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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Jabbour reported receiving grants and personal fees from Merck & Co during the conduct of the study and grants and personal fees from Merck & Co outside the submitted work. Dr Berman reported receiving nonfinancial support from Merck & Co during the conduct of the study and personal fees from IMX Medical, Varian Medical Systems, AstraZeneca, and Imedex outside the submitted work. Dr Decker reported receiving grants from Merck & Co during the conduct of the study and grants and personal fees from AstraZeneca and personal fees from Regeneron Pharmaceuticals, Inc outside the submitted work. Dr Gettinger reported receiving personal fees from Merck & Co during the conduct of the study and other from Bristol-Myers Squibb, Nektar, Genentech/Roche, and Iovance outside the submitted work. Dr Aggarwal reported receiving consulting fees from Bristol-Myers Squibb, AstraZeneca, Roche, Merck & Co, Eli Lilly and Company, and Celgene during the conduct of the study. Dr Langer reported receiving grants and personal fees from Merck & Co during the conduct of the study, personal fees from AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, and Eli Lilly and Company, and grants from Advantagene, Inc, Inovio Pharmaceuticals, Inc, and Trizell, Ltd, outside the submitted work; and serving on data-safety monitoring committees for Eli Lilly and Company and SWOG (formerly Southwest Oncology Group). Dr Simone reported receiving an honorarium from Varian Medical Systems outside the submitted work. Dr Bradley reported receiving personal fees from AstraZeneca outside the submitted work. Dr Aisner reported receiving grants from Merck & Co during the conduct of the study and personal fees from Serono AG outside the submitted work. Dr Malhotra reported receiving personal fees from Pfizer, Inc, and AstraZeneca outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Development of Adverse Events

A, Time to immune-related adverse events (IRAEs) including pneumonitis in 14 patients who developed IRAEs of at least grade 2. B and C, Axial and coronal computed tomographic (CT) images from the radiotherapy plan demonstrating radiation distribution targeting non-small cell lung cancer in the left lung. D, Axial (1D) CT image at time of diagnosis of pneumonitis showing bilateral lung involvement in a patient with grade 5 pneumonitis outside the high-dose radiation field and involving bilateral lungs. aOngoing treatment at time of last follow-up. bDeath during treatment due to grade 5 IRAE (pneumonitis).

Figure 2.. Kaplan-Meier Survival Analysis

Plus signs indicate censored; shaded areas, 95% CI. Dose cohorts are described in Table 1.