Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer

ABSTRACT PURPOSE Radiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ES-SCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiation therapy (TRT) after induction chemotherapy for SCLC. METHODS ES-SCLC patients who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity (DLTs) in the 35 days following initiation of treatment. RESULTS Thirty-eight ES-SCLC patients (median age 65 years, range, 37–79) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100-200 mg with no DLTs in the 35-day window. There were no grade 4-5 toxicities; two (6%) experienced grade 3 events (n=1 rash, n=1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range 1–13); median progression-free and overall survival were 6.1 months (95% confidence interval [CI] 4.1–8.1) and 8.4 months (95% CI 6.7-10.1). CONCLUSIONS Concurrent pembrolizumab-TRT was tolerated well, with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g. enrolling progressors on induction chemotherapy). Although randomized studies have illustrated benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.