Genetic Mutation Predicts Responses to Immunotherapy in Melanoma

For patients with melanoma, the presence of a CDKN2A mutation may prognosticate improved responses to immunotherapy because of increased tumor mutational load, which leads to more neoantigens and stronger anti-tumor immune responses, according to results from a recent clinical trial (J Med Genet. 2018 Oct 5. Epub ahead of print).

“Inherited CDKN2A mutation is a strong risk factor for cutaneous melanoma. Moreover, carriers have been found to have poor melanoma-specific survival,” explained lead investigator Hildur Helgadottir, MD, PhD, Department of Oncology Pathology, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden, and colleagues.

Although the emergence of effective immunotherapies in recent years have improved the treatment landscape for melanoma, a significant number of patients with the disease do not respond to immunotherapy.

“For this reason, it is important to increase the knowledge about predictive factors and the efficacy of the therapies in different patient groups,” Dr Helgadottir and colleagues said.

“Patients with tumours that harbour activating BRAF mutations respond equally to immune checkpoint inhibitors as those without such mutations. However, there is growing evidence that tumour mutational burden is a strong independent predictive factor for efficacy of immunotherapies,” they added.

Citing a lack of data on the effect of immunotherapy on patients with melanoma who have germline CDKN2A mutations, the investigators spearheaded a clinical trial examining the responses to new immunotherapy drugs observed in patients with metastatic melanoma and CDKN2A mutations.

The study, which was a collaborative effort between oncogenic clinics located in Sweden, Italy, The Netherlands, Spain and Australia, included patients with CDKN2A mutations who were enrolled in follow-up trials for familial melanoma. From this population, 19 patients were found to have metastatic melanoma and the CDKN2A mutation; these patients had all received immunotherapy.

Dr Helgadottir and colleagues compared the responses that these 19 patients had to immunotherapy with those reported in phase III clinical trials of patients with metastatic melanoma who were treated with ipilimumab, pembrolizumab, nivolumab, or ipilimumab plus nivolumab. Publicly available data sets were used to determine the association between melanomas with somatic CDKN2A mutation and tumor mutational load.

Of the 19 patients identified, 11 (58%) responded to immunotherapy—a significantly higher rate than previously reported in clinical trials of patients who received ipilimumab (10%), pembrolizumab (33%), nivolumab (43%), or ipilimumab plus nivolumab (57%; P = .03, binomial test against an expected rate of 37%).

A total of 6 (32%) patients had complete responses, which was also a significantly higher rate than previously reported (2%, 6%, 8%, and 12% with ipilimumab, pembrolizumab, nivolumab, and ipilimumab plus nivolumab, respectively; P = .01, binomial test against an expected rate of 7%).

Grade 3-4 treatment-related effects were observed in the patients with CDKN2A mutation at frequencies comparable with those reported in clinical trials.

“The CDKN2A mutation carriers in the study had a good response rate to the novel immunotherapy regimens, which we believe is helpful information for caregivers that manage CDKN2A mutation carriers and their families.

“Based on our findings, CDKN2A mutation predicts a good response to immunotherapies, possibly due to increased mutational load in CDKN2A mutated tumours. Further, in the light of the previous publication on poor melanoma-specific survival in the CDKN2A mutation carriers…these findings are reassuring for this group of patients. —Hina Khaliq