Pembrolizumab in combination with ipilimumab as second-line or later therapy for advanced non–small-cell lung cancer: KEYNOTE-021 cohorts D and H

Matthew A. Gubens, Lecia V. Sequist, James P. Stevenson, Steven F. Powell, Liza C. Villaruz, Shirish M. Gadgeel, Corey J. Langer, Amita Patnaik, Hossein Borghaei, Shadia I. Jalal, Joseph Fiore, Sanatan Saraf, Harry Raftopoulos, Leena Gandhi

Research output: Contribution to journalArticle

7 Scopus citations


Objectives: 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.

Original languageEnglish (US)
Pages (from-to)59-66
Number of pages8
JournalLung Cancer
StatePublished - Apr 2019



  • Combination drug therapy
  • Ipilimumab
  • Non-small-cell lung carcinoma
  • Pembrolizumab

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine
  • Cancer Research

Cite this

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, S. I., Fiore, J., Saraf, S., Raftopoulos, H., & 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, 130, 59-66.