Extra-cranial radiotherapy in anti-PD-1-treated melanoma patients: a systematic review

Anti-PD-1 monoclonal antibodies have improved outcomes of advanced melanoma patients, but improved strategies are warranted. Some melanoma studies suggest the efficacy of radiotherapy combined with anti-PD-1, but its place in melanoma care is debated. We performed a systematic review to critically analyse the place of extracranial radiotherapy combined with anti-PD-1 monoclonal antibodies in advanced melanoma patients. A PRISMA-compliant systematic review of studies in MEDLINE (PubMed) was conducted, with the following primary outcomes: response rates, abscopal response, progression-free survival (PFS) and overall survival (OS). We extracted data from 20 studies, with a total of 1020 irradiated melanoma patients. Although the quality of evidence was limited because of flaws in study designs, some key messages were found. PFS and OS were not improved when compared to non-irradiated patients, but the latter typically exhibited less severe prognostic criteria. Responses to anti-PD1 were usually better in irradiated than non-irradiated areas. An abscopal response was observed in 28% of 247 patients recruited in the 7 adequately designed studies, i.e. radiating 1-3 metastases in patients failing anti-PD-1 treatment and without modification of the anti-PD-1 regimen. High-fraction radiotherapy delivering > 5Gy/fraction to 1-3 metastases administered concurrently with anti-PD-1 might be the most effective radiotherapy regimen. In the difficult situation of anti-PD-1 failure, where limited effective treatments are available, this regimen induced abscopal responses and may improve PFS and OS. No unexpected toxicity was reported. Further studies are warranted, with better designs.