Impact of Prior Radiation Therapy on the Efficacy and Toxicity of Pembrolizumab in the Treatment of Non–small Cell Lung Cancer

Abstract

Preclinical studies show radiation therapy to enhance antitumor immune responses; however, clinical data on the impact of radiation therapy on the efficacy and toxicity of checkpoint immunotherapy is limited. We therefore sought to determine if patients who previously received radiation therapy for their non-small-cell lung cancer (NSCLC) would have enhanced disease control with pembrolizumab treatment and if patients with prior thoracic radiation would have more pulmonary toxicity with pembrolizumab treatment. We present a secondary analysis of the phase 1 KEYNOTE-001 trial. Patients (n = 97) had metastatic NSCLC and were treated at a single institution with pembrolizumab at a dose of either 2 mg or 10 mg/kg q 3 weeks or 10 mg/kg q 2 weeks. Disease response and pulmonary toxicity were prospectively assessed by the investigator using the immune related response criteria (irRC) and CTCAE grading. Patients were divided into subgroups to compare patients who previously received radiation for the treatment of their NSCLC to patients without a history of prior radiation with regards to progression-free (PFS) and overall survival (OS) and pulmonary toxicity. Among all patients, 43% previously received any radiation therapy (RT), 39% received extracranial radiation therapy (ERT) and 25% specifically received thoracic radiation therapy (TRT) for the treatment of their NSCLC. All radiation was delivered prior to the first dose of pembrolizumab. Patients with prior RT had a significantly longer PFS with pembrolizumab treatment vs. patients without prior RT (6 month PFS: 44.3% vs. 22.9%, P = 0.04). Patients with ERT had a significantly longer PFS with pembrolizumab vs. patients without ERT (median PFS: 4.1 months vs. 2.0 months; 6 month PFS: 49.3% vs. 21.4%, P < 0.01). On multivariate analysis both prior RT and ERT independently predicted for improved PFS with pembrolizumab treatment (HR, 0.60, 95% CI 0.37-0.94, P = 0.03, and HR, 0.53, 95% CI, 0.33-0.86, P = 0.01, respectively). Patients with prior RT and ERT also had a significantly longer OS with pembrolizumab treatment than patients without prior RT or ERT (P = 0.05 and P = 0.03, respectively). Patients with prior TRT had more overall treatment-related pulmonary toxicity (12.5% vs. 1.4%, P = 0.04), and pneumonitis (12.5% vs. 2.7%, P = 0.09) with pembrolizumab treatment. However, the rates of any ≥ grade 3 pulmonary toxicities were similar (12.5% vs. 9.6%. P = 0.7). Patients treated with pembrolizumab on the phase 1 KEYNOTE-001 trial who previously received radiation therapy had a significantly longer progression-free and overall survival with pembrolizumab treatment. Overall, these data suggest an acceptable safety profile and a promising efficacy with the combination of radiation therapy and pembrolizumab for the treatment of advanced NSCLC.