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Original Investigation
February 20, 2020

Phase 1 Trial of Pembrolizumab Administered Concurrently With Chemoradiotherapy for Locally Advanced Non–Small Cell Lung Cancer: A Nonrandomized Controlled Trial

Author Affiliations
  • 1Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, New Jersey
  • 2Department of Radiation Oncology, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
  • 3Department of Therapeutic Radiology, Smilow Cancer Center, Yale School of Medicine, Yale University, New Haven, Connecticut
  • 4Department of Biostatistics and Epidemiology, Rutgers School of Public Health, Piscataway, New Jersey
  • 5Biometrics Division, Rutgers Cancer Institute of New Jersey, Rutgers University, Piscataway, New Jersey
  • 6Section of Medical Oncology, Department of Medicine, Smilow Cancer Center, Yale School of Medicine, Yale University, New Haven, Connecticut
  • 7Division of Hematology Oncology, Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia
  • 8Department of Radiation Oncology, New York Proton Center, New York, New York
  • 9Department of Radiation Oncology, Winship Cancer Institute, Emory School of Medicine, Emory University Atlanta, Georgia
  • 10Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, Rutgers Robert Wood Johnson Medical School, Rutgers University
JAMA Oncol. Published online February 20, 2020. doi:10.1001/jamaoncol.2019.6731
Key Points

Question  What is the preliminary evidence of safety and tolerability of programmed cell death 1 inhibition concurrently with definitive chemoradiotherapy for stage III non–small cell lung cancer?

Findings  In this phase 1 nonrandomized controlled trial of chemoradiotherapy with concurrent programmed cell death 1 blockade, grade 4 pneumonitis was the predetermined dose-limiting toxic effect used to define safety. Programmed cell death 1 inhibition and chemoradiotherapy for stage III non–small cell lung cancer was tolerable and showed an 18% rate of grade 3 or greater immune-related adverse events, including grades 3 and 5 pneumonitis, grade 3 interstitial nephritis, and type 1 diabetes.

Meaning  First-line therapy with programmed cell death 1 inhibition and chemoradiotherapy for stage III non–small cell lung cancer appears to be tolerable and should continue to be evaluated in phase 2 and 3 clinical trials.

Abstract

Importance  Consolidative programmed death ligand-1 (PD-L) inhibition after chemoradiotherapy improves overall survival and progression-free survival (PFS) for stage III non–small cell lung cancer (NSCLC) and requires safety evaluation for incorporation of programmed cell death 1 (PD-1) inhibition at the onset of chemoradiotherapy.

Objective  To determine the safety and tolerability of PD-1 inhibition concurrently with definitive chemoradiotherapy for NSCLC.

Design, Setting, and Participants  This phase 1 prospective multicenter nonrandomized controlled trial using a 3 plus 3 design was performed from August 30, 2016, to October 24, 2018, with a median follow-up of 16.0 (95% CI, 12.0-22.6) months and data locked on July 25, 2019. Twenty-one participants had locally advanced, unresectable, stage III NSCLC as determined by multidisciplinary review, Eastern Cooperative Oncology Group performance status 0 or 1, and adequate hematologic, renal, and hepatic function. Data were analyzed from October 17, 2016, to July 19, 2019.

Interventions  Pembrolizumab was combined with concurrent chemoradiotherapy (weekly carboplatin and paclitaxel with 60 Gy of radiation in 2 Gy per d). Dose cohorts evaluated included full-dose pembrolizumab (200 mg intravenously every 3 weeks) 2 to 6 weeks after chemoradiotherapy (cohort 1); reduced-dose pembrolizumab (100 mg intravenously every 3 weeks) starting day 29 of chemoradiotherapy (cohort 2); full-dose pembrolizumab starting day 29 of chemoradiotherapy (cohort 3); reduced-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 4); and full-dose pembrolizumab starting day 1 of chemoradiotherapy (cohort 5). A safety expansion cohort of 6 patients was planned based on the maximum tolerated dose of pembrolizumab. Dose-limiting toxic effects were defined as pneumonitis of at least grade 4 within cycle 1 of pembrolizumab treatment.

Main Outcomes and Measures  Safety and tolerability of PD-1 inhibition with chemoradiotherapy for NSCLC. Secondary outcomes included PFS and pneumonitis rates.

Results  Among the 21 patients included in the analysis (11 female [52%]; median age, 69.5 [range, 53.0-85.0] years), no dose-limiting toxic effects in any cohort were observed. One case of grade 5 pneumonitis occurred in the safety expansion cohort with the cohort 5 regimen. Immune-related adverse events of at least grade 3 occurred in 4 patients (18%). Median PFS for patients who received at least 1 dose of pembrolizumab (n = 21) was 18.7 (95% CI, 11.8-29.4) months, and 6- and 12-month PFS were 81.0% (95% CI, 64.1%-97.7%) and 69.7% (95% CI, 49.3%-90.2%), respectively. Median PFS for patients who received at least 2 doses of pembrolizumab (n = 19) was 21.0 (95% CI, 15.3 to infinity) months.

Conclusions and Relevance  These findings suggest that combined treatment with PD-1 inhibitors and chemoradiotherapy for stage III NSCLC is tolerable, with promising PFS of 69.7% at 12 months, and requires further study.

Trial Registration  ClinicalTrials.gov Identifier: NCT02621398

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