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

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. 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. This phase 1 nonrandomized controlled trial assesses the safety and tolerability of programmed cell death 1 inhibition concurrently with definitive chemoradiotherapy compared with programmed cell death 1 inhibition and radiotherapy in patients with non-small cell lung cancer. (c) 2020 American Medical Association. All rights reserved.