Efficacy of Large Use of Combined Hypofractionated Radiotherapy in a Cohort of Anti-PD-1 Monotherapy-Treated Melanoma Patients

SIMPLE SUMMARY: Melanoma patients who failed anti-PD-1 therapy have limited therapeutic options. Some studies suggested the efficacy of radiotherapy combined with anti-PD-1 monoclonal antibodies. We previously reported in small-sized studies that hypofractionated radiotherapy combined with an unmodified anti-PD-1 monotherapy regimen induced long-lasting efficacy. This study shows that the large use of hypofractionated radiotherapy combined with anti-PD-1 induced high rates of complete response (32.5% [95% CI: 26.1–38.9]) in a cohort of 206 melanoma patients. Radiated patients who had confirmed failure to anti-PD-1 monotherapy had longer progression-free and overall survival than non-radiated ones. No unexpected safety concern was observed. Although no clinical predictive factors have been identified in our study, a synergy between anti-PD1 and radiotherapy is likely. Adding hypofractionated radiotherapy in metastatic melanoma patients treated with anti-PD-1 is a safe option, which may increase the response rate and could be offered in patients with lesions threatening or not responding to anti-PD1. ABSTRACT: To assess the role of radiotherapy in anti-PD-1-treated melanoma patients, we studied retrospectively a cohort of 206 consecutive anti-PD-1 monotherapy-treated advanced melanoma patients (59% M1c/d, 50% ≥ 3 metastasis sites, 33% ECOG PS ≥ 1, 33% > 1st line, 32% elevated serum LDH) having widely (49%) received concurrent radiotherapy, with RECIST 1.1 evaluation of radiated and non-radiated lesions. Overall (OS) and progression-free (PFS) survivals were calculated using Kaplan–Meier. Radiotherapy was performed early (39 patients) or after 3 months (61 patients with confirmed anti-PD-1 failure). The first radiotherapy was hypofractionated extracranial radiotherapy to 1–2 targets (26 Gy-4 weekly sessions, 68 patients), intracranial radiosurgery (25 patients), or palliative. Globally, 67 (32.5% [95% CI: 26.1–38.9]) patients achieved complete response (CR), with 25 CR patients having been radiated. In patients failing anti-PD-1, PFS and OS from anti-PD-1 initiation were 16.8 [13.4–26.6] and 37.0 months [24.6–NA], respectively, in radiated patients, and 2.2 [1.5–2.6] and 4.3 months [2.6–7.1], respectively, in non-radiated patients (p < 0.001). Abscopal response was observed in 31.5% of evaluable patients who radiated late. No factors associated with response in radiated patients were found. No unusual adverse event was seen. High-dose radiotherapy may enhance CR rate above the 6–25% reported in anti-PD-1 monotherapy or ipilimumab + nivolumab combo studies in melanoma patients.