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Background Long-term data with immune checkpoint inhibitors in non-small-cell lung cancer (NSCLC) are limited. Two phase III trials demonstrated improved overall survival (OS) and a favorable safety profile with the anti-programmed death-1 antibody nivolumab versus docetaxel in patients with previously treated advanced squamous (CheckMate 017) and nonsquamous (CheckMate 057) NSCLC. We report results from ≥3 years’ follow-up, including subgroup analyses of patients with liver metastases, who historically have poorer prognosis among patients with NSCLC. Patients and methods Patients were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks) until progression or discontinuation. The primary end point of each study was OS. Patients with baseline liver metastases were pooled across studies by treatment for subgroup analyses. Results After 40.3 months’ minimum follow-up in CheckMate 017 and 057, nivolumab continued to show an OS benefit versus docetaxel: estimated 3-year OS rates were 17% [95% confidence interval (CI), 14% to 21%] versus 8% (95% CI, 6% to 11%) in the pooled population with squamous or nonsquamous NSCLC. Nivolumab was generally well tolerated, with no new safety concerns identified. Of 854 randomized patients across both studies, 193 had baseline liver metastases. Nivolumab resulted in improved OS compared with docetaxel in patients with liver metastases (hazard ratio, 0.68; 95% CI, 0.50–0.91), consistent with findings from the overall pooled study population (hazard ratio, 0.70; 95% CI, 0.61–0.81). Rates of treatment-related hepatic adverse events (primarily grade 1–2 liver enzyme elevations) were slightly higher in nivolumab-treated patients with liver metastases (10%) than in the overall pooled population (6%). Conclusions After 3 years’ minimum follow-up, nivolumab continued to demonstrate an OS benefit versus docetaxel in patients with advanced NSCLC. Similarly, nivolumab demonstrated an OS benefit versus docetaxel in patients with liver metastases, and remained well tolerated. Clinical trial registration CheckMate 017: NCT01642004; CheckMate 057: NCT01673867.

Background Immunotherapy with or without chemo has improved survival vs chemo in 1L aNSCLC. NIVO + chemo showed encouraging activity in a phase 1 study in this setting. CheckMate 227 is a multi-part, randomized, open-label, phase 3 study evaluating NIVO-based regimens vs chemo. We present final results from Part 2, which evaluated NIVO + chemo vs chemo in 1L aNSCLC. Methods Pts (N = 755) with chemo-naive, stage IV or recurrent NSCLC, ECOG PS 0–1, and no sensitizing EGFR/ALK alterations were randomized 1:1 to receive every 3 weeks NIVO 360 mg + chemo or chemo. Pts were stratified by histology (squamous [SQ] vs non-squamous [NSQ]), sex, and PD-L1 expression ( Results Baseline characteristics were generally balanced. Minimum follow-up was 19.5 mo. In pts with NSQ NSCLC, no statistically significant improvement in OS was seen with NIVO + chemo vs chemo (HR, 0.86 [95.62% CI, 0.69–1.08; P=0.1859]); median OS was 18.8 mo vs 15.6 mo; 12-mo OS rates were 67.3% vs 59.2%. HR for OS was 0.81 (95% CI, 0.67–0.97) in all randomized pts; 0.69 (95% CI, 0.50–0.97) in pts with SQ NSCLC. Progression-free survival and objective response rates favored NIVO + chemo in NSQ, SQ, and all randomized pts (table). Grade 3–4 tx-related adverse events occurred in 45% and 35% of all pts treated with NIVO + chemo and chemo, respectively.TableLBA3 Efficacy outcomes with 1L NIVO + chemo vs chemo in pts with NSQ NSCLC, SQ NSCLC, and in all randomized ptsTableNSQ NSCLCSQ NSCLCAll Randomized PtsNIVO + chemoChemoNIVO + chemoChemoNIVO + chemoChemon=270n = 273n=107n = 105n=377n = 378OSEvents, n (%)156 (57.8)164 (60.1)68 (63.6)75 (71.4)224 (59.4)239 (63.2)Median, mo18.815.618.312.018.314.7HR (95% CI)0.86 (0.69–1.08)aP = 0.18590.69 (0.50–0.97)0.81 (0.67–0.97)12-mo OS rate, %67.359.266.148.566.956.2PFSEvents, n (%)187 (69.3)200 (73.3)79 (73.8)82 (78.1)266 (70.6)282 (74.6)Median, mo8.75.87.14.48.45.5HR (95% CI)0.67 (0.55–0.82)0.51 (0.37–0.70)0.62 (0.52–0.73)12-mo PFS rate, %39.525.731.79.337.321.3Objective response rate, n (%)130 (48.1)80 (29.3)64 (59.8)34 (32.4)194 (51.5)114 (30.2)a95.62% CI Conclusion CheckMate 227 Part 2 did not meet the primary endpoint of OS for NIVO + chemo vs chemo in NSQ NSCLC. Descriptive analyses showed longer OS with NIVO + chemo in all randomized pts and SQ NSCLC. No new safety signals were observed. Clinical trial identification NCT02477826; Release date: June 23, 2015. Editorial acknowledgement Writing and editorial assistance was provided by Namiko Abe, PhD, of Caudex, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure L. Paz-Ares: Honoraria (self): Roche, MSD, Lilly, Novartis, Boehringer Ingelheim, AstraZeneca, Amgen, Sanofi, Pharmamar, Pfizer, Bristol-Myers Squibb, Merck, Takeda, Celgene, Servier, Sysmex, Incyte, Ipsen, Adacap, Bayer, Blueprint; Leadership role: Altum Sequencing; Research grant / Funding (institution): MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb; Officer / Board of Directors: Genomica. T.E. Ciuleanu: Advisory / Consultancy: Astellas, Janssen, Bristol-Myers Squibb, Merck Serono, Amgen, Roche, Pfizer, Boehringer Ingelheim, Lilly, AstraZeneca, MSD, Sanofi, Novartis, Servier, AD Pharma. A. Pluzanski: Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Speaker Bureau / Expert testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche, Takeda; Travel / Accommodation / Expenses: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Roche. A. Nagrial: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche; Research grant / Funding (institution): Astra Zeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Roche. R. Kowalyszyn: Advisory / Consultancy: Astellas, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, MSD, Novartis; Research grant / Funding (institution): Novartis; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Lilly, MSD, Pfizer, Roche. C. Audigier-Valette: Honoraria (self): AbbVie, Pfizer; Honoraria (institution): Roche, MSD, Bristol-Myers Squibb, AstraZeneca; Advisory / Consultancy: Roche, MSD, Bristol-Myers Squibb, AstraZeneca, AbbVie, Pfizer. Y-L. Wu: Honoraria (self): AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche; Advisory / Consultancy: AstraZeneca, Boehringer Ingelheim, Roche; Research grant / Funding (institution): AstraZeneca, Boehringer Ingelheim, BMS, Roche; Non-remunerated activity/ies: AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche. H. Borghaei: Honoraria (self): University of Pennsylvania, CAR T Program, Takeda [Data and Safety Monitoring Board]; Advisory / Consultancy: Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio, GLG; Research grant / Funding (self): Millennium, Merck/Celgene, Bristol-Myers Squibb/Lilly. M.D. Hellmann: Advisory / Consultancy: Genentech, Bristol-Myers Squibb, Merck, AstraZeneca, Novartis, Janssen, Mirati, Syndax, Shattuck Labs, Immunai, Nektar, Blueprint Medicines; Research grant / Funding (institution): Bristol-Myers Squibb; Travel / Accommodation / Expenses: Bristol-Myers Squibb, AstraZeneca; Shareholder / Stockholder / Stock options: Shattuck Labs, Immunai. J. Brahmer: Advisory / Consultancy: Bristol-Myers Squibb, AstraZeneca, Genentech, Merck, Amgen. M. Reck: Honoraria (self): AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche; Advisory / Consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. S. Ramalingam: Honoraria (self): AstraZeneca, Bristol-Myers Squibb, Roche/Genentech, Loxo, Tesaro, Merck, Daichi; Advisory / Consultancy: Amgen, AbbVie, Lilly, Genentech, Takeda; Research grant / Funding (institution): Bristol-Myers Squibb, Amgen, AstraZeneca, Takeda, Advaxis, Tesaro, Merck. L. Zhang: Advisory / Consultancy: AstraZeneca, Bristol-Myers Squibb, MSD; Speaker Bureau / Expert testimony: AstraZeneca, Bristol-Myers Squibb, MSD, Roche; Research grant / Funding (institution): AstraZeneca, Bristol-Myers Squibb, Pfizer, Henrui Pharm. P. Bhagavatheeswaran: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F.E. Nathan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. K.J. O'Byrne: Advisory / Consultancy: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Novartis, Teva, Janssen-Cilag, Natera; Speaker Bureau / Expert testimony: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim, Janssen-Cilag, Mundipharma; Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim; Shareholder / Stockholder / Stock options: Carp Pharmaceuticals, Carpe Vitae Phaemaceuticals; Licensing / Royalties: Various patents issues with licensee as listed. Queensland University of Technology and Trinity College Dublin. All other authors have declared no conflicts of interest.

Background Part 1 of CheckMate 227 (NCT02477826), a phase III study in 1L NSCLC, has dual primary endpoints. The primary endpoint of progression-free survival (PFS) with NIVO + IPI vs chemo in patients (pts) with tumor mutational burden ≥ 10 mut/Mb was met, as reported previously. Here we present the primary endpoint of overall survival (OS) for NIVO + IPI vs chemo in pts with tumor PD-L1 expression ≥ 1%. Methods Pts were chemo-naive, with stage IV or recurrent NSCLC without EGFR or known ALK alterations, ECOG PS 0–1. Pts with PD-L1 ≥1% (n=1189) were randomized 1:1:1 to NIVO 3mg/kg Q2W + IPI 1mg/kg Q6W, NIVO 240mg Q2W, or histology-based chemo; pts with PD-L1 Results Baseline characteristics were balanced across tx arms. Minimum follow-up for the primary endpoint was 29.3mo. For pts with PD-L1 ≥ 1%, OS was significantly longer with NIVO + IPI vs chemo (HR 0.79, 97.72% CI: 0.65–0.96; P=0.007); PFS, objective response rates, and duration of response favored NIVO + IPI vs chemo. OS benefit was also observed in pts with PD-L1 Conclusions CheckMate 227 met its primary endpoint of significantly improved OS with NIVO + IPI vs chemo in 1L advanced NSCLC with PD-L1 ≥ 1%. OS was also improved with NIVO + IPI in PD-L1 Clinical trial identification NCT02477826; Release date: June 23, 2015. Editorial acknowledgement Writing and editorial assistance was provided by Namiko Abe, PhD, of Caudex, funded by Bristol-Myers Squibb. Legal entity responsible for the study Bristol-Myers Squibb. Funding Bristol-Myers Squibb. Disclosure S. Peters: Advisory / Consultancy, Research grant / Funding (institution): AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, Merck Sharp and Dohme, M. S.S. Ramalingam: Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Personal fees, advisory board: Amgen; Honoraria (self), Advisory / Consultancy, Personal fees, advisory board: AbbVie; Honoraria (self), Advisory / Consultancy, Personal fees, advisory board: Lilly; Honoraria (self), Advisory / Consultancy, Personal fees, advisory board: Genentech; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Personal fees, advisory board: Takeda; Honoraria (self), Personal fees: Loxo; Research grant / Funding (institution): Advaxis; Honoraria (self), Research grant / Funding (institution), Personal fees: Tesaro; Honoraria (self), Research grant / Funding (institution), Personal fees: Merck; Honoraria (self), Research grant / Funding (self), Personal fees: AstraZeneca. L. Paz-Ares: Advisory / Consultancy, Advisory board: Genomica; Honoraria (self), Personal fees: Lilly, MSD, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer, Blueprint, Bristol-Myers Squibb; Advisory / Consultancy, Scientific advice/speaker: Lilly, MSD, Roche, Pharmamar, Merck, AstraZeneca, Novartis, Boehringer Ingelheim, Celgene, Servier, Sysmex, Amgen, Incyte, Pfizer, Ipsen, Adacap, Sanofi, Bayer, Blueprint, Bristol-Myers Squibb; Officer / Board of Directors, Co-founder and board member: Altum Sequencing; Research grant / Funding (institution), Grant: MSD, AstraZeneca, Pfizer, Bristol-Myers Squibb. H. Sakai: Research grant / Funding (institution), Grant: Ono Pharmaceutical Company, Bristol-Myers Squibb Company, AstraZeneca, Chugai Pharmaceutical Company, Merck & Co, Merck KGaA; Honoraria (self), Personal fees: Ono Pharmaceutical Company, Bristol-Myers Squibb Company, AstraZeneca, Chugai Pharmaceutical Company, Merck & Co, Merck KGaA. A. Vergnenegre: Honoraria (self), Advisory / Consultancy, Personal fees, travels for medical conferences and fees for consulting: Bristol-Myers Squibb, MSD, AstraZeneca. M. Reck: Honoraria (self), Advisory / Consultancy, Honoraria for lectures and consultancy: AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Lilly, Merck, MSD, Novartis, Pfizer, Roche. H. Borghaei: Research grant / Funding (institution): Millennium, Merck/Celgene, Bristol-Myers Squibb/Lilly; Advisory / Consultancy: BMS, Lilly, Genentech, Celgene, Pfizer, Merck, EMD-Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bio, Diiachi; Advisory / Consultancy, Data Safety and Monitoring Board: University of Pennsylvania, CAR T Program; Takeda; Full / Part-time employment: Fox Chase Cancer Center. J.R. Brahmer: Advisory / Consultancy, Research grant / Funding (institution), Grant, advisory board: Bristol-Myers Squibb; Advisory / Consultancy, Advisory board: AstraZeneca, Genentech, Merck. K.J. O'Byrne: Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory board and speaker bureau fees and travel grants to national and international meetings: Bristol-Myers Squibb, Pfizer, AstraZeneca, MSD, Roche-Genentech, Boehringer Ingelheim; Advisory / Consultancy, Advisory board: Novartis, Teva, Natera; Advisory / Consultancy, Speaker Bureau / Expert testimony, Advisory board and speaker bureau fees: Janssen-Cilag; Speaker Bureau / Expert testimony, Speaker bureau: Mundipharma; Shareholder / Stockholder / Stock options, Shareholder: Carp Pharmaceuticals, Carpe Vitae Pharmaceuticals; Licensing / Royalties, Various patents issues with licensee as listed: Queensland University of Technology and Trinity College Dublin. W.J. Geese: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. P. Bhagavatheeswaran: Shareholder / Stockholder / Stock options, Full / Part-time employment: Bristol-Myers Squibb. F.E. Nathan: Full / Part-time employment: Bristol-Myers Squibb. M.D. Hellmann: Advisory / Consultancy, Fees for consulting: Genentech, Merck, Novartis, Janssen, Mirati, Syndax, Nektar, Blueprint Medicines; Advisory / Consultancy, Research grant / Funding (institution), Research grant to institution, fees for consulting and travel (grant, personal fees, non-financial support): Bristol-Myers Squibb; Advisory / Consultancy, Fees for consulting and travel: AstraZeneca; Advisory / Consultancy, Fees for consulting and equity: Shattuck Labs, Immunai; Licensing / Royalties, Patent filed by Memorial Sloan Kettering related to the use of tumor mutation burden to predict response to immunotherapy: PGDx. All other authors have declared no conflicts of interest.

Purpose BMS-936558 is a fully human monoclonal antibody that blocks the PD-1 co-inhibitory receptor expressed by activated T cells. We report here the activity and safety of BMS-936558 in pretreated pts with advanced NSCLC, a tumor not previously considered responsive to immunotherapy. Methods BMS-936558 was administered IV q2wk to pts with various solid tumors at 1 - 10 mg/kg during dose escalation and/or cohort expansion. Pts with advanced NSCLC previously treated with at least 1 prior line of therapy were eligible. Pts received up to 12 cycles (4 doses/cycle) of treatment or until unacceptable toxicity, confirmed progressive disease, or complete response. Clinical activity was assessed by RECIST v1.0. Results As of Feb 24, 2012, 122 NSCLC pts had received BMS-936558 at 1 (n = 31), 3 (n = 33), or 10 mg/kg (n = 58). ECOG performance status was ≤1 for 117/122 pts; 67/122 pts had received ≥3 prior therapies. Median duration of therapy was 12 weeks (range 2 - 101.3 wks). Common drug-related AEs in NSCLC pts were fatigue (18%), decreased appetite (10%), anemia (8%), and nausea (7%). The incidence of grade 3–4 related AEs was 8%. There were 2 drug-related deaths from pneumonitis. Of 76 evaluable pts, 14 had a partial response (PR) (Table); all 14 were treated ≥24 wk, and 8 had responses of ≥24 wk. 5 Five pts had stable disease (SD) lasting ≥24 wk. Additionally, 3 pts had a persistent decrease in target lesion tumor burden in the presence of new lesions and were not categorized as responders. Conclusions BMS-936558 had an acceptable risk: benefit profile in previously treated, advanced NSCLC. Activity in squamous NSCLC was particularly intriguing. Additional long-term follow-up data will be reported. Dose, mg/kg No. pts a ORR, No. pts (%) [95% CI] PFSR at 24 wks, % [95% CI] 1 18 1 (6) [0.1 - 27] 16 [0 - 34] 3 19 6 (32) [13 - 57] 41 [18 - 64] 10 39 7 (18) [8 - 34] 24 [11 - 38] All 76 b 14 (18) [11 - 29] 26 [16 - 36] All–Nonsquamous 56 7 (13) [5 - 24] 22 [11 - 34] All–Squamous 18 6 (33) [13 - 59] 33 [12 - 55] a Response-evaluable pts dosed by 07/01/2011 b Includes 2 pts with unknown histology, 1 with PR ORR = objective response rate ([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate Disclosure L. Horn: Consultant or Advisory Role: OSI/Astellas (myself, uncompensated). D. Spigel: Consultant or Advisory Role: Bristol-Myers Squibb (myself, uncompensated). L.V. Sequist: Consultant or Advisory Role: Clovis, Celgene, GlaxoSmithKline (myself, compensated); Daiichi-Sankyo, Merrimack (myself, uncompensated). J.M. Wigginton: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). G. Kollia: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). A. Gupta: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). All other authors have declared no conflicts of interest.

Aim: Robust responses to nivolumab (Nivo, anti-PD1 antibody) are seen in both melanomas and NSCLCs. Both of these cancers are characterized by high somatic mutation burden, suggesting a potential link between mutational burden and immunogenicity. Since smoking-related NSCLCs have significantly greater mutation burden compared to never smokers, we hypothesized that smoking history may be associated with response to nivolumab in pts with NSCLCs. Methods: Smoking status, histology, and EGFR/KRAS genotype were recorded from 88 of 129 pretreated, advanced NSCLCs treated with Nivo monotherapy at 5 of 11 centers that participated in a previously reported study (NCT00730639, Topalian et al, NEJM 2012). Self-reported smoking history was categorized as never ( 5 pk-yrs, quit > 1 yr prior), or current smokers. In smokers, time-since-quitting was also recorded. Response was assessed every 8 wks by RECIST v1.0. Associations between smoking, histology, genotype, and response were assessed using the Fisher's exact, unpaired T-, log-rank tests. Results: The response rate was significantly higher in former/current smokers (20/75, 27%, 95% CI 17-38%) vs minimal/never smokers (0/13, 0%, 95% CI 0-25%) (p = 0.034). Responders had significantly more tobacco exposure than non-responders (median 50 pk-yrs [range 15-150] vs 36 pk-yrs [range 0-100], p=0.036). Among smokers, there was no association between response and time-since-quitting (Current smokers ORR 27%; Quit 1-15 yrs ago 24%; Quit >15 yrs ago 24%, p=0.18). There was no significant difference in response rate in adeno vs squamous histology (16 vs 21%, p=0.58). In adenos, response rates in EGFR muts vs KRAS muts vs all others were 1/9 vs 3/13 vs 4/27; the one EGFR mut responder was a 40 pk-yr current smoker. Conclusions: In advanced NSCLCs, the response rate to Nivo was significantly higher in former/current smokers compared to never/minimal smokers. There were no objective responses in never or minimal smokers in this subset of pts. Smoking history should be considered as a stratification factor for trials of PD-1 pathway inhibitors in lung cancer. Further work is needed to identify the underlying basis of this differential response rate. Disclosure: S.J. Antonia: Dr. Antonia receives research funding and/or serves as an advisor for Bristol-Myers Squibb. L. Horn: Dr. Horn receives research funding and/or serves as an advisor for Bristol-Myers Squibb; J.R. Brahmer: Dr. Brahmer receives research funding and serves as an advisor for Bristol-Myers Squibb; S. Gettinger: Dr. Gettinger receives research funding and serves as an advisor for Bristol-Myers Squibb; C. Harbison: Dr. Harbison is an employee and stock holder of Bristol-Myers Squibb; N. Rizvi: Dr. Rizvi receives research funding and serves as an advisor for Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

Aim: We report interim data from a phase 1 study of nivolumab (N), a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, combined with PT-DC or ERL in advanced chemotherapy-naive NSCLC patients (pts). Methods: Pts (n = 56) were assigned by histology to receive N 10 mg/kg IV Q3W + concurrent IV gemcitabine 1250 mg/m2 + cisplatin 75 mg/m2 (squamous [sq]) or pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 (non-sq), or N 5 or 10 mg/kg IV Q3W + IV paclitaxel 200 mg/m2 + carboplatin AUC6 (sq + non-sq). N + PT-DC was given for 4 cycles, with continued N to progression/unacceptable toxicity. EGFR mutant (EGFR MT) NSCLC pts (n = 21) received N 3 mg/kg IV Q2W + ERL 150 mg PO daily until progression/unacceptable toxicity. Objective response rate (ORR) was assessed by RECIST 1.1. Results: Across N + PT-DC arms (median follow-up [mF/U] 75 wks), grade 3–4 related AEs occurred in 45% of pts (25–73% across arms); 4 pts (7%) had grade 3–4 pneumonitis; 0–33% discontinued due to related AEs, any-grade pneumonitis (7%) most common. ORR with N + PT-DC was 33–47%; PD as best overall response (BOR) was infrequent (7%). Progression-free survival (PFS) rate at wk 24 was 38–71%; 1-yr OS rate was 50–87%. With N + ERL (mF/U 72 wks), grade 3–4 related AEs occurred in 5 pts; no pneumonitis was observed. Related AEs led to discontinuation in 4 pts (grade 3 AST ↑, grade 3 diarrhea, grade 2 nephritis, grade 2 flushing). ORR was 19% (median duration of response [DOR] not reached; range 60.1, 72.3+ wks); 24-wk PFS rate was 51%. Three of 20 pts (15%) with acquired ERL resistance achieved PR (DOR 60.1, 64.6 + , 70+ wks; 2 ongoing); 9/20 pts had BOR of SD, with 3/9 not progressed (time to progression/death 9.9+–53 wks); 1 pt had an ongoing unconventional response. One pt was EGFR TKI naive and achieved PR (DOR 72.3+ wks; ongoing). Conclusions: N + PT-DC demonstrated acceptable antitumor activity and safety reflecting additive nivolumab and PT-DC toxicities in pts with advanced NSCLC. N + ERL may provide durable clinical benefit and an acceptable safety profile in TKI-refractory, EGFR MT pts. These data support further evaluation of nivolumab combination regimens in pts with advanced NSCLC. Disclosure: S. Gettinger: Consultant advisor BMS; Honoraria for BMS advisory board; N. Rizvi: Consultant Advisor-BMS; Honoraria-BMS, Medimmune, Genentech/Roche; L.Q. Chow: BMS Stock; Research Funding-Bristol-Myers Squibb funding goes to University of Washington; H. Borghaei: Consultant advisor-Genentech, BMS; Research Funding- Pfizer, Arisaph, Millenium; Honoraria-Genentech; J.R. Brahmer: Consultant advisor BMS; Stock BMS; Research Funding BMS; R. Juergens: Research funding BMS; F.A. Shepherd: Consultant advisor (compensated), honoraria-BMS; J. Goldman: Research funding-BMS, Genentech; Y. Shen: BMS Employee; BMS Stock; C. Harbison: BMS-employee, stock; A. Chen: BMS-employee, stock; S.J. Antonia: Consultant advisor, honoraria, research funding for BMS MedImmune provides funding for clinical trials. All other authors have declared no conflicts of interest.

Aim: This ongoing Phase I, multicenter, open-label study (NCT01693562) evaluates the safety and efficacy of MEDI4736 in patients (pts) with multiple solid tumor types including non-small cell lung cancer (NSCLC). MEDI4736 is a human IgG1 mAb, engineered to prevent ADCC activity, that blocks PD-L1 binding to PD-1 and CD-80. PD-L1 is expressed in many NSCLC tumors and may be associated with poor prognosis. Methods: MEDI4736 was administered IV every 2 weeks (q2w) or every 3 weeks (q3w) using a standard 3 + 3 dose escalation (6 dose levels: 0.1–10 mg/kg q2w; 15 mg/kg q3w). In dose expansion, NSCLC pts were assigned to cohorts by histology and line of therapy and administered MEDI4736 10 mg/kg q2w. Retreatment was permitted for progression after 12 months of therapy. Response is assessed by immune-related response criteria in escalation and RECIST v1.1 in expansion. Results: As of 14 April 2014, 114 NSCLC pts have been treated with MEDI4736 in dose escalation and expansion cohorts. Of the 101 pts treated at the 10 mg/kg q2w dose (median 3 doses received; range 1–14), mean age 63 y (37–83), all were PS 0–1, with a median of 2.5 prior treatments (range1–8). In this group, treatment-related adverse events (AEs) were reported in 20% of pts; most frequently dyspnea (16%), fatigue (15%) and nausea (15%). Grade ≥ 3 treatment-related AEs were reported in 4 pts. AEs led to study discontinuation in 6 pts, none of which were treatment-related. Pneumonitis (grade 2) occurred in 1 pt. With a median follow up of 10 wks, 46 pts were followed ≥ 12 wks. Objective response + stable disease was observed in 18 pts to date. While some responses or stabilization were reported at first assessment (6 wks), others appeared following initial progression. Benefit was durable; 72/114 pts remain on study (including 4 pts >52 wks) at data cutoff. Assessment of clinical activity by PD-L1 expression, underlying mutation, smoking history, and line of therapy continues. Conclusions: Durable clinical activity has been observed with manageable AEs, no grade ≥3 pneumonitis, and no colitis of any grade. Further development of MEDI4736 alone and in combination is ongoing in NSCLC. Disclosure: S. Antonia: Received honoraria from BMS and MedImmune/AstraZeneca for work related to designing, implementing, and analyzing various clinical trials. MedImmune considers research funding received for conduct of a MedImmune-sponsored study as conflict of interest; Ou: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; S. Khleif: MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest. I also function as a clinical advisor; J.R. Brahmer: My institution receives funding for the conduct of a MedImmune-sponsored study. MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest; A. Blake-Haskins: Employee of Medimmune and own stock/stock options in AstraZeneca; P.B. Robbins: Employee of Medimmune and own stock/stock options in AstraZeneca; X. Li: Employee of Medimmune and own stock/stock options in AstraZeneca; J. Vasselli: Employee of Medimmune and own stock/stock options in AstraZeneca; N. Rizvi: I receive consulting income from MedImmune, Roche, Merck and BMS MedImmune considers the research funding received for the conduct of a MedImmune-sponsored study as conflict of interest.

Purpose Blockade of PD-1, a co-inhibitory receptor expressed by activated T cells, can overcome immune resistance and mediate tumor regression. This study describes the activity and safety of BMS-936558, an anti-PD-1 monoclonal antibody, in pts with advanced cancers. Methods Pts received BMS-936558 IV q2wk at 0.1 - 10 mg/kg during dose escalation and/or cohort expansion. Tumors were assessed by RECIST v1.0. Pts received up to 12 cycles (4 doses/cycle) or until unacceptable toxicity, confirmed progressive disease, or complete response. Results As of Feb 24, 2012, 296 pts with melanoma (MEL, n = 104), non-small cell lung (NSCLC, n = 122), renal cell (RCC, n = 34), colorectal (n = 19), and prostate (n = 17) cancer were treated. Median duration of therapy was 16 wks (range 2.0 - 121.7 wks). MTD was not reached. Grade ≥3 drug-related AEs occurred in 14% of pts. AEs of special interest included pneumonitis, vitiligo, colitis, hepatitis, hypophysitis, and thyroiditis. There were 3 deaths due to pneumonitis. In evaluable pts, objective responses (ORs) or prolonged stable disease was observed in MEL, RCC, and NSCLC (Table). Some had a persistent reduction in overall tumor burden in the presence of new lesions and were not categorized as responders. To assess PD-1 ligand (PD-L1) as a potential predictive molecular marker, immunohistochemistry was performed on pretreatment tumor biopsies from 42 pts. Of 25 pts with PD-L1(+) tumors, 9 (36%) achieved OR vs 0/17 with PD-L1(-). Conclusions BMS-936558 produces durable activity in advanced NSCLC, MEL, and RCC, supporting further clinical development. Preliminary data suggest a relationship between PD-L1 expression status on tumor cells and OR. Additional long-term follow-up data will be reported. Tumor type Dose, mg/kg No. pts a ORR, No. pts (%) [95% CI] SD ≥24 wks, No. pts (%) [95% CI] PFSR at 24 wks, % [95% CI] MEL 0.1 - 10 94 26 (28) * [19 - 38] 6 (6) [2 - 13] 41 [30 - 51] NSCLC 1 - 10 76 14 (18) [11 - 29] 5 (7) [2 - 15] 26 [16 - 36] RCC 1 - 10 33 9 (27) * [13 - 46] 9 (27) [13 - 46] 56 [39 - 73] a Response-evaluable pts dosed by 07/01/2011 * 1 CR ORR = objective response rate ([{CR + PR} ÷ n] × 100); PFSR = progression-free survival rate; SD = stable disease Disclosure S.L. Topalian: Consultant/Advisory Role: Bristol-Myers Squibb (myself, uncompensated); Amplimmune Inc (immediate family member, compensated). Research Funding: Bristol-Myers Squibb. F.S. Hodi: Consultant or Advisory Role: Bristol-Myers Squibb (myself, uncompensated). Research Funding: Bristol-Myers Squibb (myself). D.F. McDermott: Advisory Board Role: Bristol-Myers Squibb (Ad board participation). D.C. Smith: Research Funding: BMS Oncology (myself). J.M. Taube: Research Funding: Bristol-Myers Squibb (myself). A. Gupta: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). J.M. Wigginton: Employment or Leadership Role: Bristol-Myers Squibb (employment, myself, compensated). Stock Ownership: Bristol-Myers Squibb (myself). M. Sznol: Consultant or Advisory Role: Bristol-Myers Squibb (myself, compensated). Research Funding: Bristol-Myers Squibb (clinical trial funding, myself). All other authors have declared no conflicts of interest.