Roche COBAS® EGFR v2 test, the EntroGen® EGFR test and digital droplet PCR (ddPCR). In this study, we compared the detection of the EGFR p.(T790M) mutation by ddPCR and COBAS in plasma specimens, and ddPCR and EntroGen in tissue specimens.

      Method:
      Blood from 14 NSCLC was collected in STRECK™ blood collection tubes. Plasma was prepared and circulating cell-free (ccf) DNA extracted with the COBAS and Qiagen method. DNA was analyzed for the presence of the EGFR TKI sensitizing and p.(T790M) mutation by COBAS, or the p.(T790M) mutation only by ddPCR on a Biorad QX200 platform. In addition, 26 biopsies from EGFR-positive patients who progressed on TKI, and which were tested p.(T790M) negative by Entrogen were re-analyzed by ddPCR.

      Result:
      Nine out of fourteen plasma samples were found to contain DNA with the sensitizing EGFR mutation by COBAS. The p.(T790M) mutation was found in four of these nine cases. ddPCR revealed one additional p.(T790M)-positive plasma sample that was tested negative by COBAS. ddPCR detected ten p.(T790M)-positive cases in the 26 EntroGen p.(T790M) negative samples, and suggests a 38% of false negative rate of the EntroGen method in this small cohort of samples.

      Conclusion:
      ddPCR for the detection of the EGFR p.(T790M) mutation in plasma and tissue appears to be associated with a higher sensitivity compared to the COBAS and EntroGen methods, respectively.

  • +

    P3.03 - Chemotherapy/Targeted Therapy

    • Type: Poster Session with Presenters Present
    • Track: Chemotherapy/Targeted Therapy
    • Moderators:
    • +

      P3.03-008 - Organoid Cultures of Lung Squamous Cell Carcinoma for Drug Screening

      09:30 - 16:00  |  Presenting Author(s): Ruoshi Shi  |  Author(s): N. Radulovich, M. Cabanero, M. Pintille, V. Raghavan, R. Quevedo, L. Tamblyn, C. Ng, V. Stambolic, T. Pugh, N. Moghal, Ming Sound Tsao

      • Abstract

      Background:
      The difficulty of establishing lung squamous cell carcinoma (LUSC) derived cell lines have posed significant challenges for identifying potential therapeutic targets and understanding the complexity of this disease. We have previously developed a LUSC patient-derived xenograft (PDX) platform in which over 50 models have been characterized on the genomic and transcriptomic level. We describe a method to culture and establish LUSC organoids from PDX models and demonstrate their utility for drug testing.

      Method:
      Surgically resected LUSC were implanted into the subcutaneous flank of NOD/SCID mice to establish PDXs. To generate organoids, PDX tissue was dissociated into single cells using Liberase and TypLE and plated in growth factor reduced matrigel dome with media overlay. Organoids were processed for histological and immunohistochemical marker characterization. Organoids and matched PDX were subjected to shallow next generation sequencing for mutation and copy number analysis. Drug screening was performed in 384 well plates and viability was determined by Celltiter Glo 3D assay.

      Result:
      Of the 17 LUSC PDX models attempted, organoid lines from 3 PDX models were propagated beyond 20 passages for over 100 days. The success rate of organoid establishment is 18%, which is higher than establishing LUSC cell lines. Organoids exhibited various doubling rates ranging from 38 to 48 hours. Organoid tumor cells faithfully recapitulated the immuno-phenotypes of the matched PDX, expressing p63 and CK5/6 and were EpCAM positive and H2K negative by flow cytometry analysis. Organoids implanted in NOD/SCID mice formed tumors that reflected the histology of the matched PDX. Shallow sequencing revealed similar copy number status between the organoid and matched PDX. RNA sequencing analysis is pending and will be reported. Organoids were amenable for drug testing and exhibited varying sensitivities to the PI3K inhibitors BKM120 and BYL719 based on each model’s PI3K pathway status.

      Conclusion:
      We describe a method of developing LUSC PDX-derived organoids that can be propagated long term and faithfully recapitulate the histological and molecular characteristics of the original tumor. Additionally, we demonstrate their utility for in vitro drug testing. Organoids may be useful for preclinical modeling and therapeutic evaluation of LUSC.

  • +

    PR 04 - Press Conference

    • 10:00 - 10:45
    • 10/18/2017
    • Location: Room 418
    • Type: Press Conference
    • Track:
  • +

    OA 12 - Emerging Genomic Targets

    • Type: Oral
    • Track: Advanced NSCLC
    • +

      OA 12.01 - The Preclinical and Clinical Activity of Poziotinib, a Potent, Selective Inhibitor of EGFR Exon 20 Mutant NSCLC

      11:00 - 12:30  |  Presenting Author(s): Y.Y. Elamin  |  Author(s): Jacqulyne Ponville Robichaux, Vincent K Lam, Anne Tsao, C. Lu, G. Blumenschein, J. Kurie, Julie R Brahmer, S. Li, T. Chen, A. Estrada-Bernal, A. Truini, M. Nilsson, A.T. Le, Z. Tan, S. Zhang, Robert C. Doebele, K. Politi, Z. Yang, S. Liu, Kwok-Kin Wong, John V Heymach

      • Abstract

      Background:
      Approximately 10% of EGFR mutant NSCLCs have an insertion/mutation in exon 20 of EGFR resulting in primary resistance to currently available tyrosine kinase inhibitors (TKIs). We previously reported that the structural features of poziotinib could potentially enable it to circumvent the steric hindrance induced by exon 20 mutations. Here we further characterize the preclinical activity of poziotinib and report on initial clinical activity of poziotinib in patients with EGFR exon 20 mutations from an ongoing phase II study.

      Method:
      We evaluated poziotinib activity in vitro using human NSCLC cell lines and the BAF3 model as well as several patient-derived xenograft (PDX) models and genetically engineered mouse models (GEMMs) of exon 20 insertion. We launched a phase 2 investigator-initiated trial of poziotinib in patients with metastatic NSCLC with EGFR exon 20 insertions (NCT03066206).

      Result:
      In vitro poziotinib was approximately 100x more potent than osimertinib and 40x more potent than afatinib against a common panel of EGFR exon 20 insertions. Furthermore, it had ~65-fold greater potency against common exon 20 insertions compared with EGFR T790M mutations; 3[rd] generation inhibitors osimertinib, EGF816, and rociletinib were all significantly less potent for exon 20 mutations/insertions compared with T790M. in vivo poziotinib led to >85% reduction in tumor burden in GEM models of EGFR exon 20 insertion (D770insNPG) NSCLC and the PDX model LU0387 (H773insNPH). To date, 8 platinum-refractory patients with EGFR exon 20 insertion mutation metastatic NSCLC have been enrolled in the clinical trial and treated with poziotinib at a dose of 16 mg PO daily. Two patients have reached the first interval-imaging time point (at 8 weeks of therapy per protocol). Both patients exhibited dramatic partial response, with one patient reporting improvement in dyspnea and cough at one week of therapy. In this early stage of the study, one case of grade 3 paronchycia was observed. One additional platinum- and erlotinib-refractory patient with EGFR exon 20 insertion was treated with poziotinib on compassionate basis. The patient achieved partial response after three weeks of treatment.

      Conclusion:
      Poziotinib has selective activity against EGFR exon 20 mutations and potent activity in cell lines, PDX, and GEM models. Three platinum-refractory patients with EGFR exon 20 mutations have been treated thus far and are evaluable for response; all three had partial responses at the time of the initial scan. Updated data from the ongoing phase 2 clinical trial of poziotinib will be presented at the meeting.

  • +

    MA 20 - Recent Advances in Pulmonology/Endoscopy

    • Type: Mini Oral
    • Track: Pulmonology/Endoscopy
    • +

      MA 20.11 - Chronic Obstructive Pulmonary Disease Prevalence in a Lung Cancer Screening Population

      14:30 - 16:15  |  Presenting Author(s): John R Goffin  |  Author(s): G. Pond, A. Tremblay, M. Johnston, Glenwood Goss, G. Nicholas, S. Martel, R. Bhatia, G. Liu, H. Roberts, M. Tammemägi, S. Atkar-Khattra, Ming Sound Tsao, Stephen Lam, S. Puksa

      • Abstract

      Background:
      Chronic obstructive pulmonary disease (COPD) and lung cancer are associated through tobacco use. COPD is underdiagnosed in both the primary care and lung cancer populations. Diagnosis of COPD should lead to improved care and quality of life. Screening programs could provide an opportunity to capture undiagnosed COPD. We analyzed the Pan-Canadian Early Detection of Lung Cancer Study (PanCan Study) to evaluate the prevalence of COPD in a screening population.

      Method:
      The PanCan Study was a single arm lung cancer screening trial which recruited individuals to low dose CT scan, autofluorescence bronchoscopy, and biomarker screening. Eligible individuals were 50-75 years of age, had smoked within 15 years, and had a minimum six-year risk of lung cancer ≥ 2% based on a risk prediction model derived from PLCO study data, which included COPD as a risk factor. Consenting subjects completed a questionnaire including background medical conditions, high-risk work exposures, and smoking history. Baseline spirometry was performed, and COPD was defined by GOLD criteria. For individuals not receiving post-bronchodilator spirometry, COPD was defined as ‘probable’ if GOLD criteria were met pre-bronchodilator and there was no prior diagnosis of asthma. Individuals with definite or probable COPD were defined as having COPD.

      Result:
      Of 2537 individuals recruited, 2514 had available spirometry data. Mean age was 62.3 years, 55.3% were male, median pack-years smoked was 50, 62.3% were active smokers, 45.1% had symptoms of dyspnea, 52.4% cough, and 37.5% wheeze. 35.2% had worked in a high-risk occupation. Overall, 1136 (45.2%) met spirometry criteria for COPD. Of 1987 individuals without a prior history of COPD, 41.9% met spirometry criteria for COPD, of which 53.7% had moderate to severe disease. Of 527 individuals (21%) reporting a diagnosis of COPD at baseline, 57.5% met spirometry criteria for COPD, 32.2% did not, and 10.3% had a prior diagnosis of asthma. In a multivariate model for risk of COPD, age (odds ratio (OR)~per year~ 1.06), dyspnea (OR 1.42), being a current smoker (OR 1.43), and pack-years (log transformed OR 1.42) were significant (all p < 0.001) as were high-risk occupation (OR 1.24, p=0.013) and wheeze (OR 1.24, p = 0.024).

      Conclusion:
      A diagnosis of COPD by spirometry is common in a lung cancer screening trial population. Individuals with a pre-existing self-reported diagnosis of COPD often fail to meet spirometry criteria for their diagnosis. Testing a lung cancer screening population for COPD could significantly improve COPD diagnosis and treatment.

  • +

    OA 15 - Diagnostic Radiology, Staging and Screening for Lung Cancer II

    • Type: Oral
    • Track: Radiology/Staging/Screening
  • +

    OA 17 - Immunotherapy II

    • Type: Oral
    • Track: Immunology and Immunotherapy
    • +

      OA 17.01 - Pemetrexed-Carboplatin Plus Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC: KEYNOTE-021 Cohort G Update

      14:30 - 16:15  |  Presenting Author(s): Hossein Borghaei  |  Author(s): Corey J Langer, Shirish M Gadgeel, Vassiliki A Papadimitrakopoulou, A. Patnaik, S.F. Powell, R.D. Gentzler, R.G. Martins, J.P. Stevenson, S.I. Jalal, A. Panwalkar, James Chih-Hsin Yang, Matthew A Gubens, Lecia V Sequist, M.M. Awad, J. Fiore, S. Saraf, H. Raftopoulos, L. Gandhi

      • Abstract

      Background:
      Cohort G of the multicenter, open-label, phase 1/2 KEYNOTE-021 study (ClinicalTrials.gov, NCT02039674) evaluated efficacy and safety of pembrolizumab + pemetrexed and carboplatin (PC) compared with PC alone as first-line therapy for patients with advanced nonsquamous NSCLC. At the primary analysis of cohort G (minimum follow up, 6 months; median, 10.6 months), pembrolizumab significantly improved ORR (estimated treatment difference, 26%; P=0.0016) and PFS (hazard ratio [HR], 0.53; P=0.010). The HR for OS was 0.90 (95% CI, 0.42‒1.91). In a subsequent analysis (median follow-up, 14.5 months), the HR for OS was 0.69 (95% CI, 0.36‒1.31). We present results from the May 31, 2017 data cutoff.

      Method:
      Patients with stage IIIB/IV nonsquamous NSCLC, no prior systemic therapy, and no EGFR mutation or ALK translocation were randomized 1:1 (stratified by PD-L1 TPS ≥1% versus <1%) to receive 4 cycles of carboplatin AUC 5 + pemetrexed 500 mg/m[2] Q3W with or without pembrolizumab 200 mg Q3W. Pembrolizumab treatment continued for up to 2 years; maintenance pemetrexed was permitted in both arms. Eligible patients in the PC arm with radiologic progression could cross over to pembrolizumab monotherapy. Response was assessed by blinded, independent central review per RECIST v1.1. All P values are nominal (one-sided P<0.025).

      Result:
      123 patients were randomized. Median follow-up was 18.7 months (range, 0.8‒29.0 months). 40 of 53 (75%) patients in the PC arm who discontinued received subsequent anti-PD-1/anti-PD-L1 therapy (including 25 who received pembrolizumab in the on-study cross over). ORR was 57% with pembrolizumab + PC versus 32% with PC (estimated difference, 25%; 95% CI, 7%‒41%; P=0.0029). PFS was significantly improved with pembrolizumab + PC versus PC (HR, 0.54; 95% CI, 0.33‒0.88; P=0.0067) with median (95% CI) PFS of 19.0 (8.5‒NR) months versus 8.9 (6.2‒11.8) months. The HR for OS was 0.59 (95% CI, 0.34‒1.05; P=0.0344). Median (95% CI) OS was not reached (22.8‒NR) months for pembrolizumab + PC and 20.9 (14.9‒NR) months for PC alone; 18-month OS rates were 70% and 56%, respectively. Grade 3–5 treatment-related AEs occurred in 41% of patients in the pembrolizumab + PC arm versus 29% in the PC arm.

      Conclusion:
      Over the course of the 3 analyses, the HR for OS continues to improve for pembrolizumab + PC versus PC (HR: 0.90 to 0.69 to 0.59). The significant improvements in PFS and ORR with pembrolizumab + PC versus PC first observed in the primary analysis have been maintained with longer follow-up (median, 18.7 months).

    • +

      OA 17.02 - Updated Efficacy Results From the BIRCH Study: First-Line Atezolizumab Therapy in PD-L1–Selected Patients With Advanced NSCLC

      14:30 - 16:15  |  Presenting Author(s): Enric Carcereny  |  Author(s): Enriqueta Felip, Martin Reck, J. Patel, R. Heist, A. Balmanoukian, Laura Q Chow, Luis Paz-Ares, J. Qiu, S. Coleman, S. Mocci, A. Sandler, T. Kurata, Frances A Shepherd

      • Abstract

      Background:
      The anti–PD-L1 mAb atezolizumab blocks the interactions between PD-L1 and its receptors, PD-1 and B7.1, thus restoring anti-tumor immunity. A Phase II study of atezolizumab monotherapy was conducted across multiple lines of therapy in PD-L1–selected patients with advanced NSCLC (BIRCH; NCT02031458). The primary analyses showed meaningful and durable clinical benefit with atezolizumab monotherapy in 1L and 2L+ NSCLC. Here we present updated survival data (median follow-up, 29.7 months) in patients receiving 1L atezolizumab.

      Method:
      Eligible patients had chemotherapy-naive, locally advanced or metastatic NSCLC without CNS metastases. Prior TKI therapy was required in patients with EGFR mutation or ALK rearrangement. PD-L1 expression on tumor cells (TC) and tumor-infiltrating immune cells (IC) was centrally evaluated (VENTANA SP142 IHC assay). Patients who were TC2/3 or IC2/3 (PD-L1 expression on ≥ 5% of TC or IC) were enrolled. Atezolizumab 1200 mg was administered IV q3w until disease progression or unacceptable toxicity. The primary endpoint was independent review facility (IRF)–assessed ORR. Secondary endpoints included investigator (INV)-assessed ORR, DOR, PFS (RECIST v1.1) and OS.

      Result:
      With a median follow-up of 29.7 months, median OS was 26.9 months (TC3 or IC3 subgroup) and 24.0 months (all treated patients); INV-assessed ORR was 35% (TC3 or IC3 subgroup) and 26% (all treated patients; Table). Among evaluable patients, the ORR was 31% for mutant EGFR (4/13) vs 23% for wild-type EGFR patients (24/103), and 31% for mutant KRAS (10/32) vs 24% for wild-type KRAS patients (16/66). No new safety signals were observed.

      Conclusion:
      With more than 2 years of follow-up, atezolizumab continued to demonstrate durable clinical activity in 1L NSCLC, regardless of EGFR and KRAS mutational status. These data suggest that atezolizumab monotherapy has promising activity as a frontline therapy. Ongoing Phase III trials are evaluating atezolizumab-based regimens vs chemotherapy in 1L NSCLC.

      Endpoint (95% CI) TC3 or IC3[a ](n = 65) TC2 or IC2[b] (n = 73) All Treated Patients (N = 138)
      INV-assessed ORR, % 35% (23.9, 48.2) 18% (9.8, 28.5) 26% (19.0, 34.2)
      EGFR mutant/wild-type, % 25%/33% 33%/15% 31%/23%
      KRAS mutant/wild-type, % 38%/33% 25%/15% 31%/24%
      mDOR, mo 16.5 (8.5, NE) 12.5 (8.3, 17.9) 13.1 (9.9, NE)
      mOS, mo 26.9 (12.0. NE) 23.5 (18.1, NE) 24.0 (18.1, 31.9)
      12-mo OS rate, % 61% (49.0, 74.0) 71% (59.8, 81.5) 66% (58.1, 74.6)
      24-mo OS rate, % 52% (39.3, 65.2) 49% (37.0, 61.1) 50% (41.5, 59.2)
      30-mo OS rate, % 48% (35.3, 61.5) 39% (27.2, 51.2) 43% (34.3, 52.1)
      mPFS, mo 7.3 (4.9, 12.0) 7.6 (4.0, 9.7) 7.6 (5.7, 9.7)
      12-mo PFS rate, % 38% (25.1, 49.9) 30% (19.2, 41.2) 34% (25.3, 41.9)
      24-mo PFS rate, % 28% (16.5, 40.0) 13% (4.5, 21.5) 20% (12.9, 27.5)
      30-mo PFS rate, % 19% (5.4, 33.5) 9% (1.4, 16.4) 14% (6.5, 21.9)
      NE, not estimable. [a ]TC ≥ 50% or IC ≥ 10% PD-L1–expressing cells.[b ]TC2/3 or IC2/3 excluding TC3 or IC3.


    • +

      OA 17.03 - First-Line Nivolumab plus Platinum-Based Doublet Chemotherapy for Advanced NSCLC: CheckMate 012 3-Year Update

      14:30 - 16:15  |  Presenting Author(s): Rosalyn J. Juergens  |  Author(s): M.D. Hellmann, Julie R Brahmer, Hossein Borghaei, Scott N. Gettinger, Laura Q Chow, David E Gerber, S.A. Laurie, J. Goldman, Frances A Shepherd, W.J. Geese, T.C. Young, X. Li, S. Antonia

      • Abstract

      Background:
      Platinum-based doublet chemotherapy is the standard-of-care first-line treatment for most patients with advanced NSCLC, but responses are not durable (~4.5–6 mo). Chemotherapy may sensitize NSCLC tumors to immune checkpoint inhibitors. Nivolumab, a fully human programmed death (PD)-1 antibody, demonstrated long-term survival benefit in patients with previously treated advanced NSCLC. Here we report the 3-year update of safety and efficacy of first-line nivolumab combined with chemotherapy in the phase 1 CheckMate 012 study (NCT01454102).

      Method:
      Chemotherapy-naïve patients with stage IIIB/IV NSCLC were randomly assigned based on histology in 3 cohorts combining nivolumab Q3W with 3 platinum-based doublet chemotherapy regimens: nivolumab 10 mg/kg + gemcitabine-cisplatin (all squamous histology), nivolumab 10 mg/kg + pemetrexed-cisplatin (all non-squamous), and nivolumab 10 mg/kg or 5 mg/kg + paclitaxel-carboplatin (any histology). After 4 cycles of nivolumab plus chemotherapy, patients received nivolumab monotherapy until progression or unacceptable toxicity. The primary objective was safety. ORR, PFS, and OS were secondary/exploratory endpoints.

      Result:
      56 patients were treated. Median age was 63.5 years, 46% were male, and 14% were never-smokers; 29% of tumors had squamous histology. At database lock (September 19, 2016) the minimum follow-up was 45.5 mo. Median duration of chemotherapy treatment was ~12 weeks (4 cycles; range: 3–18 weeks) and median duration of nivolumab treatment was 17–22 weeks across cohorts (range: 3–204). No new safety signals were observed in patients receiving nivolumab maintenance compared with the September 2014 database lock. ORR was 46%. Median duration of response was 10.4 mo (95% CI: 5.1, 26.3). Median PFS was 6.0 mo (95% CI: 4.8, 8.3). Median OS was 19.2 mo (95% CI: 14.1, 23.8), and the 3-year OS rate was 25%. ORR and OS were similar in patients with tumor PD-L1 expression <1% (n=23) vs ≥1% (n=23): ORR 48% vs 52%; median OS 19.2 mo (95% CI: 12.2, 23.8) vs 20.2 mo (95% CI: 10.9, 27.2). The 3-year OS rate was 22% in both PD-L1 expression subgroups.

      Conclusion:
      Nivolumab plus chemotherapy resulted in prolonged survival in a subset of patients, with a 3-year OS rate of 25%. In all patients, ORR and OS were similar irrespective of tumor PD-L1 expression. These results support further evaluation of nivolumab-chemotherapy combinations as first-line treatment for advanced NSCLC, which are being explored in CheckMate 227 (NCT02477826).

    • +

      OA 17.04 - Discussant - OA 17.01, OA 17.02, OA 17.03

      14:30 - 16:15  |  Presenting Author(s): Martin Schuler

      • Abstract

      Abstract not provided

    • +

      OA 17.05 - IFCT-1502 CLINIVO: Real-Life Experience with Nivolumab in 600 Patients (Pts) with Advanced Non-Small Cell Lung Cancer (NSCLC)

      14:30 - 16:15  |  Presenting Author(s): Nicolas Girard  |  Author(s): O. Molinier, C. Audigier-Valette, J. Cadranel, I. Monnet, J. Hureaux, W. Hilgers, E. Fauchon, E. Fabre, Benjamin Besse, P. Brun, D. Coëtmeur, E. Quoix, P. Mourlanette, Fabrice Barlesi, S. Bordenave-Caffre, T. Egenod, P. Missy, F. Morin, D. Moro-Sibilot

      • Abstract

      Background:
      Nivolumab is a standard option for second‐line treatment in pts with advanced NSCLC. Real‐life data are lacking regarding the efficacy of nivolumab and post‐nivolumab treatment.

      Method:
      This analysis included the first 600 consecutive pts with stage IIIB/IV NSCLC who received ≥1 dose of nivolumab 3mg/kg q2w through the French EAP from 01/2015 for Squamous ﴾Sq﴿ and 06/2015 for Non‐Sq NSCLC, until 08/2015.

      Result:
      Median age was 64 yo, there were 409 ﴾68%﴿ men, 521 ﴾87%﴿ smokers, 478 ﴾80%﴿ PS0/1 pts, 230 ﴾38%﴿ Sq and 370 ﴾62%﴿ Non‐Sq NSCLC, 130 ﴾22%﴿ pts with brain metastases. Nivolumab was administered as 2nd/3rd/≥4th‐line for 26%/33%/41% pts, respectively. Best response was PR/SD/PD for 17%/30%/37% of patients, respectively, with 16% not assessable. Toxicities occurred in 187 ﴾31%﴿ pts, including 10% grade ≥3 events. After a median follow‐up of 22.1 ﴾95% CI 21.6‐22.6﴿ months, median PFS and OS from the initiation of nivolumab were 2.1 ﴾95%CI 1.9‐2.3﴿ and 9.5 ﴾95%CI 8.4‐10.8﴿ months, respectively. In the 92 pts with PS2 at initiation of nivolumab, PR/SD rates were 7%/28%; median OS was 3.6 (95%CI 2.7-5.2) months. A total of 130 pts had brain metastases at initiation of nivolumab: PR/SD rates were 12%/25%; median OS was 6.6 (95%CI 3.8-8.3) months. Post‐nivolumab treatment was administered to 262 ﴾44%﴿ pts, and mostly consisted of gemcitabine ﴾19%﴿, docetaxel ﴾18%﴿, paclitaxel ﴾14%﴿, erlotinib ﴾12%﴿, vinorelbine ﴾9%﴿, platin‐based doublet ﴾8%﴿, or pemetrexed ﴾8%﴿. Access to post‐nivolumab treatment was higher in PS0/1 vs. PS2 pts ﴾48% vs. 23%, p<0.001﴿, but was not different according to histology or treatment line or disease control with nivolumab. Best response to post‐nivolumab treatment was PR/SD/PD for 15%/42%/42% of pts, respectively. In the whole cohort, median post‐nivolumab OS was 4.0 ﴾95%CI 2.8‐4.6﴿ months, and was significantly higher in case of PR to nivolumab ﴾HR=0.38; 95%CI 0.23‐0.64; p<0.001﴿, and if subsequent treatment was delivered ﴾HR=0.30; 95%CI 0.24‐0.38; p<0.001﴿; median post‐nivolumab OS in pts receiving post‐nivolumab treatment was 7.5 ﴾95%CI 6.8‐8.7﴿ months, and did not differ based on histology or treatment line.

      Conclusion:
      Efficacy and safety of nivolumab was in line with available data. Post‐nivolumab treatment may be delivered in many pts, including pts with PS2 and brain metastases, with favorable impact on response and OS. Data on the whole cohort of 900 pts enrolled in the EAP will be presented.

    • +

      OA 17.06 - Updated Analysis of KEYNOTE-024: Pembrolizumab vs Platinum-Based Chemotherapy for Advanced NSCLC With PD-L1 TPS ≥50%

      14:30 - 16:15  |  Presenting Author(s): Julie R Brahmer  |  Author(s): D. Rodríguez-Abreu, A.G. Robinson, R. Hui, T. Csőszi, A. Fülöp, Maya Gottfried, Nir Peled, A. Tafreshi, S. Cuffe, M. O'Brien, S. Rao, K. Hotta, A. Riccio, J. Yang, M..C. Pietanza, Martin Reck

      • Abstract

      Background:
      KEYNOTE-024 (ClinicalTrials.gov, NCT02142738) is a multicenter, international, phase 3, randomized, open-label, controlled trial of treatment with the anti‒PD-1 antibody pembrolizumab vs platinum-based chemotherapy as first-line therapy for patients with advanced NSCLC of any histology with PD-L1 tumor proportion score (TPS) ≥50% and without EGFR mutations or ALK translocations. Results from the primary analysis of KEYNOTE-024 demonstrated that after a median follow-up of 11.2 months, pembrolizumab significantly improved PFS (HR=0.50; P<0.001) and OS (HR=0.60; P=0.005) and was associated with a lower rate of treatment-related AEs compared with chemotherapy.

      Method:
      Patients were randomly assigned to receive either 35 cycles of pembrolizumab 200 mg every 3 weeks or 4–6 cycles of investigator's choice of carboplatin/cisplatin + gemcitabine, carboplatin + paclitaxel, or carboplatin/cisplatin + pemetrexed with optional pemetrexed maintenance (for those with non-squamous histology). Randomization was stratified by ECOG performance status (0 vs 1), histology (squamous vs nonsquamous), and geographic region (East Asia vs non–East Asia). Treatment continued until disease progression per RECIST version 1.1, intolerable toxicity, or withdrawal of consent. Patients in the chemotherapy arm who experienced disease progression could cross over to receive pembrolizumab monotherapy. Response was assessed every 9 weeks by blinded independent central review per RECIST version 1.1. The primary endpoint was PFS; secondary endpoints were OS, ORR, and safety.

      Result:
      305 patients were enrolled (pembrolizumab, n=154; chemotherapy, n=151). At the time of data cutoff (July 10, 2017) after a median follow-up of 25.2 months, 73 patients (47.4%) in the pembrolizumab arm and 96 patients (63.6%) in the chemotherapy arm had died. The hazard ratio for OS was 0.63 (95% CI, 0.47–0.86; nominal P=0.002). Median (95% CI) OS was 30.0 (18.3–not reached) months in the pembrolizumab arm and 14.2 (9.8–19.0) months in the chemotherapy arm. The Kaplan-Meier estimate of OS at 12 months was 70.3% (95% CI, 62.3%–76.9%) for the pembrolizumab group and 54.8% (95% CI, 46.4%–62.4%) for the chemotherapy group. 82 patients allocated to the chemotherapy arm crossed over to receive pembrolizumab upon meeting eligibility criteria. Treatment-related adverse events were less frequent in the pembrolizumab arm than in the chemotherapy arm (76.6% versus 90.0%, respectively) as were treatment-related grade 3-5 adverse events (31.2% versus 53.3%).

      Conclusion:
      With more than half of patients having OS events and prolonged follow‒up, first-line pembrolizumab monotherapy remains superior to platinum-based chemotherapy despite the crossover from the control arm to an anti-PD1 inhibitor as subsequent therapy.

    • +

      OA 17.07 - Long-Term Survival in Atezolizumab-Treated Patients with 2L+ NSCLC from Ph III Randomized OAK Study

      14:30 - 16:15  |  Presenting Author(s): Miyako Satouchi  |  Author(s): L. Fehrenbacher, Manuel Cobo Dols, Ji-Youn Han, J. Von Pawel, R. Bordoni, T. Hida, Keunchil Park, D. Moro-Sibilot, P. Conkling, C. Matheny, W. Yu, P. He, Marcin Kowanetz, M. Gandhi, M. Ballinger, A. Sandler, David R. Gandara

      • Abstract

      Background:
      Atezolizumab (anti–PD-L1) inhibits PD-L1 binding to PD-1 and B7.1, restoring anti-cancer immunity. OAK, a Phase III study of atezolizumab vs docetaxel demonstrated superior OS of atezolizumab. The characteristics of the long-term survivors (LTS) in the OAK primary population (n = 850) are evaluated and describe the largest cohort of cancer immunotherapy-treated NSCLC LTS yet reported.

      Method:
      Patients received IV q3w atezolizumab (1200 mg) until PD / loss of clinical benefit or docetaxel (75 mg/m[2]) until PD / unacceptable toxicity. No crossover was allowed. LTS were defined as patients with OS ≥ 24 months and non-LTS as those who died within 24 months of randomization. Patients with OS censored prior to 24 months were not included. Data cutoff, January 23, 2017.

      Result:
      A higher 2-year survival rate was observed for the atezolizumab-arm (31%) vs docetaxel-arm (21%). After a minimum follow-up of 26 months, there were 119 LTS vs 279 non-LTS in the atezolizumab-arm and 77 LTS vs 299 non-LTS in the docetaxel-arm. Characteristics of atezolizumab-arm LTS and non-LTS are shown (Table). Atezolizumab-arm LTS were enriched for non-squamous histology and high PD-L1–expressing tumors, but also included low/no PD-L1–expressing tumors (40.3%). Atezolizumab-arm LTS had higher ORR (39.5%) than non-LTS (5.0%) but included LTS subjects with PD. 52.9% atezolizumab-arm vs 71.4% docetaxel-arm LTS received anti-cancer non-protocol therapy (NPT) after discontinuation of protocol-defined therapy. 51.9% of docetaxel-arm LTS vs 12.7% non-LTS received non-protocol immunotherapy. Median treatment exposure in atezolizumab-arm LTS was 18.0 months. Atezolizumab-arm LTS had a comparable safety profile to all atezolizumab-treated population.

      Conclusion:
      Atezolizumab provides superior 2-year OS benefit vs docetaxel and is well tolerated. The majority of docetaxel-arm LTS received a checkpoint inhibitor as NPT. Atezolizumab LTS appeared to have favorable prognostic factors, including non-squamous histology, but notably were not limited to patients with RECIST v1.1 response or with PD-L1 expression.

      Table. Characteristics of Atezolizumab-Arm Long-Term Survivors (LTS) vs Non-Long Term Survivors (Non-LTS)
      Atezolizumab LTS (n = 119) n (%) Atezolizumab Non-LTS (n = 279) n (%)
      Sex
      Male 61 (51.3) 183 (65.6)
      Female 58 (48.7) 96 (34.4)
      Tobacco use history
      Never smoker 29 (24.4) 47 (16.8)
      Current/previous smoker 90 (75.6) 232 (83.2)
      Histology
      Non-squamous 101 (84.9) 195 (69.9)
      Squamous 18 (15.1) 84 (30.1)
      No. of prior therapies, 1 89 (74.8) 209 (74.9)
      ECOG performance status at baseline
      0 60 (50.4) 89 (31.9)
      1 59 (49.6) 190 (68.1)
      EGFR mutation status, positive 11 (9.2) 26 (9.3)
      PD-L1 IHC subgroup
      TC3 or IC3 28 (23.5) 39 (14.0)
      TC1/2/3 or IC1/2/3 71 (59.7) 156 (55.9)
      TC0 and IC0 48 (40.3) 119 (42.7)
      Best overall response
      Complete response 5 (4.2) 0 (0)
      Partial response 42 (35.3) 14 (5.0)
      Stable disease 47 (39.5) 97 (34.8)
      Progressive disease 25 (21.0) 142 (50.9)
      IC, tumor-infiltrating immune cell; TC, tumor cell. TC3 or IC3 = PD-L1 ≥ 50% TC or 10% IC; TC1/2/3 or IC1/2/3 = PD-L1 ≥ 1% on TC or IC; TC0 and IC0 = PD-L1 < 1% on TC and IC. NCT02008227.


    • +

      OA 17.08 - Phase II Study of Pembrolizumab for Oligometastatic Non-Small Cell Lung Cancer (NSCLC) Following Completion of Locally Ablative Therapy (LAT)

      14:30 - 16:15  |  Presenting Author(s): Joshua Michael Bauml  |  Author(s): R. Mick, C. Ciunci, C. Aggarwal, T. Evans, L. Miller, N. Muhammad, E. Alley, C. Knepley, F. Mutale, R.B. Cohen, Corey J Langer

      • Abstract

      Background:
      Patients (pts) with oligometastatic NSCLC may benefit from LAT (e.g., surgery, stereotactic radiation (SRT)). It is unclear if systemic therapy can provide additional benefit after LAT. We are running a Phase II study to evaluate the efficacy of pembrolizumab after LAT, hypothesizing that immunotherapy will be effective in the setting of a minimal disease burden.

      Method:
      Eligibility stipulates oligometastatic NSCLC (up to 4 sites) with completion of LAT to all known sites of disease. Within 4-12 weeks of completing LAT, pts begin pembrolizumab 200 mg every 21 days for 6 mos, with a provision to continue for a full year in the absence of progression or toxicity. Progression free survival (PFS) and overall survival (OS) are measured from the start of LAT. A sample size of 42 pts provides 80% power for a test at 5% 1-sided type I error to increase PFS to >=10 mos compared to a historical control PFS of 6.6 mo.

      Result:
      Since January 2015, 39 pts have been enrolled. The median age is 64 years; 54% are male; 90% Caucasian. Current and former smokers comprise 90% of the cohort, with a median of 32 pack yrs. Most common metastatic sites are lung (15 pts), brain (13), and bone (8). LAT has included surgery (24 pts), SRT (23), and concurrent chemoradiotherapy (17). Attributable adverse events (AEs) have been mostly mild and self-limited. There has been one episode of Grade 3 pneumonitis and one episode of Grade 3 adrenal insufficiency. Median follow-up from start of LAT is 16 mos. To date, 11 pts have had progression or death. The median PFS has not yet been reached. The PFS rates (+ SE) at 6, 12 and 18 mos are 92%+5%, 64%+9% and 64%+9%, with 16 and 5 pts at risk beyond 12 and 24 mos, respectively. To date, 8 pts (21%) have died. The median OS has not yet been reached. The OS rates (+ SE) at 6, 12 and 18 mos are 100%, 90%+6% and 75%+9%, with 22 and 5 pts at risk beyond 12 and 24 mos, respectively.

      Conclusion:
      Use of pembrolizumab after LAT for oligometastatic NSCLC is feasible and well tolerated. In a preliminary analysis, PFS appears favorable. Continued follow-up is necessary to confirm these findings. It is expected that accrual will be complete as of September 2017. Updated survival estimates will be presented.

    • +

      OA 17.09 - Discussant - OA 17.05, OA 17.06, OA 17.07, OA 17.08

      14:30 - 16:15  |  Presenting Author(s): Penelope Bradbury

      • Abstract

      Abstract not provided