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M. Reck

Moderator of

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    ISS09 - Industry Supported Symposium: Targeted Therapy on the Horizon for SCLC - AbbVie (ID 442)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 5
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      ISS09.01 - Challenges in SCLC Across Decades (ID 7019)

      07:30 - 08:30  |  Author(s): M. Reck

      • Abstract

      Abstract not provided

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      ISS09.02 - Advancing the Study in SCLC – What is the Underlying Biology? (ID 7020)

      07:30 - 08:30  |  Author(s): J. Soria

      • Abstract

      Abstract not provided

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      ISS09.03 - Emerging Novel Agents – A New Day for SCLC Treatment (ID 7021)

      07:30 - 08:30  |  Author(s): R. Govindan

      • Abstract

      Abstract not provided

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      ISS09.04 - Panel Discussion: Looking Over the Horizon – Future Treatment of SCLC (ID 7022)

      07:30 - 08:30  |  Author(s): M. Reck, J. Soria, R. Govindan

      • Abstract

      Abstract not provided

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      ISS09.05 - Question & Answer (ID 7023)

      07:30 - 08:30  |  Author(s): M. Reck, J. Soria, R. Govindan

      • Abstract

      Abstract not provided

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    MA14 - Immunotherapy in Advanced NSCLC: Biomarkers and Costs (ID 394)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 12
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      MA14.01 - Updated Dataset Assessing Tumor Mutation Burden (TMB) as a Biomarker for Response to PD-1/PD-L1 Targeted Therapies in Lung Cancer (LC) (ID 4011)

      16:00 - 17:30  |  Author(s): A.B. Schrock, N. Sharma, N. Peled, J.A. Bufill, G. Srkalovic, D.R. Spigel, D. Fabrizio, G.M. Frampton, C. Connelly, M.B. Lipka, A. Belilovski, J. Lo, Y. Li, J. Sun, K. Gowen, G. Kalemkerian, L.E. Raez, S. Ou, J.S. Ross, P.J. Stephens, S. Ali, V.A. Miller

      • Abstract
      • Presentation
      • Slides

      Background:
      Immune checkpoint inhibitors (ICPIs) nivolumab and pembrolizumab have been FDA-approved in non-small cell LC (NSCLC). Current IHC based diagnostics are challenged by assay and slide scoring issues and modest predictive value, and more robust and comprehensive biomarkers of ICPI efficacy are needed. A discovery set of 64 NSCLCs treated with ICPIs suggested that high TMB (≥15 mutations/Mb) significantly correlated with longer time on drug (Spigel et al., ASCO 2016, Abstract:9017).

      Methods:
      Comprehensive genomic profiling (CGP) was performed during the course of clinical care. TMB was assessed as the number of somatic, coding, base substitution and indels per Mb of genome. Microsatellite instability-high (MSI-H) or stable (MSS) status was determined using a proprietary algorithm.

      Results:
      15,529 LCs: 66% adenocarcinoma, 1% sarcomatoid, 14% NSCLC NOS, 11% squamous, 5% small cell, and 2% large cell were assessed. TMB was similar across all lung histologies (median: 6.3, 8.1, 9.0, 9.9, 9.9, and 10.8); the median was 7.6 for all LC cases (TMB ≥15 in 24% of cases), compared to 4.5 for 80,000+ samples of diverse tumor types in the database. Of LCs assessed 0.3% were MSI-H, of which 30/31 were TMB-high; however, 24% of MSS-stable cases were also TMB-high. PD-L1 amplification and DNA repair pathway mutation (MLH1, MSH2, POLE) were found in 1.0% and 1.1% of LC cases analyzed, respectively. Tumors harboring known drivers (ALK, ROS1, EGFR, BRAF V600E, MET splice) had low TMB (median: 2.5, 3.6, 3.8, 3.8, 4.5), whereas tumors with KRAS mutation, non-V600E BRAF mutation, PD-L1 amplification, or DNA repair alterations were more likely to be TMB-high (median: 9.0, 10.8, 14.4, 21.6).

      Conclusion:
      High TMB may be a predictive biomarker of response to ICPIs. Several factors including lack of a known driver, MSI-H status, PD-L1 amplification, and DNA repair mutation correlated with high TMB (P<0.0001 for all cases). However, 95% of TMB-high cases assessed were MSS and lacked both PD-L1 amplification and DNA repair mutation, and thus would likely not be selected for immunotherapy by assessment of individual genomic alterations or MSI status alone. A validation cohort of NSCLC patients treated with anti-PD-1/PD-L1 therapies including analysis of clinical outcome, TMB, genomic profile, and available clinicopathologic characteristics will be presented. CGP of LC to simultaneously determine TMB, MSI status, PD-L1 amplification, and the presence of driver alterations may provide clinically useful predictors of response to ICPI and other targeted therapies using a single platform, but prospective clinical trials are needed to confirm these observations.

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      MA14.02 - Evaluation of PD1/PDL1 Expression on Peripheral Blood Cells Subpopulations in Patients with Non-Small Cell Lung Cancer (ID 5192)

      16:00 - 17:30  |  Author(s): O. Arrieta, E. Montes-Servín

      • Abstract
      • Presentation
      • Slides

      Background:
      Currently the immune system is considered an important target of study within the therapeutic alternatives for many tumors that have developed resistance in lung cancer. Many molecules called checkpoints regulate antitumor immunity as PD-L1 it is expressed in tumour cells and is a biomarker for anti PD-L1/PD-1 therapy. PD-1 / PD-L1 is expressed on exhausted activated T cells. This signaling pathway is involved in tumor evasion of the immune system. It has recently been demonstrated that the blockade of PD-1 or its ligand PD-L1 and PD-L2, restore the antitumor immune response leading to a durable tumor regression. However, the expression of PD-1/PD-L1 in T cells from peripheral blood of patients with non-small cell lung cancer has not been widely studied.

      Methods:
      We investigated the expression of PD-1 and its ligands PD-L1 and PD-L2 on peripheral blood T cells subpopulations (CD3+ CD4+ / CD8+) of patients with non-small cell lung cancer. We included 50 NSCLC patients (stage IIIB and IV) naive to treatment and 10 healthy subjects. Immunophenotyping was performed using multiparametric flow cytometry. Analyzing its prognostic significance regarding outcome analysis as well as its potential biomarker.

      Results:
      Our results showed that the percentage of PD-1, PD-L1 and PD-L2 expression in peripheral blood cells in NSCLC patients was lower compared to healthy subjects [P<0.005] and the Mean Fluorescence Intensity (MFI) was higher in patients compared to the control group [P<0.001]; The expression of PD-1 in T-helper or CD4+ of NSCLC patients was significantly higher than in cells from control subjects [P<0.001]. Similarly, the expression of PD-1 in T cytotoxic cells or CD8+ patients was significantly higher than in controls [P<0.001]. In the clinical analysis, we found that a higher percentage of PD-1+ CD3+ cells was statistically associated with tobacco exposure [P=0.0160], and de MFI was associated with the non-adenocarcinoma histology [P=0.0001] additionally, the presence of 3 or more metastases was associated to a higher MFI of PD-1 on CD3+ CD8+ [P=0.0490]. In the overall survival (OS) analysis the percentage of CD3+/CD4+/PD-1+ ≤20.91 was associated with a higher median OS [P= 0.045].

      Conclusion:
      Several studies demonstrate the importance of infiltrating PD-1+ T cells within tumors; however these results showed that the PD-1/PD-L1/PDL-2 expression in peripheral blood cells could be used also as a potential biomarkers in NSCLC patients.

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      MA14.03 - The Impact of Genomic Landscape of EGFR Mutant NSCLC on Response to Targeted and Immune Therapy (ID 6242)

      16:00 - 17:30  |  Author(s): Y.Y. Elamin, W. Rinsurongkawong, H.T. Tran, K.A. Gold, J. Lewis, E. Roarty, A. Futreal, J. Zhang, J. Heymach

      • Abstract
      • Presentation
      • Slides

      Background:
      EGFR mutations define a distinct subset of NSCLC characterized by clinical benefit from tyrosine kinase inhibitors. The impact of genomic alterations that coexist with EGFR mutations is not fully understood. In addition, the responsiveness of EGFR mutant NSCLC to immune checkpoint blockade is not well defined.

      Methods:
      We queried our prospectively collected MD Anderson Lung Cancer Moon Shot GEMINI Database to identify EGFR mutant NSCLC patients. We analyzed the genomic landscape of these tumors derived from next generation sequencing, performed as part of routine clinical care, to comprehensively describe the concurrent genomic aberrations in EGFR mutant NSCLC and their impact on clinical outcomes. We used log rank and Fisher’s exact tests to identify associations between co-concurrent mutations and clinical outcomes.

      Results:
      1958 non-squamous NSCLC patients were identified in the GEMINI database. The frequency of EGFR mutations was 14.1% (n=276). Among EGFR mutant patients, 188 underwent targeted next generation sequencing of a minimum of 46 cancer related genes. The majority of EGFR mutant patients (77.6%, n=146) had at least one coexisting mutation. The most frequent co-mutations identified were TP53 (47%, n=88), CTNNB1 (7.5%, n= 14) and PIK3CA (6.5%, n=12). ALK and ROS1 translocations were found to coexist with EGFR mutations in one patient each. Of patients treated with a first or second generation TKI, concurrent TP53 mutations were associated with a shorter progression free survival (HR= 1.81, P= 0.039). Eight patients with EGFR/CTNNB1 co-mutations developed acquired TKI resistance with T790M secondary mutation being the resistance mechanism in six (75%) of them suggesting that coexisting mutation can dictate emerging resistance mechanisms. Twenty patients were treated with anti PD1/PD-L1 agents (nivolumab n= 18, pembrolizumab n=2). Only two (10%) patients achieved confirmed radiological response, one lasting for 6 months and the second ongoing at 6 months. Both patients were never smokers, one with EGFR exon 20 insertion and no concurrent mutations, and the other with EGFR exon 19 deletion and TP53 mutation. Sixteen patients developed confirmed progressive disease. Finally, one patient with 17 pack-year smoking history, EGFR G719/S768I double mutation and concurrent PIK3CA mutation achieved stable disease lasting for four months. The median progression free survival for the cohort treated with immunotherapy was 2 months (range: 1-not reached).

      Conclusion:
      Concurrent genomic aberrations may predict response duration to TKIs and may be associated with particular emerging resistance mechanisms to TKIs in EGFR mutant NSCLC. Immunotherapy results in durable clinical benefit in a subset of EGFR mutant NSCLC patients.

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      MA14.04 - Discussant for MA14.01, MA14.02, MA14.03 (ID 7087)

      16:00 - 17:30  |  Author(s): M. Moniuszko

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.05 - Implications of Implementation of a PD-L1 Biomarker-Based Strategy for Treatment of Advanced NSCLC (ID 5042)

      16:00 - 17:30  |  Author(s): M. Huang, J. Pellissier, T. Burke, R. Xu

      • Abstract
      • Presentation
      • Slides

      Background:
      The KEYNOTE-010 (KN010) clinical trial, a multi-center, worldwide, randomized Phase II/III trial of pembrolizumab 2m/kg every 3 weeks and docetaxel 75mg/m2 every 3 weeks in patients with previously treated advanced NSCLC with PD-L1 positive tumors showed a significant overall survival (OS) advantage for patients receiving pembrolizumab. We examined the improvement in prognoses for patients who elect to learn their PD-L1 biomarker results using extrapolative survival modeling.

      Methods:
      Partitioned survival models to project long-term outcomes were developed using data from patients enrolled in KN010, with treated patients in the pembrolizumab 2m/kg and docetaxel 75mg/m2 arms included in these analyses. As OS for docetaxel patients is not dependent on PD-L1 status, KN010 results were assumed to represent docetaxel efficacy in all patients irrespective of PD-L1 status.The model projected expected lifetime using Kaplan Meier estimates of PFS and OS from the trial with extrapolation based on parametric functions and long term registry data.

      Results:
      Results directly from KN010 showed for patients with TPS≥50%, median survival to be 8.2 months (6.4, 10.7) and 14.9 months (10.4, NA) for docetaxel and pembrolizumab, respectively (HR= 0.54 (0.38, 0.77)). Model-based projections show that should all patients be treated with docetaxel, expected mean lifetime is 1.0 years. For patients receiving a PD-L1 biomarker test per KN010 28.49% will be identified as PD-L1 strong positive (TPS≥50%). PD-L1 (TPS ≥50%) predicts a life expectancy with biomarker directed pembrolizumab of 2.25 years on average.

      Conclusion:
      Use of PD-L1 biomarker identification can significantly improve OS prognoses for patients considering pembrolizumab and docetaxel with advanced NSCLC based on both clinical trial results and model-based projections from KN010.

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      MA14.06 - Nivolumab in Never Smoker Patients with Advanced Squamous NSCLC: Results from the Italian Expanded Access Programme (EAP) (ID 4765)

      16:00 - 17:30  |  Author(s): G. Lo Russo, L. Crinò, D. Galetta, A. Ardizzoni, E. Cortesi, F. Cappuzzo, P. Bordi, L. Calabrò, F. Barbieri, A. Santo, G. Altavilla, G. Cartenì, E. Mini, E. Vasile, F. Morgillo, A. Scoppola, C. Bengala, G. Fasola, N. Tedde, F. Piantedosi

      • Abstract
      • Presentation
      • Slides

      Background:
      Nivolumab is the first checkpoint inhibitor approved for the treatment of Sq-NSCLC to show a survival benefit vs the standard of care docetaxel in the randomised, phase III, CheckMate 017 study. In the nivolumab development program, a greater clinical benefit was shown in current and former smokers than in never smokers. Nevertheless, no data are available in this respect from a real world setting. For this reason, we decided to use the data collected in the EAP in order to assess the effectiveness and tolerability of nivolumab treatment in the never smoker patient population.

      Methods:
      Nivolumab was provided upon physician request for patients aged ≥18 years who had relapsed after a minimum of one prior systemic treatment for stage IIIB/stage IV Sq-NSCLC. Nivolumab 3 mg/kg was administered intravenously every 2 weeks for <24 months. Patients included in the analysis had received ≥1 dose of nivolumab and were monitored for adverse events using Common Terminology Criteria for Adverse Events.

      Results:
      Of 372 patients with Sq-NSCLC participating in the EAP in Italy, 38 (10.2%) were never smokers, a proportion very similar to the one observed in Checkmate 017 (10%). With a median number of doses of 8 (range, 1–22) and a median follow-up of 5.6 months, the disease control rate in this group was 50%, including 9 patients with a partial response and 10 with stable disease. Eight patients were treated beyond RECIST-defined progression, with 4 of them achieving disease control. As of April 2016, median progression-free survival and overall survival were 3.5 months and not reached, respectively. 17 patients (44.7%) discontinued treatment for any reason except toxicity and 5 (13.1%) discontinued due to AE.

      Conclusion:
      These preliminary results, although obtained from a small sample size, suggest that nivolumab is effective and well tolerated in a never smoker group of patients with advanced Sq-NCLCS in the real life and warrant further investigation in this area.

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      MA14.07 - Real Life Experience with Immunotherapy in the Netherlands (ID 4689)

      16:00 - 17:30  |  Author(s): R.D. Schouten, P. Baas, M. Van Den Heuvel

      • Abstract
      • Presentation
      • Slides

      Background:
      Randomized phase III trials have shown that the PD-1 blocking monoclonal antibody Nivolumab is effective in advanced NSCLC. Nivolumab is registered by the FDA and EMA for treatment of NSCLC. However, approval in The Netherlands was put on hold because of Nivolumab's high price per quality adjusted life year (QALY). From August 2015, Nivolumab was provided through a compassionate use program. Here we present our experience in treating NSCLC patients with Nivolumab in real life.

      Methods:
      Efficacy and safety of Nivolumab was assessed in patients with advanced NSCLC, previously treated with at least one line of platinum-based chemotherapy and an ECOG-PS of ≤2. Nivolumab was administered 2-weekly at a dose of 3 mg/kg intravenously. Response evaluation took place according to RECIST 1.1 at 12 and 24 weeks after start of treatment.

      Results:
      In the 10-month period in a single center 189 patients started treatment with Nivolumab, with a mean follow up time of 106 days after start of treatment. Mean age was 62 years (range 29–83), 57% male, 18,5% never smoked, 68% had adenocarcinoma, 20% had squamous histology and 12% were other, mixed or unspecified types. Figure 1 Twenty-four percent of patients experience immunotherapy related toxicity, most toxicities were short-term or easily manageable. No grade 5 toxicities, one grade 4 hepatitis and one grade 3 hypophysitis were observed. Hypothyroidism was most frequently observed (gr.1-2; 9,5%), followed by skin-reactions (gr.1-3; 3,8%) and colitis (gr.1-2; 3,2%). Other immune related toxicities were hepatitis (gr.1-4; 2,5%), infusion reactions (gr.1; 2,5%), pneumonitis (gr.2; 1,9%), hyperthyroidism (gr.1; 1,3%), arthritis (gr.2; 0,6%), hypophysitis (gr.3; 0,6%) and diabetes mellitus type 1 (gr.3, 0,6%).



      Conclusion:
      Although follow up is short and response data not yet mature, real-life efficacy and safety data from Nivolumab are comparable to phase III trial data.

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      MA14.08 - Discussant for MA14.05, MA14.06, MA14.07 (ID 6988)

      16:00 - 17:30  |  Author(s): L.E. Raez

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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      MA14.09 - Demonstrating Life Expectancy Gains with Immuno-Oncology (IO) Therapies (ID 4634)

      16:00 - 17:30  |  Author(s): J. Sullivan, A. Sexton Ward, B. Korytowsky, D. Peneva, J. Benner, D.N. Lakdawalla, B. Bolinder, R.A. Figlin, A.B. Jena

      • Abstract
      • Presentation
      • Slides

      Background:
      Immuno-oncology (IO) therapies offer the possibility of long-term survival to metastatic cancer patients. Prior analyses have shown that lung cancer reduces life expectancy by an average of 11.8 years (Burnet NG, et al. Br J Cancer. 2005;92:241‒245.). We aimed to investigate the impact of IO therapies on life extension of patients with non-small cell lung cancer (NSCLC).

      Methods:
      We used The Health Economics Medical Innovation Simulation (THEMIS) alongside available clinical trial data to estimate the anticipated increase in NSCLC patient survival post-diagnosis resulting from the introduction of IO therapy. THEMIS is an established microsimulation with a 50-year time horizon that tracks a representative sample of patients aged ≥51 years to project longevity. These outcomes were estimated for metastatic NSCLC patients under a pre-IO scenario and compared to a post-IO scenario where IO is available for either first- or second-line treatment. Patients were classified as either heavy, medium, or light responders, corresponding to reductions in mortality hazards of 96.5%, 64.4%, and 0%, respectively, based on extrapolations of clinical trial results for nivolumab (see table). Health state transitions probabilities and medical expenditures were estimated from nationally representative datasets. Mortality and disease stage were estimated using the Surveillance and Epidemiology End Results (SEER) database.

      Results:
      In the pre-IO simulation, metastatic NSCLC patients lose 11.3 years of life (comparable with the published 11.8 years). The results from the post-IO scenarios are shown in the table. For comparison, SEER data suggest that survival in metastatic NSCLC patients has only increased by 0.3 years since 1998.

      Population Heavy Responder Prevalence Medium Responder Prevalence Heavy Responder Hazard Reduction Medium Responder Hazard Reduction Light Responder Hazard Reduction Additional Life Years
      Second-line monotherapy, All patients 20% 30% 96.5% 64.4% 0% 2.1
      First-line monotherapy, PD-L1 >1% 30% 40% 96.5% 64.4% 0% 3.25
      First-line monotherapy, PD-L1 >50% 50% 40% 96.5% 64.4% 0% 4.72
      First-line combination therapy, PD-L1 >1% 60% 30% 96.5% 64.4% 0% 4.22
      First-line combination therapy, PD-L1 >50% 100% 0% 96.5% N/A N/A 7.06


      Conclusion:
      Current IO therapies represent a significant step towards extending life expectancy for metastatic NSCLC patients.

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      MA14.10 - Relative Impact of Disease Management Costs in the Economics of Pembrolizumab in Previously Treated PD-L1 Positive Advanced NSCLC (ID 5439)

      16:00 - 17:30  |  Author(s): M. Huang, Y. Lou, J. Pellissier, T. Burke, F.X. Liu, V. Velcheti

      • Abstract
      • Presentation
      • Slides

      Background:
      This study aimed to understand the impact on disease management costs beyond drug acquisition costs in the context of an economic evaluation of pembrolizumab compared with docetaxel in patients in patients with previously treated PD-L1 positive (TPS>=50%) advanced NSCLC. The analysis was conducted from a US third-party payer perspective.

      Methods:
      A partitioned-survival model was developed using data from patients from the KEYNOTE-010 (KN010) clinical trial. The model used KM estimates of PFS and OS from the trial for patients treated with pembrolizumab 2mg/kg and docetaxel 75kg/m[2] with extrapolation based on fitted parametric functions and long-term registry data. Costs of clinical management of advanced NSCLC along with drug acquisition/administration and adverse event management costs were included in the model. The base-case analysis used a time horizon of 20 years. Costs and health outcomes were discounted at a rate of 3% per year.

      Results:
      Base case results project for PD-L1 positive (TPS>=50%) patients treated with pembrolizumab a mean survival of 2.25 years. For docetaxel, a mean survival time of 1.07 years was estimated. Weekly disease management costs observed in KN010 for the progression-free state were $866 and $1,298 for pembrolizumab and docetaxel, respectively. Weekly disease management costs for the progressive disease state were $1,938 based on a US healthcare claim database. Results projected total disease management costs to be $166K per patient treated with pembrolizumab compared with $93K for docetaxel because of extended progression-free and post-progression survival with pembrolizumab. Nearly half (45%) of total expected cost differences between pembrolizumab and docetaxel are due to the incremental disease management costs. Further analyses that exclude drug treatment costs show that the additional disease management costs associated with extended progression-free and overall survival exceed $50,000 per LY gained ($61,864).

      Conclusion:
      Pembrolizumab improves outcomes compared to docetaxel in PD-L1 positive (TPS>=50%) pre-treated advanced NSCLC patients in the US. The improved overall survival with pembrolizumab is accompanied by the economic reality of additional non-pembrolizumab costs that represent their own substantial economic burden.

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      MA14.11 - An Estimate of the Economic Impact of Immunotherapy Relative to PD-L1 Expression in Brazil - An Update with Brazilian Costs (ID 4251)

      16:00 - 17:30  |  Author(s): P. Aguiar Jr, R. De Mello, H. Tadokoro, H. Babiker, G. Lopes

      • Abstract
      • Presentation
      • Slides

      Background:
      Delivering high quality cancer care at an affordable cost is one of the main challenges for health care professionals and policy makers, especially in low- and middle-income countries. The objective of our study is to assess the economic impact of nivolumab and pembrolizumab with and without the use of PD-L1 as a biomarker in Brazil.

      Methods:
      We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and the second-line treatment with NIVO or PEMBRO versus docetaxel. The model used outcomes data from randomized clinical trials and drug acquisition costs were estimated using current prices in Brazil. Thereafter, we used Brazilian epidemiologic data to estimate the economic impact.

      Results:
      We included three RCTs (two with NIVO and one with PEMBRO). The estimated number of cases eligible for therapy with immune checkpoint inhibitors is 4,733. Treating all patients with NIVOLUMAB would cost US$ 173 million dollars each year, representing an increase of 21% in current Brazilian expenses for cancer drugs acquisition. Treating only patients with PD-L1 > 1% with NIVOLUMAB would cost 93 million dollars every year, leading to an increase of 11.3% in expenses for cancer drugs acquisition. However, with such selection, up to 46% of cases would not be treated and 315 years of life would be lost compared to treating all patients regardless of PD-L1 expression. The cost of each year-of-life saved was improved by PD-L1 selection (from US$ 196,000 to US$ 164,000). Table 1 summarizes our findings for five different scenarios of treatment. The results were similar with NIVOLUMAB and PEMBROLIZUMAB.

      SCENARIO QALY GAIN ICER (US$) LIFE-YEARS SAVED YEARS OF LIFE NOT SAVED % NOT TREATED TOTAL COST (US$) IMPACT ON TOTAL CANCER DRUG EXPENDITURE COST/LYS (US$)
      NIVO ALL COMERS 0.148 129 K 885 0 0% 173 Million 21.1% 196 K
      NIVO PD-L1 > 1% 0.201 108 K 570 315 46% 93 11.3% 164 K
      PEMBRO PD-L1 > 1% 0.138 137 K 666 NA 34% 100 12.1% 150 K
      NIVO ALL SQ/ > 1% NSQ 0.216 99 K 738 147 35% 116 14.0% 157 K
      PEMBRO PD-L1 > 50% 0.164 116 K 285 NA 72% 43 5.2% 151 K


      Conclusion:
      The use of PD-L1 expression as a biomarker for treatment with immune checkpoint inhibitors decreases the overall economic impact and the cost per life-year saved. Further study and societal discussion is needed in order to find the optimal strategy for patient selection.

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      MA14.12 - Discussant for MA14.09, MA14.10, MA14.11 (ID 6944)

      16:00 - 17:30  |  Author(s): G.R. Simon

      • Abstract
      • Presentation
      • Slides

      Abstract not provided

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Author of

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    ISS09 - Industry Supported Symposium: Targeted Therapy on the Horizon for SCLC - AbbVie (ID 442)

    • Event: WCLC 2016
    • Type: Industry Supported Symposium
    • Track:
    • Presentations: 3
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      ISS09.01 - Challenges in SCLC Across Decades (ID 7019)

      07:30 - 08:30  |  Author(s): M. Reck

      • Abstract

      Abstract not provided

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      ISS09.04 - Panel Discussion: Looking Over the Horizon – Future Treatment of SCLC (ID 7022)

      07:30 - 08:30  |  Author(s): M. Reck

      • Abstract

      Abstract not provided

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      ISS09.05 - Question & Answer (ID 7023)

      07:30 - 08:30  |  Author(s): M. Reck

      • Abstract

      Abstract not provided

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    MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      MA07.05 - EUCROSS: A European Phase II Trial of Crizotinib in Advanced Adenocarcinoma of the Lung Harboring ROS1 Rearrangements - Preliminary Results (ID 4451)

      11:00 - 12:30  |  Author(s): M. Reck

      • Abstract
      • Presentation
      • Slides

      Background:
      ROS1 rearrangements are present in the tumors of 1-2% of patients with lung adenocarcinoma (LAD). This patient subgroup is characterized by non-smoking history and younger than average age compared to the overall NSCLC population. In a phase I trial the ALK/ROS1/MET inhibitor crizotinib has shown to be highly effective in these patients (NCT00585195). EUCROSS is a prospective phase II trial of the Lung Cancer Group Cologne in collaboration with the Spanish Lung Cancer Group to evaluate crizotinib in ROS1-positive LAD. Here, we present preliminary data on efficacy and safety.

      Methods:
      Patients with advanced LAD harboring ROS1 rearrangements as confirmed by central FISH were eligible for the trial irrespectively of the number of prior treatment lines. Patients received treatment with crizotinib 250 mg BID - doses were adapted for management of AEs. Trial design: Fleming’s single stage phase II design. Primary endpoint: ORR (95% CI, H~0~: ORR≤20% vs. H~1~: ORR>20%). Secondary endpoints: a.o. PFS, OS and safety. All efficacy endpoints were assessed by investigator’s RECIST v1.1 and will be analyzed by IRB at a later stage. Baseline tumor tissue was analyzed by DNA-sequencing to identify the translocation Partners of ROS1, to validate FISH results and to identify additional biomarkers for prediction of response. Data-cut off for this report was March 2016.

      Results:
      In total, 34 patients were enrolled in EUCROSS at the time of data cut-off. Twenty-nine patients were eligible for efficacy assessment. Tumor tissue of 20 of these patients was suitable for further sequencing - 18 were sequenced positive for ROS1 fusion. The fusion partners involved were CD74 (N=9;50%), EZR (N=4;22%), SCL34A2 (N=3;17%), TPM3 and SDC4(N=1;6% each). The investigator assessed ORR was 69% (95% CI, 49.1-84.3) in the overall trial population and 83% (95% CI, 67.7-94.2) in the ROS1-positive by sequencing population (N=18;P=0.324 for difference of ORR). Three patients (10.3%;95% CI, 3.6-26.4) exhibited primary progression, two of them were sequenced ROS1-negative. All patients were included in the safety population (N=34). Most common AEs irrespectively of relatedness or grade were visual disorders (N=16;48%), edema (N=14;41%), diarrhea (N=13;38%) and bradycardia (N=11;32%).

      Conclusion:
      Crizotinib is a highly effective and safe treatment in the subset of ROS1 rearranged NSCLC patients as determined by FISH and DNA-sequencing. Although, the number of patients with tissue available for sequencing was low at the time of data cut-off, sensitivity and specificity support sequencing as the potential new gold-standard for the identification of clinically relevant ROS1 gene-rearrangements.

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    OA11 - Angiogenesis in Advanced Lung Cancer (ID 387)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
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      OA11.02 - Randomized Phase 1b/3 Study of Erlotinib plus Ramucirumab in First-Line EGFR Mut + Stage IV NSCLC: Phase 1b Safety Results (ID 3827)

      11:00 - 12:30  |  Author(s): M. Reck

      • Abstract
      • Presentation
      • Slides

      Background:
      Ramucirumab, an antiangiogenic IgG1 VEGFR2-targeted monoclonal antibody, and erlotinib, an EGFR tyrosine kinase inhibitor, are both active in advanced NSCLC. This global phase 1b/3 study (NCT02411448) will assess safety, tolerability and efficacy of the combination of ramucirumab with erlotinib in previously untreated patients with EGFR mutation-positive stage IV NSCLC. Here we report phase 1b safety results.

      Methods:
      Eligible patients with ECOG PS 0-1, an activating EGFR mutation, and previously untreated stage IV NSCLC received ramucirumab 10 mg/kg intravenously on day 1 of repeating 14-day (± 3 days) cycle and erlotinib 150 mg orally daily. Treatment continued until disease progression or unacceptable toxicity. The primary objective of part A was to assess the safety and tolerability, in terms of dose limiting toxicities (DLT), of adding the recommended dose of ramucirumab for phase 3 (part B) to standard dose erlotinib. Data were analyzed separately for Japan (JP) (cohort 1) and US/EU (cohort 2). The DLT assessment occurred during the first 2 cycles (approximately 28 days).

      Results:
      As of Dec 16th, 2015, 14 patients were treated in the phase 1b part of this trial and 12 were DLT evaluable (6 JP; 6 US/EU). Overall, 6 grade (Gr) 3 treatment-emergent adverse events (TEAE) were noted, with at least one TEAE in 5 patients; no serious adverse events or Gr 4-5 TEAEs occurred. In the JP cohort the median age was 73 (64-79), 57% had ECOG PS 1 and 29% had a history of smoking. Four patients (57%) experienced a Gr 3 TEAE, of which one was a DLT (elevation of alanine aminotransferase) while the others (hypertension [n=2], dermatitis acneiform, and diarrhea) were not DLTs. In the US/EU cohort the median age was 71 (31-83), 86% had ECOG PS 1, and no patients had a history of smoking. One patient experienced Gr 3 TEAE of rash; no DLTs were observed in this cohort.

      Conclusion:
      Enrollment on the phase 1b portion of this trial is complete and the safety results were consistent with previous combinations of antiangiogenic/erlotinib in this patient population. No unexpected toxicities were identified. Phase 3 enrollment has been initiated maintaining the dose of ramucirumab at 10 mg/kg Q2W.

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    OA22 - Novel Trials and Biomarkers in Malignant Pleural Mesothelioma (ID 403)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
    • Presentations: 1
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      OA22.02 - Nintedanib plus Pemetrexed/Cisplatin in Patients with MPM: Phase II Findings from the Placebo-Controlled LUME-Meso Trial (ID 4191)

      14:20 - 15:50  |  Author(s): M. Reck

      • Abstract
      • Presentation
      • Slides

      Background:
      Standard first-line treatment for patients with unresectable malignant pleural mesothelioma (MPM) is pemetrexed/cisplatin, yielding a median overall survival (OS) of only ~1 year, thus new approaches are required. As demonstrated by the bevacizumab MAPS study, inhibition of the VEGF pathway is of interest as a treatment approach for MPM. Nintedanib is an oral, triple angiokinase inhibitor of VEGFR, PDGFR and FGFR. This study will evaluate the efficacy and safety of nintedanib plus pemetrexed/cisplatin in patients with advanced MPM.

      Methods:
      Patients with unresectable MPM (chemo-naïve, ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomised (1:1) to receive up to 6 cycles of pemetrexed (500 mg/m[2])/cisplatin (75 mg/m[2]) on Day 1 plus nintedanib (200 mg bid)/placebo on Days 2–21. Patients without disease progression received maintenance treatment with nintedanib/placebo. The primary endpoint was progression-free survival (PFS).

      Results:
      87 patients were randomised to receive pemetrexed/cisplatin, plus nintedanib/placebo. Patient characteristics were comparable between the groups. PFS was longer in the nintedanib vs the placebo arm, in both the overall study population and in epithelioid patients (Table 1). Preliminary OS data also favour nintedanib. All patients experienced at least one adverse event (AE, any grade), with 7% of patients in the nintedanib arm discontinuing due to AEs, vs 15% with placebo. Serious AEs occurred in 36% vs 42% of patients in the nintedanib and placebo arms, respectively. The most common ≥grade 3 AEs occurring in nintedanib vs placebo patients were neutropenia (34% vs 10%), ALT increase (14% vs 2%) and gamma glutamyltransferase increase (14% vs 0%).

      Conclusion:
      Nintedanib plus pemetrexed/cisplatin demonstrated clinical efficacy with improved PFS and a tolerable safety profile in patients with unresectable MPM. Based on these promising findings, this Phase II study was extended to a confirmatory Phase III trial, which is currently enrolling patients. Clinical trial identifier: NCT01907100.

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    P3.02c - Poster Session with Presenters Present (ID 472)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 3
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      P3.02c-030 - Use of a 200-Mg Fixed Dose of Pembrolizumab for the Treatment of Advanced Non–Small Cell Lung Cancer (NSCLC) (ID 6129)

      14:30 - 15:45  |  Author(s): M. Reck

      • Abstract

      Background:
      Previous analyses showed no clinically significant exposure-efficacy relationship for pembrolizumab doses of 2-10 mg/kg. Population pharmacokinetics (popPK) modeling suggested weight-based or fixed pembrolizumab doses could maintain exposures within the established safety/efficacy bounds. Fixed dose advantages include increased convenience, reduced dosing error risk, and less discarded product. Pembrolizumab 200 mg Q3W was evaluated in the KEYNOTE-024 study of pembrolizumab versus platinum-doublet chemotherapy for treatment-naive advanced NSCLC with PD-L1 TPS ≥50% (NCT02142738).

      Methods:
      Pembrolizumab serum concentration was quantified with an electrochemiluminescence-based immunoassay (lower limit of quantitation, 10 ng/mL). The existing 2-compartment popPK model derived from studies of weight-based pembrolizumab dosing was extended with KEYNOTE-024 concentration-time data. Correlation between pembrolizumab exposure (ie, area under the serum-concentration curve over 6 weeks [AUC~ss-6weeks~]) and efficacy was assessed.

      Results:
      Median (range) weight was 69.7 kg (38-110) in KEYNOTE-024 and 75 kg (35.7-210) in the existing popPK model studies. In treatment-naive advanced NSCLC, there was a flat relationship between pembrolizumab exposure and efficacy for the 200-mg fixed dose and weight-based doses (linear regression P>0.05). Observed pembrolizumab concentrations for 200 mg (median 1976 μg·d/mL, 90% CI 1124-3322) were consistent with predictions (median 1751 μg·d/mL, 90% prediction interval 955-3136) and fell within the previously observed therapeutic window for 2 and 10 mg/kg (Figure). There was considerable overlap in exposures for 2 mg/kg and 200 mg, regardless of whether weight was >90 or <90 kg for 200 mg (Figure). Figure 1



      Conclusion:
      Pembrolizumab exposure at 200 mg Q3W is similar to that of 2 mg/kg Q3W. Including data from patients with advanced NSCLC treated with 200 mg did not change the flat exposure-efficacy relationship. Along with the superior PFS and OS provided by pembrolizumab over platinum-doublet chemotherapy as first-line therapy for advanced NSCLC with TPS ≥50%, these data support 200 mg Q3W as an alternative to the approved 2-mg/kg Q3W dose.

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      P3.02c-038 - First-Line Atezolizumab plus Chemotherapy in Chemotherapy-Naïve Patients with Advanced NSCLC: A Phase III Clinical Program (ID 4956)

      14:30 - 15:45  |  Author(s): M. Reck

      • Abstract

      Background:
      First-line treatments for patients with advanced NSCLC include targeted therapies and platinum-based doublet chemotherapy±bevacizumab and/or pemetrexed. Although immunotherapies targeting the PD-L1/PD-1 pathway are available for advanced NSCLC beyond the first line, chemotherapy is a key first-line option for patients, despite poor survival outcomes, highlighting the need for additional treatment options. Atezolizumab, a monoclonal anti–PD-L1 antibody, inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy has been reported with atezolizumab monotherapy in patients with squamous and nonsquamous NSCLC, with a survival benefit observed across all PD-L1 expression levels. Additionally, Phase Ib data showed the potential for chemotherapy to further enhance responses to atezolizumab, with tolerable safety, in patients with NSCLC. Bevacizumab in combination with atezolizumab may enhance efficacy in non-squamous NSCLC by inhibiting VEGF-mediated immunosuppression. Four global, Phase III, randomized, open-label trials are evaluating atezolizumab+platinum-based chemotherapy±bevacizumab in chemotherapy-naive patients with stage IV NSCLC.

      Methods:
      Eligible patients must have stage IV NSCLC, measurable disease (RECIST v1.1) and ECOG PS 0-1 and be chemotherapy naive. Exclusion criteria include untreated CNS metastases, autoimmune disease and prior exposure to immunotherapy. Patients will be enrolled regardless of PD-L1 expression status. Patients randomized to the experimental arm will receive atezolizumab 1200 mg with standard platinum-based chemotherapy in IMpower130 and 131 and also ±bevacizumab in IMpower150 for four or six 21-day cycles, then maintenance with atezolizumab in IMpower130 and 131 and atezolizumab+bevacizumab in IMpower150. In IMpower132, experimental-arm patients will receive atezolizumab+platinum-based chemotherapy+pemetrexed, then maintenance with atezolizumab+pemetrexed. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are progression-free survival and overall survival. Secondary endpoints include objective response rate and safety. Evaluation of predictive biomarkers associated with efficacy will be performed.

      Trial IMpower130 IMpower131 IMpower132 IMpower150
      Histology Nonsquamous Squamous Nonsquamous Nonsquamous
      Planned enrollment(N) 650 1025 568 1200
      Experimental Atezolizuma +carboplatin +nab-paclitaxel Atezolizuma +carboplatin +paclitaxel or Atezolizumab +carboplatin +nab-paclitaxel Atezolizuma +carboplatin or cisplatin +pemetrexed Atezolizumab +carboplatin +paclitaxel or Atezolizumab +carboplatin +paclitaxel +bevacizumab
      Comparator Carboplatin +nab-paclitaxel Carboplatin +nab-paclitaxel Carboplatin or cisplatin +pemetrexed Carboplatin +paclitaxel +bevacizumab
      Stratification factors Sex Liver metastases Centrally assessed PD-L1 expression by IHC Sex Liver metastases Centrally assessed PD-L1 expression by IHC Sex ECOG PS Chemotherapy type (carboplatin vs cisplatin) Smoking status Sex Liver metastases Centrally assessed PD-L1 expression by IHC
      Identifier NCT02367781 NCT02367794 NCT02657434 NCT02366143
      ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry.

      Results:
      Section not applicable

      Conclusion:
      Section not applicable

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      P3.02c-041 - IMpower133: A Phase I/III Study of 1L Atezolizumab with Carboplatin and Etoposide in Patients with Extensive-Stage SCLC (ID 4789)

      14:30 - 15:45  |  Author(s): M. Reck

      • Abstract

      Background:
      Platinum-based chemotherapy with etoposide is the current first-line (1L) standard of care for the majority of patients with extensive-stage small cell lung cancer (ES-SCLC). Although initial response rates with chemotherapy range from 50% to 70%, survival outcomes remain poor (median overall survival [mOS] < 1 year), and new treatment approaches are needed. Atezolizumab is an anti–PDL1 monoclonal antibody that inhibits the binding of PD-L1 to its receptors PD-1 and B7.1, thereby restoring anti-tumor T-cell activity. In a Phase Ia study, single-agent atezolizumab demonstrated a tolerable safety profile and promising durability of response in patients with ES-SCLC: confirmed ORR was 6% (n = 1/17 [partial response]; DOR of 7 months) by RECIST v1.1 and 24% by immune-related response criteria (irRC) (n = 4/17, with 2 patients on atezolizumab for ≥ 12 months). In addition, pre-clinical and Phase I data suggest that atezolizumab plus platinum-based chemotherapy in NSCLC may be synergistic, resulting in durable responses that could potentially translate into improved survival over monotherapy alone. Taken together, these findings provide a rationale to investigate whether atezolizumab + carboplatin + etoposide can improve survival compared with carboplatin + etoposide in the 1L treatment of ES-SCLC.

      Methods:
      IMpower133 (NCT02763579) is a global, Phase I/III, randomized, multicenter, double-blinded, placebo-controlled trial comparing the efficacy and safety of atezolizumab + carboplatin + etoposide with that of placebo + carboplatin + etoposide in treatment-naive patients with ES-SCLC. Patients will be enrolled regardless of PD-L1 expression status. Exclusion criteria include untreated CNS metastases, autoimmune disease or prior anti-cancer therapy for ES-SCLC. The study stratification factors include sex, ECOG performance status and presence of CNS metastases. Eligible patients will be randomized 1:1 to receive four 21-day cycles of atezolizumab (1200 mg IV) or placebo in combination with carboplatin (AUC 5 mg/mL/min IV, day 1) and etoposide (100 mg/m[~2~], days 1-3), followed by maintenance with atezolizumab or placebo until PD per RECIST v1.1. Patients can continue with treatment until persistent radiographic PD, symptomatic deterioration or unacceptable toxicity. Co-primary endpoints of investigator-assessed progression-free survival per RECIST v1.1 and OS will be evaluated. Secondary efficacy endpoints include ORR and DOR. Safety and tolerability will also be assessed. Approximately 400 patients will be enrolled in this trial.

      Results:
      Section not applicable

      Conclusion:
      Section not applicable

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    PL04a - Plenary Session: Immune Checkpoint Inhibitors in Advanced NSCLC (ID 430)

    • Event: WCLC 2016
    • Type: Plenary
    • Track: Chemotherapy/Targeted Therapy/Immunotherapy
    • Presentations: 1
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      PL04a.01 - Health-Related Quality of Life for Pembrolizumab vs Chemotherapy in Advanced NSCLC with PD-L1 TPS ≥50%: Data from KEYNOTE-024 (Abstract under Embargo until December 7, 7:00 CET) (ID 7153)

      08:45 - 09:40  |  Author(s): M. Reck

      • Abstract
      • Presentation
      • Slides

      Background:
      In KEYNOTE-024 (NCT02142738), pembrolizumab provided superior progression-free survival (PFS) over platinum-based chemotherapy as first-line therapy for patients with advanced non-small cell lung cancer (NSCLC) with PD-L1 expression on ≥50% of tumor cells (ie, PD-L1 tumor proportion score [TPS] ≥50%) and no sensitizing EGFR or ALK aberrations (HR 0.50, P < 0.001). Despite a 44% crossover rate from chemotherapy to pembrolizumab, pembrolizumab also significantly improved overall survival (OS) (HR 0.60, P = 0.005). Any-grade (73% vs 90%) and grade 3-5 (27% vs 53%) treatment-related adverse events were less frequent with pembrolizumab. Health-related quality of life (HRQoL) is an important consideration for anticancer therapy, particularly in the first-line setting. We present data from the prespecified exploratory patient-reported outcomes (PRO) analysis of KEYNOTE-024.

      Methods:
      305 patients were randomized to pembrolizumab 200 mg Q3W or investigator-choice platinum-doublet chemotherapy plus optional pemetrexed maintenance therapy for nonsquamous disease. The EORTC QLQ-C30 and QLQ-LC13 were administered at cycles 1-3 and every 9 weeks thereafter. The key PRO end points were change from baseline to week 15 in the QLQ-C30 global health status/QoL score and time to deterioration in the QLQ-LC13 composite of cough, chest pain, and dyspnea. PROs were analyzed for all patients who received study treatment and completed ≥1 PRO instrument (n = 299).

      Results:
      Across treatment arms, PRO compliance was >90% at baseline and ~80% at week 15. Least squares (LS) mean (95% CI) change from baseline to week 15 in QLQ-C30 global health status/QoL score was 6.95 (3.29 to10.58) for pembrolizumab (n = 151) and –0.88 (–4.78 to 3.02) for chemotherapy (n = 148). The difference in LS means was 7.82 (95% CI 2.85-12.79; nominal 2-sided P = 0.002). The proportion of improved global health status/QoL score at week 15 was 40.0% for pembrolizumab and 26.5% for chemotherapy. Fewer patients in the pembrolizumab arm had deterioration in the QLQ-LC13 composite of cough, dyspnea, and chest pain (30% vs 39%), and time to deterioration was also prolonged with pembrolizumab (HR 0.66, 95% CI 0.44-0.97; nominal 2-sided P = 0.029).

      Conclusion:
      Pembrolizumab was associated with a clinically meaningful improvement in HRQoL compared with platinum-based chemotherapy. Combined with the superior PFS and OS and manageable safety profile, these data suggest pembrolizumab may be a new standard of care for first-line treatment of PD-L1–expressing advanced NSCLC.

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    SC26 - Angiogenesis Inhibition: Advances & Perspectives (ID 350)

    • Event: WCLC 2016
    • Type: Science Session
    • Track: Biology/Pathology
    • Presentations: 1
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      SC26.03 - Predictive Biomarkers for Angiogenesis Inhibitors: An Update (ID 6711)

      11:00 - 12:30  |  Author(s): M. Reck

      • Abstract
      • Presentation
      • Slides

      Abstract:
      The concept of tumor-induced neoangiogenesis has been shown to be a relevant factor for tumor proliferation and metastasis already a couple of years ago (1). Therefore interaction with proangiogenic pathways appears to be a promising therapeutic target across several solide tumors. In eligible patients with advanced non-squamous NSCLC the addition of the anti vascular endothelial growth factor (anti VEGF) antibody bevacizumab to platinum based chemotherapy has shown consistent improvement of response, progression free survival (PFS) and overall survival. However also the combination did increase the incidence of characteristic adverse events like hypertension, arterial and venous vascular events, bleeding events, proteinuria and other (2). Recently two large randomised phase III trials revealed a significant increase in efficacy by the combination of antiangiogenic agents and chemotherapy in pretreated patients with advanced NSCLC. In the LUME 1 trial the combination of the oral angiokinase inhibitor nintedanib and docetaxel revealed a significant improvement of PFS (median PFS 3.4 vs 2.7 months, HR 0.79, 95% CI 0.68-0.92) and OS in patients with adenocarcinoma histology (median OS 12.6 vs 10.3 months, HR 0.82, 95% CI 0.7-0.99) compared to docetaxel (3). The combination of the anti VEGF receptor 2 antibody ramucirumab and docetaxel did show a significant improvement of response (response rate: 23% versus 14%, p<0.0001), PFS (median PFS 4.5 versus 3.0 months, HR 0.76, 95% CI 0.68-0.86) and OS (median OS 10.5 versus 9.1 months, HR 0.86, 95% CI 0.75-0.98) compared to docetaxel in pretreated patients with NSCLC regardless of histology (4). The identification of potential predictive biomarkers remains a challenge due to the complexity of angiogenesis, the interaction between the tumor and the host and due to dynamic changes of the system. In a very large trial (Abigail), specifically designed to identify potential tissue based or blood based markers of efficacy, no predictive markers could be determined. However the relevant prognostic nature of angiogenesis marker could be confirmed (5). Recent analyses revealed that besides molecular markers clinical factors like rapid progressive diseases or tumors refractory to conventional chemotherapy could be associated with improved outcomes of angiogenesis inhibitors. Preplanned as well as exploratory analyses did show pronounced efficacy for the combination of antiangiogenic agents like nintedanib, ramucirumab and bevacizumab compared to chemotherapy alone supporting the hypothesis that fast progressing tumors are more dependant on neo angiogenesis. The translational exploration of these clinical findings is on the way in several programs and trials. The understanding of this correlation will be important for the optimal placement of antiangiogenic agents e.g. in the combination with immunotherapies. Folkman J, Merler E, Abernathy C et al. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 1971; 133: 275-288 Soria JC, Mauguen A, Reck M et al. Systematic review and meta-analysis of randomised phase II/III trials adding bevacizumab to platinum based chemotherapy as first-line treatment in patients with advanced non-small-cell lung cancer. Ann Oncol 2013; 24: 20-30 Reck M, Kaiser R, Mellemgaard A et al. Docetaxel plus nintedanib versus docetaxel plus placebo in patients with previously treated non-small-cell lung cancer (LUME-Lung 1): a phase 3, double blind, randomised controlled trial. Lancet Oncol 2014; 15: 143-50 Garon E, Ciuleanu TE, Arrieta O et al. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet 2014; 384: 665-773 Mok T, Gorbunova V, Juhasz E et al. A correlative biomarker analysis of bevacizumab and carboplatin-based chemotherapy for advanced nonsquamous non-small cell lung cancer: results of the phase II randomized ABIGAIL study (BO21015). J Thorac Oncol 2014; 9: 848-55.

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