Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non-Small Cell Lung Cancer: Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial

Abstract

Importance: Many patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy show primary resistance. High-dose radiotherapy can lead to increased tumor antigen release, improved antigen presentation, and T-cell infiltration. This radiotherapy may enhance the effects of checkpoint inhibition.

Objective: To assess whether stereotactic body radiotherapy on a single tumor site preceding pembrolizumab treatment enhances tumor response in patients with metastatic NSCLC.

Design, setting, and participants: Multicenter, randomized phase 2 study (PEMBRO-RT) of 92 patients with advanced NSCLC enrolled between July 1, 2015, and March 31, 2018, regardless of programmed death-ligand 1 (PD-L1) status. Data analysis was of the intention-to-treat population.

Interventions: Pembrolizumab (200 mg/kg every 3 weeks) either alone (control arm) or after radiotherapy (3 doses of 8 Gy) (experimental arm) to a single tumor site until confirmed radiographic progression, unacceptable toxic effects, investigator decision, patient withdrawal of consent, or a maximum of 24 months.

Main outcomes and measures: Improvement in overall response rate (ORR) at 12 weeks from 20% in the control arm to 50% in the experimental arm with P < .10.

Results: Of the 92 patients enrolled, 76 were randomized to the control arm (n = 40) or the experimental arm (n = 36). Of those, the median age was 62 years (range, 35-78 years), and 44 (58%) were men. The ORR at 12 weeks was 18% in the control arm vs 36% in the experimental arm (P = .07). Median progression-free survival was 1.9 months (95% CI, 1.7-6.9 months) vs 6.6 months (95% CI, 4.0-14.6 months) (hazard ratio, 0.71; 95% CI, 0.42-1.18; P = .19), and median overall survival was 7.6 months (95% CI, 6.0-13.9 months) vs 15.9 months (95% CI, 7.1 months to not reached) (hazard ratio, 0.66; 95% CI, 0.37-1.18; P = .16). Subgroup analyses showed the largest benefit from the addition of radiotherapy in patients with PD-L1-negative tumors. No increase in treatment-related toxic effects was observed in the experimental arm.

Conclusions and relevance: Stereotactic body radiotherapy prior to pembrolizumab was well tolerated. Although a doubling of ORR was observed, the results did not meet the study's prespecified end point criteria for meaningful clinical benefit. Positive results were largely influenced by the PD-L1-negative subgroup, which had significantly improved progression-free survival and overall survival. These results suggest that a larger trial is necessary to determine whether radiotherapy may activate noninflamed NSCLC toward a more inflamed tumor microenvironment.

Trial registration: ClinicalTrials.gov identifier: NCT02492568.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Theelen reported receiving grants from Merck Sharp & Dohme during the conduct of the study. Dr Peulen reported receiving grants from KWF during the conduct of the study. Dr Aerts reported receiving personal fees from Merck Sharp & Dohme, Lilly, Bristol-Myers Squibb, Boehringer Ingelheim, Amphera, Roche, Takeda, and AstraZeneca outside the submitted work; having a patent for allogenic tumor cell lysate licensed to Amphera; and having patents pending for combination treatment dendritic cell therapy, dendritic cell therapy with allogenic lysate in pancreatic tumors, and Janus kinase inhibition in solid tumors. Dr Bahce reported receiving grants from Merck Sharp & Dohme during the conduct of the study. Dr de Langen reported receiving grants from Merck Sharp & Dohme during the conduct of the study; grants from Merck Sharp & Dohme, Boehringer, Bristol-Myers Squibb, and AstraZeneca outside the submitted work; and nonfinancial support from Roche and Merck Serono outside the submitted work. Dr Monkhorst reported receiving personal and consultancy fees from Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, AbbVie, AstraZeneca, and Takeda outside the submitted work. Dr Baas reported receiving grants and medication delivery from Merck Sharp & Dohme during the conduct of the study as well as grants and consultancy fees from Bristol-Myers Squibb outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. CONSORT Diagram

Figure 2.. Progression-Free Survival in the Intent-to-Treat Population

A, Experimental arm comprised patients who received pembrolizumab after stereotactic body radiotherapy; control arm comprised patients who received pembrolizumab alone. Hazard ratio was 0.71 (95% CI, 0.42-1.18) with a 2-sided significance level of P = .19. B, ECOG indicates Eastern Cooperative Oncology Group; PD-L1, programmed death–ligand 1.

Figure 3.. Overall Survival in the Intent-to-Treat Population

A, Experimental arm comprised patients who received pembrolizumab after stereotactic body radiotherapy; control arm comprised patients who received pembrolizumab alone. Hazard ratio was 0.66 (95% CI, 0.37-1.18) with a 2-sided significance level of P = .16. B, ECOG indicates Eastern Cooperative Oncology Group; PD-L1, programmed death–ligand 1.