Identifying the optimal fractionation schedules for improved response rates and survival in patients with metastatic melanoma treated with ipilimumab and radiotherapy

Objective: There is a growing body of evidence that combining ipilimumab with higher doses of radiotherapy may improve the response rates and survival in patients with metastatic melanoma compared to lower doses of radiotherapy. However, the dose cutoff at which improved outcomes are more likely to occur has not been properly identified. Methods: We conducted a retrospective analysis of 100 patients treated with ipilimumab and radiotherapy for metastatic melanoma at a single institution from May 2011 to January 2017. Demographic, clinical, and treatment factors, including the biological equivalent dose (BED) with an α/β of 7, were recorded. Endpoints of interest included infield and global complete response (CR) after the completion of radiation and ipilimumab based on the RECIST criteria (v1.1) and 12-month overall survival (OS). Results: The BED cutoffs at which improved outcomes are more likely to occur are 46.5 Gy for infield CR, 50.9 Gy for global CR, and 46.5 Gy for 12 month OS. The least aggressive fractionation schedules used in this patient population that have a BED above the threshold for all 3 outcomes include 40 Gy in 20 fractions, 30 Gy in 6 fractions, and 24 Gy in 3 fractions. Conclusion: This hypothesis-generating study suggests that patients who cannot receive ablative intent radiotherapy may be more likely to benefit from concurrent radiotherapy with ipilimumab if their fractionation schedule has a BED above 46.5-50.9 Gy. Prospective trials evaluating this question should be considered.