Phase 1 Study of Pembrolizumab and Stereotactic or Hypofractionated Radiation for Metastatic Non–small Cell Lung Cancer

Preclinical models suggest the potential for systemic disease control with PD1 inhibition and radiation. Despite promising clinical efficacy as a monotherapy in NSCLC, PD1 inhibitors have produced instances of serious immune-related pneumonitis. We describe early outcomes from a completed two-arm phase I trial combining pembrolizumab with radiation for non-small cell lung cancer (NSCLC). In NCT02444741 metastatic NSCLC were enrolled in one of two parallel arms. In the stereotactic ablative radiation (SABR) arm, patients were treated to 50 Gy in 4 fractions to a single lung or a liver lesion. In the hypofractionated radiation arm, patients were treated to 45 Gy in 15 fractions to a larger field. A simultaneous integrated boost was allowed up to 60 Gy. Pembrolizumab was given every 3 weeks and initiated the day of or day before the first dose of radiation. The trial design was a 3 + 3 phase I dose escalation testing pembrolizumab at 100 mg and then 200 mg. Both arms were independently escalated. Dose-limiting toxicities (DLTs) were grade 3+ toxicity attributable to the combination of both therapies. Progression-free survival (PFS) and overall survival (OS) were estimated by the method of Kaplan and Meier. A total of 21 patients were enrolled. Among them, 2 patients did not receive treatment (1 died and 1 withdrew consent). The maximum tolerated pembrolizumab dose was 200 mg for both arms. Among the remaining 19 patients, 10 were treated with SABR (all lung lesions) and 9 with hypofractionated radiation (7 liver and 2 lung lesions). No DLTs were observed. Eight and 3 patients had grade 2 and 3 treatment-related toxicity, respectively. No grade 4 or 5 toxicities were observed. Among the 3 patients who experienced grade 3 toxicities, 1 had pneumonitis and lung infection, 1 had anemia and fatigue, and the last had a maculopapulary rash. Thirteen patients were taken off study for disease progression (n = 9), toxicity (n = 2), and withdrawal of consent (n = 2). The median follow-up time was 7.5 months, with 6-month OS 77% (95% CI: 56%-97%) and PFS 55% (95% CI: 31%-78%). Of the 19 patients who received treatment, the best recorded response was partial response in 6 patients (32%), stable disease in 7 patients (36%), and progressive disease in 6 patients (32%). Toxicity associated with pembrolizumab and chest radiation was acceptable. The efficacy, although preliminary, is promising and is being further assessed in the randomized phase II portion comparing radiation and pembrolizumab versus pembrolizumab.