Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline mutations.

BACKGROUND

Inherited mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival. In this study, responses to novel immunotherapy agents in mutation carriers with metastatic melanoma were evaluated.

METHODS

mutation carriers that have developed metastatic melanoma and undergone immunotherapy treatments were identified among carriers enrolled in follow-up studies for familial melanoma. The carriers' responses were compared with responses reported in phase III clinical trials for CTLA-4 and PD-1 inhibitors. From publicly available data sets, melanomas with somatic mutation were analysed for association with tumour mutational load.

RESULTS

Eleven of 19 carriers (58%) responded to the therapy, a significantly higher frequency than observed in clinical trials (p=0.03, binomial test against an expected rate of 37%). Further, 6 of the 19 carriers (32%) had complete response, a significantly higher frequency than observed in clinical trials (p=0.01, binomial test against an expected rate of 7%). In 118 melanomas with somatic mutations, significantly higher total numbers of mutations were observed compared with 761 melanomas without mutation (Wilcoxon test, p<0.001).

CONCLUSION

Patients with mutated melanoma may have improved immunotherapy responses due to increased tumour mutational load, resulting in more neoantigens and stronger antitumorous immune responses.