Gubens, M. A.Sequist, L. V.Stevenson, J. P.Powell, S. F.Villaruz, L. C.Gadgeel, S. M.Langer, C. J.Patnaik, A.Borghaei, H.Jalal, Shadia I.Fiore, J.Saraf, S.Raftopoulos, H.Gandhi, L.2019-01-242019-01-242019Gubens, M. A., Sequist, L. V., Stevenson, J. P., Powell, S. F., Villaruz, L. C., Gadgeel, S. M., … Gandhi, L. (2019). Pembrolizumab in Combination with Ipilimumab as Second-Line or Later Therapy for Advanced Non–Small-Cell Lung Cancer: KEYNOTE-021 Cohorts D and H. Lung Cancer. https://doi.org/10.1016/j.lungcan.2018.12.015https://hdl.handle.net/1805/18220Objectives Combination immunotherapy may result in improved antitumor activity compared with single-agent treatment. We report results from dose-finding and dose-expansion cohorts of the phase 1/2 KEYNOTE-021 study that evaluated combination therapy with anti‒programmed death 1 (PD-1) antibody pembrolizumab plus anti‒cytotoxic T-lymphocyte antigen-4 (CTLA-4) antibody ipilimumab in patients with previously treated advanced non–small-cell lung cancer (NSCLC). Materials and Methods Eligibility criteria stipulated histologically/cytologically confirmed advanced NSCLC and treatment failure on ≥1 prior systemic therapy (platinum-based chemotherapy or targeted therapy for patients with EGFR/ALK aberrations). In the dose-finding cohort, patients initially received pembrolizumab 10 mg/kg plus ipilimumab 1 or 3 mg/kg once every 3 weeks for 4 cycles followed by pembrolizumab 10 mg/kg monotherapy for up to 2 years. Based on emerging published data, subsequent patients received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg. Objective response rate (ORR; primary efficacy endpoint) was assessed per RECIST version 1.1 by blinded, independent central review. Phase 2 hypothesis that ORR would be greater than the 20% rate for historical controls was evaluated using the exact binomial test. Results Fifty-one patients were enrolled; 71% received ≥2 prior lines of therapy. No dose-limiting toxicities occurred at any dose level. Among patients who received pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg (n = 44), ORR was 30% (95% CI, 17%–45%), but not statistically significantly >20% (P = 0.0858). Median progression-free survival in this group was 4.1 (95% CI, 1.4–5.8) months; median overall survival was 10.9 (95% CI, 6.1–23.7) months. With pembrolizumab 2 mg/kg plus ipilimumab 1 mg/kg, incidences of treatment-related adverse events, grade 3–5 treatment-related adverse events, and immune-mediated adverse events and infusion reactions were 64%, 29% and 42%, respectively. Conclusions In patients with heavily pretreated advanced NSCLC, pembrolizumab plus ipilimumab showed evidence of antitumor activity, but was associated with meaningful toxicity.enPublisher Policydrug therapycombinationcarcinomaArticle