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D.R. Spigel
Moderator of
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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
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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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 - 16:06 | 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
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)
16:06 - 16:12 | Author(s): O. Arrieta, E. Montes-Servín
- Abstract
- Presentation
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)
16:12 - 16:18 | 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
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)
16:18 - 16:30 | Author(s): M. Moniuszko
- Abstract
- Presentation
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)
16:30 - 16:36 | Author(s): M. Huang, J. Pellissier, T. Burke, R. Xu
- Abstract
- Presentation
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)
16:36 - 16:42 | 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
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)
16:42 - 16:48 | Author(s): R.D. Schouten, P. Baas, M. Van Den Heuvel
- Abstract
- Presentation
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)
16:48 - 17:00 | Author(s): L.E. Raez
- Abstract
- Presentation
Abstract not provided
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MA14.09 - Demonstrating Life Expectancy Gains with Immuno-Oncology (IO) Therapies (ID 4634)
17:00 - 17:06 | 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
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)
17:06 - 17:12 | Author(s): M. Huang, Y. Lou, J. Pellissier, T. Burke, F.X. Liu, V. Velcheti
- Abstract
- Presentation
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 ($61,864).
Conclusion:
Pembrolizumab improves outcomes compared to docetaxel in PD-L1 positive (TPS>=50%) pre-treated advanced NSCLC patients in the US. The improved overall survival with pembrolizumab is accompanied by the economic reality of additional non-pembrolizumab costs that represent their own substantial economic burden.
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MA14.11 - An Estimate of the Economic Impact of Immunotherapy Relative to PD-L1 Expression in Brazil - An Update with Brazilian Costs (ID 4251)
17:12 - 17:18 | Author(s): P. Aguiar Jr, R. De Mello, H. Tadokoro, H. Babiker, G. Lopes
- Abstract
- Presentation
Background:
Delivering high quality cancer care at an affordable cost is one of the main challenges for health care professionals and policy makers, especially in low- and middle-income countries. The objective of our study is to assess the economic impact of nivolumab and pembrolizumab with and without the use of PD-L1 as a biomarker in Brazil.
Methods:
We developed a decision-analytic model to determine the cost-effectiveness of PD-L1 assessment and the second-line treatment with NIVO or PEMBRO versus docetaxel. The model used outcomes data from randomized clinical trials and drug acquisition costs were estimated using current prices in Brazil. Thereafter, we used Brazilian epidemiologic data to estimate the economic impact.
Results:
We included three RCTs (two with NIVO and one with PEMBRO). The estimated number of cases eligible for therapy with immune checkpoint inhibitors is 4,733. Treating all patients with NIVOLUMAB would cost US$ 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)
17:18 - 17:30 | Author(s): G.R. Simon
- Abstract
- Presentation
Abstract not provided
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Author of
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MA09 - Immunotherapy Combinations (ID 390)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:M. Sebastian, E.B. Garon
- Coordinates: 12/06/2016, 14:20 - 15:50, Strauss 2
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MA09.05 - Nivolumab Alone or with Ipilimumab in Recurrent Small Cell Lung Cancer (SCLC): 2-Year Survival and Updated Analyses from the Checkmate 032 Trial (ID 4397)
14:50 - 14:56 | Author(s): D.R. Spigel
- Abstract
- Presentation
Background:
Patients with SCLC and disease progression during/after first-line platinum-based chemotherapy have poor prognoses and limited treatment options. Nivolumab alone and in combination with ipilimumab has shown survival benefit and durable responses in multiple tumor types. Here we present updated results for the SCLC cohort of the phase 1/2 CheckMate 032 trial (NCT01928394), which was designed to evaluate nivolumab or nivolumab/ipilimumab in advanced solid tumors.
Methods:
Patients with advanced SCLC that progressed following ≥1 platinum-based chemotherapy regimens were assigned to receive nivolumab monotherapy (nivolumab-3 Q2W) or nivolumab/ipilimumab combination therapy (nivolumab-1/ipilimumab-3 or nivolumab-3/ipilimumab-1 Q3W for 4 cycles, then nivolumab-3 Q2W). Patients were eligible regardless of platinum sensitivity or tumor programmed death ligand 1 (PD-L1) expression. The primary endpoint was ORR. Additional endpoints were duration of response (DOR), OS, PFS, safety, and correlation of tumor PD-L1 expression with activity.
Results:
214 patients have been enrolled to date (nivolumab-3, n=98; nivolumab-1/ipilimumab-3, n=61; nivolumab-3/ipilimumab-1, n=55), including 96 and 118 patients treated with 1 or ≥2 prior regimens, respectively. Efficacy and safety data are shown (table). In the nivolumab-1/ipilimumab-3 cohort, ORR was 23% and 1-year OS was 43%. The proportion of patients with PD-L1–expressing tumors was substantially lower in previously treated SCLC in this study than that previously observed with pretreated NSCLC (16% vs 53%–54% with ≥1% PD-L1 expression). In SCLC, responses were observed regardless of PD-L1 expression. ORR and median OS were similar in patients treated with 1 or ≥2 prior regimens. Rate of discontinuation due to treatment-related AEs ranged from 5% to 11%; there were 3 treatment-related deaths. Figure 1
Conclusion:
Durable objective responses were observed with nivolumab and nivolumab/ipilimumab in patients with previously treated SCLC, and safety profiles were consistent with other tumor types. Updated efficacy (including 2-year OS and DOR), safety, and additional subgroup analyses will be presented from the August 2016 DBL.
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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: 1
- Moderators:M. Reck, D.R. Spigel
- Coordinates: 12/06/2016, 16:00 - 17:30, Strauss 2
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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 - 16:06 | Author(s): D.R. Spigel
- Abstract
- Presentation
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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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 2
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OA03.03 - JAVELIN Solid Tumor: Safety and Clinical Activity of Avelumab (Anti-PD-L1) as First-Line Treatment in Patients with Advanced NSCLC (Abstract under Embargo until December 5, 7:00 CET) (ID 3717)
11:20 - 11:30 | Author(s): D.R. Spigel
- Abstract
- Presentation
Background:
Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody that has shown antitumour activity in various malignancies. We report safety and clinical activity of avelumab as first-line therapy in a cohort of patients with non-small–cell lung cancer (NSCLC) from a phase 1b trial (NCT01772004).
Methods:
Patients with advanced NSCLC not previously treated systemically for metastatic or recurrent disease, without an activating EGFR mutation or ALK rearrangement, and not preselected for PD-L1 expression, received avelumab 10 mg/kg IV over 1 hour Q2W until progression, unacceptable toxicity, or study withdrawal. Objective response rate (ORR) and progression-free survival (PFS) were evaluated by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0.
Results:
As of 23 Oct 2015, 145 patients had received avelumab (median 10 weeks of treatment; range 2-30) and were followed for a median of 13 weeks (range 0-31). Median age was 70 years (range 41-90), ECOG PS was 0 (31.0%) or 1 (69.0%), and tumour histology was adenocarcinoma (63.4%) or squamous (26.9%) in most patients. Eighty-two patients (56.6%) had a treatment-related (TR) AE; those occurring in ≥10% were infusion-related reaction (IRR; n=24, 16.6%) and fatigue (n=21, 14.5%). Thirteen patients (9.0%) had a grade ≥3 TRAE; only IRR and fatigue occurred in >1 patient (each n=3, 2.1%). Four patients (2.8%) had a potential immune-mediated TRAE, all grade 1-2 (pneumonitis n=3, 2.1%; hypothyroidism n=1, 0.7%). There were no treatment-related deaths. Among 75 patients with ≥3 months’ follow-up, unconfirmed ORR was 18.7% (95% CI: 10.6, 29.3) based on 1 complete response and 13 partial responses; 12 were ongoing. Thirty-four additional patients (45.3%) had stable disease as best response (disease control rate 64.0%). Updated analysis will be presented, including efficacy data with ≥3 months’ follow-up in all patients and PD-L1 analysis.
Conclusion:
First-line avelumab monotherapy showed clinical activity and was well-tolerated in patients with EGFR-wildtype/ALK-negative NSCLC unselected for PD-L1 expression. A phase 3 trial of avelumab vs platinum-doublet in first-line NSCLC is in progress. *Proposed nonproprietary name.
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OA03.05 - Analysis of Early Survival in Patients with Advanced Non-Squamous NSCLC Treated with Nivolumab vs Docetaxel in CheckMate 057 (Abstract under Embargo until December 5, 7:00 CET) (ID 4392)
11:45 - 11:55 | Author(s): D.R. Spigel
- Abstract
- Presentation
Background:
Nivolumab significantly improved OS versus docetaxel in patients with previously treated advanced non-squamous NSCLC (CheckMate 057; NCT01673867). Kaplan−Meier OS curves for nivolumab and docetaxel crossed at ~7 months, suggesting non-proportional hazards between arms.
Methods:
Post-hoc analyses were conducted to explore relationships between baseline patient/disease characteristics, including PD-L1 expression, and death within the first 3 months of treatment (3motx). Additionally, the association between PD-L1 expression level and magnitude of clinical benefit was explored.
Results:
During the first 3motx, risk of death (rDt) was numerically higher with nivolumab versus docetaxel (59 versus 44 deaths among 292 and 290 patients, respectively). Early deaths were most commonly attributed to disease progression (no treatment-related deaths occurred). At 3motx, 80% of nivolumab-treated patients (233/292) and 85% of docetaxel-treated patients (246/290) were alive. After 3motx, the rDt was consistently higher in the docetaxel arm. In univariate analyses, no single baseline factor, including PD-L1 expression, EGFR mutation, ECOG PS, or smoking status, reliably characterized the rDt within the first 3motx with nivolumab. Among patients alive >3 months, the OS HR (95% CI) favored nivolumab in the overall population (0.59 [0.47−0.74]) and PD-L1 non-expressors (PD-L1 expression <1%; 0.66 [0.45−0.97]). In a multivariate analysis, factors associated with higher rDt within the first 3motx on nivolumab versus docetaxel were ECOG PS=1, time since last treatment <3 months, and/or progressive disease as best response to prior treatment combined with lower or no PD-L1 expression. However, the majority of nivolumab-treated patients with these attributes (including PD-L1 non-expressors), did not die within the first 3motx and experienced subsequent benefit. PD-L1 expression was a continuum, ranging from 1 to 100%, with increasing expression associated with enhanced ORR/OS benefit from nivolumab.
Conclusion:
In CheckMate 057, the benefit−risk profile of nivolumab versus docetaxel was favorable across the overall patient population. During the first 3motx, a small difference in the number of deaths (n=15) was observed; thereafter the OS rate consistently favored nivolumab (2-year OS was >2-fold higher with nivolumab versus docetaxel). Patients with poorer prognostic factors and/or more aggressive disease combined with lower or no PD-L1 expression appeared to be at higher rDt within the first 3motx on nivolumab versus docetaxel. With the exception of PD-L1 status, these are recognized prognostic factors. While PD-L1 expression may help inform individual treatment decisions, PD-L1 status alone is not considered an appropriate biomarker for nivolumab treatment selection in pre-treated advanced NSCLC, but rather should be considered in the context of other patient/disease characteristics.
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OA05 - Treatment Advances in SCLC (ID 373)
- Event: WCLC 2016
- Type: Oral Session
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 2
- Moderators:A. Ardizzoni, J. Pujol
- Coordinates: 12/05/2016, 14:20 - 15:50, Strauss 2
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OA05.03 - Single-Agent Rovalpituzumab Tesirine, a Delta-Like Protein 3 (DLL3)-Targeted Antibody-Drug Conjugate (ADC), in Small-Cell Lung Cancer (SCLC) (ID 4648)
14:40 - 14:50 | Author(s): D.R. Spigel
- Abstract
- Presentation
Background:
SCLC is one of the most deadly malignancies. Rovalpituzumab tesirine (SC16LD6.5, Rova-T) is a first-in-class ADC directed against DLL3, a novel target identified in tumor initiating cells and expressed in over 80% of SCLC cases.
Methods:
Seventy-four patients with progressive SCLC after at least one previous systemic therapy were enrolled in a first-in-human study (NCT01901653), irrespective of DLL3 expression, including 68 at active doses of 0.2-0.4 mg/kg administered intravenously every 3 or 6 weeks. Available archived tumor tissue (n=48) was assessed retrospectively by immunohistochemistry for DLL3.
Results:
Among 60 evaluable subjects, active dose levels resulted in a confirmed objective response rate (ORR) of 18% and a confirmed clinical benefit rate (CBR; stable disease or better) of 68%. Among 26 evaluable subjects with DLL3 expression in at least 50% of tumor cells (DLL3-high), confirmed ORR and CBR were 39% and 89%, respectively. Median duration of response was 5.6 months. One-year survival rates among all and DLL3-high subjects were 18% and 32%, respectively. Among primary sensitive relapse patients, confirmed ORR and CBR among all subjects were 24% (8/33) and 67% (22/33); and among DLL3-high subjects were 53% (8/15) and 100% (15/15), with one-year survival rates of 17% and 33%, respectively. Among primary resistant/refractory relapse patients, confirmed ORR and CBR among all subjects were 12% (3/25) and 72% (18/25); and among DLL3-high subjects were 18% (2/11) and 73% (8/11), with one-year survival rates of 21% and 29%, respectively. The most common grade 3 or higher toxicities included thrombocytopenia (12%), serosal effusions (11%), and skin reactions (8%). ADC pharmacokinetics were linear with a terminal half-life of 10 - 14 days and anti-therapeutic antibodies did not develop
Conclusion:
Rovalpituzumab tesirine demonstrates encouraging single-agent anti-tumor activity with a manageable safety profile, including among patients with disease resistant or refractory to primary chemotherapy. Further development of rovalpituzumab tesirine in SCLC is warranted.
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OA05.05 - Randomized Phase 2 Study: Alisertib (MLN8237) or Placebo + Paclitaxel as Second-Line Therapy for Small-Cell Lung Cancer (SCLC) (ID 4855)
15:05 - 15:15 | Author(s): D.R. Spigel
- Abstract
- Presentation
Background:
Alisertib, an investigational selective Aurora A kinase inhibitor, showed single-agent antitumor activity in preclinical in vivo SCLC models and was synergistic with paclitaxel in this setting. We report the efficacy, quality of life (QoL), and safety from this study.
Methods:
Patients ≥18 years with SCLC relapsed <180 days after standard first-line platinum-based chemotherapy were randomized 1:1 to alisertib 40 mg orally twice-daily on days 1–3, 8–10, 15–17 + paclitaxel 60 mg/m[2] IV on days 1, 8, 15 (Arm A) or matched placebo + paclitaxel 80 mg/m[2] (Arm B) in 28-day cycles. Patients were stratified using an interactive voice response system (IVRS) by type of relapse post-frontline platinum (sensitive vs resistant/refractory) and presence/absence of brain metastases at baseline. Protocol Amendment 2 corrected the definition for relapse per standard guidance; stratification factors were corrected accordingly. Primary endpoint was progression-free survival (PFS) per stratified log-rank test. QoL outcomes were assessed per EORTC QLQ-C30 and -LC13.
Results:
178 patients were randomized, 89/89 to Arm A/B (median age 62/62 years). Survival, response, QoL, and safety results are presented in the Table. The analysis of PFS using IVRS stratification favored Arm A, as did the analysis per corrected stratification factors. Mean EORTC QLQ-C30 QoL scores were similar between arms, as were mean change-from-baseline values at end of treatment (-5.7 in Arm A vs -4 in Arm B). Figure 1
Conclusion:
Alisertib + paclitaxel shows favorable PFS over placebo + paclitaxel with both initial and updated IVRS stratification. A similar favorable trend was also observed for OS and ORR although not statistically significant. Comparable changes in QoL scores were observed from baseline in both arms. The alisertib + paclitaxel arm showed higher rates of AEs and discontinuation due to AEs. Updated survival analyses are pending.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-030 - nab-Paclitaxel/Carboplatin Induction Therapy in Squamous (SCC) NSCLC: Interim Quality of Life (QoL) Results From ABOUND.sqm (ID 4343)
14:30 - 14:30 | Author(s): D.R. Spigel
- Abstract
Background:
Despite a high symptom burden in many patients with advanced NSCLC, limited data exist on QoL with first-line chemotherapy. Here we report results of an interim QoL analysis in patients with SCC NSCLC treated with nab-paclitaxel/carboplatin in the induction part of the ongoing ABOUND.sqm study.
Methods:
Chemotherapy-naive patients with advanced SCC NSCLC received 4 cycles of induction therapy with nab-paclitaxel 100 mg/m[2] on days 1, 8, and 15 + carboplatin AUC 6 on day 1 (21-day cycles). Patients without progression after induction received (2:1) maintenance nab-paclitaxel 100 mg/m[2] on days 1 and 8 (21-day cycles) + best supportive care (BSC) or BSC alone until progression/unacceptable toxicity. The primary endpoint is progression-free survival (randomization to maintenance). Patient-reported QoL (exploratory endpoint) was assessed on day 1 of each cycle using the Lung Cancer Symptom Scale (LCSS) and Euro-QoL-5 Dimensions-5 Levels (EQ-5D-5L).
Results:
207 patients were treated in the induction phase. Median age was 68 years; 66% of patients were male, and 99% had an ECOG PS 0-1. Out of 200 patients treated for ≥ 2 cycles, 180 (90%) completed baseline + ≥ 1 postbaseline QoL assessments. The mean change from baseline in LCSS symptom burden index and total score ranged from 6.6%-10.3% and 5.5%-9.5%, respectively. Clinically meaningful improvements (≥ 10 mm [visual analog scale]) from baseline were observed in composite LCSS pulmonary symptom items of cough, shortness of breath, and hemoptysis in 46% of patients. For individual EQ-5D-5L dimensions, ≥ 82% of patients maintained/improved from baseline and ≥ 33% reported complete resolution (Table).Figure 1
Conclusion:
In this interim analysis, 4 cycles of nab-paclitaxel/carboplatin treatment led to clinically meaningful improvements in LCSS pulmonary symptom items. Complete resolution of problems reported at baseline in EQ-5D-5L dimensions was observed in ≥ 33% of patients at least once during treatment. NCT02027428
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-026 - Is Nivolumab Safe and Effective in Elderly and PS2 Patients with Non-Small Cell Lung Cancer (NSCLC)? Results of CheckMate 153 (ID 5383)
14:30 - 14:30 | Author(s): D.R. Spigel
- Abstract
Background:
CheckMate 153 (NCT02066636) is an ongoing, predominantly community-based, phase 3B/4 safety study of nivolumab in patients with previously treated metastatic NSCLC in the US/Canada. Here we report safety, efficacy, and patient-reported outcome (PRO) data for subgroups of patients aged ≥70 years or with a poor baseline ECOG PS (PS2).
Methods:
Patients were enrolled in four subgroups based on histology and prior regimen number; one subgroup enrolled patients with squamous (SQ) or non-SQ NSCLC, PS2, and ≥1 prior therapies. Data on elderly patients were pooled across subgroups. The primary objective was assessment of high-grade (grade 3–4 and 5) select (those with a potential immunologic cause) treatment-related AE (TRAE) incidences. Exploratory endpoints included efficacy, biomarkers, pharmacokinetics, and PROs.
Results:
Of 1,308 patients, 520 (40%) were aged ≥70 years and 108 (8%) had PS2. TRAE incidences for the age and PS subgroups were comparable with those for the overall population (table), as were select TRAE incidences for the subgroups. Estimated 6-month OS was lower with PS2 than PS0‒1, but similar between age subgroups and the overall population (table). Early PRO data revealed significant improvements overall in both age subgroups using LCSS and EQ-5D VAS, with younger patients showing greater improvement on some scales. Patients with SQ disease and PS2 generally reported stable quality-of-life/symptom control, whereas patients with non-SQ disease had statistically significant improvements on most scales. Updated data, including 1-year OS, will be presented.
Conclusion:
In this large study of advanced, previously treated, predominantly community-based patients with NSCLC, the nivolumab safety profile for age and PS subgroups was comparable with those for the overall population and from prior nivolumab NSCLC studies. OS was similar in younger and older patients, but lower in PS2 patients at early time points. Nivolumab appears to have similar risks/benefits in older and poorer PS patients as in the general population. Figure 1
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P3.02c-042 - IMpower110: Phase III Trial Comparing 1L Atezolizumab with Chemotherapy in PD-L1–Selected Chemotherapy-Naive NSCLC Patients (ID 5094)
14:30 - 14:30 | Author(s): D.R. Spigel
- Abstract
Background:
For patients with advanced NSCLC without genetic driver alterations, cisplatin/carboplatin+pemetrexed is a standard-of-care first-line (1L) treatment for non-squamous histology; and cisplatin/carboplatin+gemcitabine for squamous histology. Although immunotherapies targeting PD-L1/PD-1 are currently available for 2L+ NSCLC, chemotherapy remains the main 1L option despite poor survival and toxicities. Atezolizumab, an anti–PDL1 mAb, prevents PD-L1 from interacting with its receptors PD-1 and B7.1, restoring tumor-specific T-cell immunity. Clinical efficacy was demonstrated with atezolizumab in non-squamous and squamous NSCLC, with Phase I and II studies exhibiting durable responses and survival benefit that increases with higher PD-L1 expression on tumor cells (TC) and/or tumor-infiltrating immune cells (IC). IMpower110, a global Phase III randomized, multicenter, open-label trial, will evaluate efficacy and safety of atezolizumab vs cisplatin/carboplatin+pemetrexed or gemcitabine as 1L therapy for PD-L1–selected chemotherapy-naive patients with advanced non-squamous or squamous NSCLC, respectively.
Methods:
Eligibility criteria include stage IV non-squamous or squamous NSCLC, measurable disease (RECIST v1.1), ECOG PS 0-1, no prior chemotherapy for advanced NSCLC and centrally-assessed PD-L1 expression ≥1% on TC or IC (TC1/2/3 or IC1/2/3 with VENTANA SP142 IHC assay; expected prevalence, ≈65%). Exclusion criteria include active or untreated CNS metastases, prior immune checkpoint blockade therapy or autoimmune disease. Patients will be randomized 1:1 to receive atezolizumab or cisplatin/carboplatin+pemetrexed (non-squamous)/gemcitabine (squamous) for 4 or 6 21-day cycles. Patients in comparator arms can receive pemetrexed (non-squamous)/best supportive care (squamous) until RECIST v1.1 disease progression. Patients receiving atezolizumab may continue until loss of clinical benefit. Co-primary endpoints are PFS and OS. Key secondary efficacy endpoints include ORR, DOR, IRF-assessed PFS (RECIST v1.1) and TTD. Safety and PK will also be evaluated. Tumor biopsies at RECIST v1.1 progression will be assessed for immunologic biomarkers associated with responses to atezolizumab and to differentiate non-conventional responses from radiographic progression.Planned enrollment, N 570 Histology Non-squamous Squamous Experimental arm Atezolizumab (1200 mg q3w) Comparator arm Cisplatin (75 mg/m[2] IV q3w) + pemetrexed (500 mg/m[2] IV q3w) or Carboplatin (AUC 6 mg/mL/min IV q3w) + pemetrexed (500 mg/m[2] IV q3w) Cisplatin (75 mg/m[2] IV q3w) + gemcitabine (1200 mg/m[2] IV days 1, 8) or Carboplatin (AUC 5 mg/mL/min IV q3w) + gemcitabine (1000 mg/m[2] IV days 1, 8) Stratification factors Sex ECOG Histology (non-squamous vs squamous) PD-L1 expression by IHC ClinicalTrials.gov identifier NCT02409342
Results:
Section not applicable
Conclusion:
Section not applicable
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SC14 - Immunotherapy of NSCLC (ID 338)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:N. Rizvi, C. Zielinski
- Coordinates: 12/06/2016, 11:00 - 12:30, Hall C2
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SC14.03 - Combination Immunotherapy - Basic Considerations and First Outcomes (ID 6655)
11:40 - 11:55 | Author(s): D.R. Spigel
- Abstract
- Presentation
Abstract not provided
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