Immunotherapy Improves Survival in Metastatic Melanoma

The use of CTLA-4, PD-1, or a combination approach achieved high response rates and improved overall survival in patients with CDKN2A mutations with metastatic melanoma, based on the results of a study by Helgadottir et al.

CDKN2A is a tumor suppressor gene that has been identified as one of the greatest risk factors for cutaneous melanoma. Patients who carry CDKN2A mutations have a risk of melanoma that is >65-fold increased and a lifetime penetrance of >70%. CDKN2A mutation carriers also have poorer melanoma survival rates compared with other patients with melanoma. The CDKN2A deletions and loss of p16 protein from the mutations cause increased tumor proliferation and increased risk of metastases.

In the current era, immunotherapy has redefined cancer treatment and has led to considerably improved overall and progression free survival in multiple cancer types, including melanoma. In their study, Helgadottir et al administered immunotherapy to patients with metastatic melanoma and CDKN2A mutations to determine if survival outcomes improved.

In this study, 19 patients with melanoma and germline mutations for CDKN2A were identified to have undergone immunotherapy treatment. Most of these patients had extremely disseminated melanoma with metastasis already reaching distinct organs, including the brain. Of the patients observed, 8 patients received CTLA-4 blockade (ipilimumab), 8 patients received PD-1 blockade (nivolumab, pembrolizumab), 1 patient received adoptive T-cell transfer therapy, 3 patients received dual CTLA-4 and PD-1 blockade, and 1 patient received a combination of PD-1, BRAF, and MEK inhibitors.

Of the 19 patients, 11 responded to immunotherapy (58%), with 6 patients having a complete response (CR). Both results were significant compared with their counterpart trial expectations (P = .03, binomial test against expected rate of 37% for response rate; P = .01, binomial test against expected rate of 7% for CR). Of the patients who received only CTLA-4 blockade, 6 (75%) were alive 1 year after the start of treatment, and 5 (63%) were alive 2 years after the start of treatment. These overall survival (OS) rates were much better than 1- and 2-year OS seen in phase 3 ipilimumab trials (46% and 24%, respectively). One- and 2-year survival rates for PD-1 inhibitor and CTLA-4/PD-1 inhibitor combination are ongoing.

Total mutation burden (TMB) has been highly correlated to immunotherapy response. In these patients, TMB was found to be higher in patients with CDKN2A mutations than patients without the mutations (P < .001). Investigators believe that this may be one of the primary reasons for the improved response to immunotherapies.

Patients with metastatic melanoma and CDKN2A mutations have been shown to benefit from immunotherapy, most likely from the increased TMB. In this patient population where many standard chemotherapy agents are shown to have no effect on patient survival, immunotherapy may be considered as an alternative solution.

Reference

Helgadottir H, Ghiorzo P, van Doorn R, et al. Efficacy of novel immunotherapy regimens in patients with metastatic melanoma with germline CDKN2A mutations [published online October 5, 2018]. J Med Genet. doi: 10.1136/jmedgenet-2018-105610.