A Phase I Trial of Pembrolizumab with Hypofractionated Radiation Therapy (HFRT) in Patients with Metastatic Cancers

Based on reports suggesting that radiation can potentiate systemic response to immune checkpoint blockade therapy, we opened a stratified phase I trial. The 1o objective was to determine the safety of the anti-PD-1 antibody pembrolizumab combined with HFRT in patients with metastatic cancer. A 2o objective was to assess radiologic response (by RECIST criteria) in non-irradiated metastatic lesions (abscopal effect). In the Safety Phase, 12 patients were enrolled into each of 2 strata: (i) NSCLC or melanoma with progression on prior anti-PD-1 therapy and (ii) other cancer types (5 GI, 4 breast, 1 head and neck, 2 RCC), with no prior anti-PD-1 therapy. Patients were required to have a ≥ 1 cm index lesion amenable to HFRT and at least 1 other non-irradiated lesion that could be followed for response. Pembrolizumab 200 mg was given 1 week prior to start of HFRT, then continued every 3 weeks for 5 more cycles. The dose of HFRT was 8 Gy x 3 for the first 6 patients in each stratum and 17 Gy x 1 for the next 6. Dose-limiting toxicity (DLT) was defined as any Grade 3 or higher non-heme and any Grade 4 heme toxicity related to the combination of pembrolizumab and HFRT. Treatment-related adverse events (AEs) occurred in 20 of 24 patients (83%), with AEs in 17 of the 20 attributable to pembrolizumab. All were grade 1 or 2, most commonly nausea, vomiting, diarrhea, constipation, fever, fatigue, and weakness. There were two grade 2 immune-related toxicities (hypothyroidism and pneumonitis) in one patient. Three other patients had radiation-related AEs, all grade 1. No DLTs were observed. There were 9 grade 3 toxicities, none of which was attributed to treatment. No patient experienced a grade 4 or 5 adverse event. In Cohort 1 (prior PD-1 therapy), two patients had a partial response. One patient, with NSCLC, initially had a good response to nivolumab but then began progressing. Nivolumab was stopped, and he was enrolled on the trial. After receiving pembrolizumab and 8 Gy x 3 to an abdominal mass, he experienced a response in both the abdominal mass and a non-irradiated chest lesion. A second patient, with melanoma, initially had a good response to pembrolizumab but then progressed. He was enrolled on the trial and after receiving pembrolizumab followed by 17 Gy to an inguinal mass, he experienced a radiologic response in both the inguinal mass and a non-irradiated calf lesion. In Cohort 2 (no prior PD-1 therapy), there was one patient with RCC that experienced a complete response. Two patients had stable disease as their best response, one with RCC, and one with adenoid cystic cancer. The combination of HFRT and pembrolizumab was safe with no DLTs. Two patients experienced an abscopal response to pembrolizumab and HFRT after progression on prior anti-PD-1 therapy. These data suggest that radiation may increase the immune response to anti-PD-1 therapy, leading to tumor regression.