Allen C. Chen

First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer

BACKGROUND Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non–small‐cell lung cancer (NSCLC). In an open‐label phase 3 trial, we compared first‐line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD‐L1)–positive NSCLC. METHODS We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD‐L1 tumor‐expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum‐based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression‐free survival, as assessed by means of blinded independent central review, among patients with a PD‐L1 expression level of 5% or more. RESULTS Among the 423 patients with a PD‐L1 expression level of 5% or more, the median progression‐free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment‐related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment‐related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. CONCLUSIONS Nivolumab was not associated with significantly longer progression‐free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD‐L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol‐Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533.)

Nivolumab in Combination With Platinum‐Based Doublet Chemotherapy for First-Line Treatment of Advanced Non–Small-Cell Lung Cancer

PURPOSE Nivolumab, a fully human immunoglobulin G4 programmed death-1 immune checkpoint inhibitor antibody, has demonstrated improved survival in previously treated patients with advanced non-small-cell lung cancer (NSCLC). CheckMate 012, a phase I, multicohort study, was conducted to explore the safety and efficacy of nivolumab as monotherapy or combined with current standard therapies in first-line advanced NSCLC. Here, we report results for nivolumab plus platinum-based doublet chemotherapy (PT-DC). PATIENTS AND METHODS Patients (N = 56) received nivolumab (intravenously) plus PT-DC concurrently every 3 weeks for four cycles followed by nivolumab alone until progression or unacceptable toxicity. Regimens were nivolumab 10 mg/kg plus gemcitabine-cisplatin (squamous) or pemetrexed-cisplatin (nonsquamous) or nivolumab 5 or 10 mg/kg plus paclitaxel-carboplatin (all histologies). The primary objective was to assess safety and tolerability. Secondary objectives included objective response rate and 24-week progression-free survival rate (per Response Evaluation Criteria in Solid Tumors version 1.1); exploratory objectives included overall survival (OS) and response by tumor programmed death ligand-1 expression. RESULTS No dose-limiting toxicities occurred during the first 6 weeks of treatment. Forty-five percent of patients (25 of 56 patients) reported grade 3 or 4 treatment-related adverse events (AEs); 7% of patients (n = 4) had pneumonitis. Twenty-one percent of patients (n = 12) discontinued all study therapy as a result of treatment-related AEs. Objective response rates for nivolumab 10 mg/kg plus gemcitabine-cisplatin, nivolumab 10 mg/kg plus pemetrexed-cisplatin, nivolumab 10 mg/kg plus paclitaxel-carboplatin, and nivolumab 5 mg/kg plus paclitaxel-carboplatin were 33%, 47%, 47%, and 43%, respectively; 24-week progression-free survival rates were 51%, 71%, 38%, and 51%, respectively; 2-year OS rates were 25%, 33%, 27%, and 62%, respectively. Responses were achieved regardless of tumor programmed death ligand-1 expression. CONCLUSION The safety profile of nivolumab plus PT-DC was consistent with that expected for individual agents; however, treatment discontinuation related to AEs was greater with the combination. Encouraging activity was observed, especially for the nivolumab 5 mg/kg plus paclitaxel-carboplatin group, with a 2-year OS rate of 62%.

Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma

BACKGROUND Nivolumab plus ipilimumab produced objective responses in patients with advanced renal‐cell carcinoma in a pilot study. This phase 3 trial compared nivolumab plus ipilimumab with sunitinib for previously untreated clear‐cell advanced renal‐cell carcinoma. METHODS We randomly assigned adults in a 1:1 ratio to receive either nivolumab (3 mg per kilogram of body weight) plus ipilimumab (1 mg per kilogram) intravenously every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks, or sunitinib (50 mg) orally once daily for 4 weeks (6‐week cycle). The coprimary end points were overall survival (alpha level,0.04), objective response rate (alpha level,0.001), and progression‐free survival (alpha level,0.009) among patients with intermediate or poor prognostic risk. RESULTS A total of 1096 patients were assigned to receive nivolumab plus ipilimumab (550 patients) or sunitinib (546 patients); 425 and 422, respectively, had intermediate or poor risk. At a median follow‐up of 25.2 months in intermediate‐ and poor‐risk patients, the 18‐month overall survival rate was 75% (95% confidence interval [CI], 70 to 78) with nivolumab plus ipilimumab and 60% (95% CI, 55 to 65) with sunitinib; the median overall survival was not reached with nivolumab plus ipilimumab versus 26.0 months with sunitinib (hazard ratio for death, 0.63; P<0.001). The objective response rate was 42% versus 27% (P<0.001), and the complete response rate was 9% versus 1%. The median progression‐free survival was 11.6 months and 8.4 months, respectively (hazard ratio for disease progression or death, 0.82; P=0.03, not significant per the prespecified 0.009 threshold). Treatment‐related adverse events occurred in 509 of 547 patients (93%) in the nivolumab‐plus‐ipilimumab group and 521 of 535 patients (97%) in the sunitinib group; grade 3 or 4 events occurred in 250 patients (46%) and 335 patients (63%), respectively. Treatment‐related adverse events leading to discontinuation occurred in 22% and 12% of the patients in the respective groups. CONCLUSIONS Overall survival and objective response rates were significantly higher with nivolumab plus ipilimumab than with sunitinib among intermediate‐ and poor‐risk patients with previously untreated advanced renal‐cell carcinoma. (Funded by Bristol‐Myers Squibb and Ono Pharmaceutical; CheckMate 214 ClinicalTrials.gov number, NCT02231749.)

1054PDNIVOLUMAB (ANTI-PD-1; BMS-936558, ONO-4538) IN COMBINATION WITH PLATINUM-BASED DOUBLET CHEMOTHERAPY (PT-DC) OR ERLOTINIB (ERL) IN ADVANCED NON-SMALL CELL LUNG CANCER (NSCLC)

ABSTRACT 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.