A Phase 1 Clinical Trial of Ipilimumab, Nivolumab and Radiation Therapy for Patients with Metastatic Melanoma

Abstract

Combined blockade of immune checkpoints CTLA-4 and PD-1 with ipilimumab and nivolumab (ipi/nivo) represents the most effective strategy for the systemic treatment of metastatic melanoma. Preclinical studies suggest that tumor radiation therapy (RT) may modulate immune response in conjunction with ipi/nivo, and that the dose-fractionation of RT is relevant to this effect. This study was designed to assess the safety of combining ipi/nivo with 2 different RT dose-fractionation regimens: lower dose, conventionally-fractionated RT (Cohort A) and higher dose, hypofractionated RT (Cohort B). The hypothesis for this study is that the combination of ipi/nivo and RT is safe in metastatic melanoma. After IRB approval, a prospective, single-arm, two-cohort, Phase 1 clinical trial (NCT02659540) was initiated at 2 cancer centers. Eligible patients had ≥2 sites of metastatic melanoma: ≥1 site was amenable to RT and ≥1 site was observed for response by RECIST v1.1. Patients (n=9 per cohort) were enrolled in 2 consecutive cohorts (Cohort A, RT 30 Gy/10 fractions; Cohort B, RT 27 Gy/3 fractions) and started RT between the first and second doses of ipi/nivo given at the FDA-approved dose and schedule. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 24 weeks of the first dose of ipi/nivo were characterized according to CTCAE v4.03. Exploratory analyses of irradiated tumor and overall objective response rate (ORR, exclusive of the irradiated tumor) were performed in patients who received at least one dose of ipi/nivo and RT. In Cohort A, 10 patients (median age: 65 [range: 28-86] years; 6 female) were enrolled because 1 patient withdrew consent after ipi/nivo/RT, but before disease assessment. Grade 3-4 TEAEs were observed in 7/10 patients, while Grade 3-4 TRAEs were observed in 4/10 patients and included pruritus, anemia, thrombocytopenia, and lipase elevation. Irradiated tumor ORR was 44% (95% confidence interval [CI]: 14-79%), and ORR outside of the irradiated tumor was 44% (95% CI: 14-79%), with 2 patients dying of disease progression. Cohort B has enrolled 5 of 9 patients; safety and efficacy analyses are anticipated to be complete at the time of presentation. This is the first prospective clinical trial to report on the combination of ipi/nivo and RT. Despite the small number of planned accruals in this Phase 1 trial, the TRAE rate after ipi/nivo/lower dose, conventionally-fractionated RT was similar to what has been observed after ipi/nivo without RT, suggesting this regimen is safe. Further analyses will be required to better characterize the safety and efficacy of this regimen in Cohort B, as well as potential immunologic differences between the two RT cohorts in this study.