Clinical response under MEK inhibitor alone in metastatic melanoma with a novel fusion involving the RAF1 gene.

Currently, in the absence of BRAFV600 mutation, the management of advanced melanomas is based on immunotherapies, but only half of the patients are responders. RAF1 (also named CRAF) fusions occur in 1-2.1% of wild-type melanomas. Preclinical data suggest that the presence of RAF fusion may be sensitive to MEK inhibitors. We report the case of a patient with an advanced melanoma harboring an EFCC1-RAF1 fusion who showed a clinical benefit from and a partial response to a MEK inhibitor.

Positive Association Between Location of Melanoma, Ultraviolet Signature, Tumor Mutational Burden, and Response to Anti-PD-1 Therapy.

Emerging evidence suggests a correlation between the tumor mutational burden (TMB) and the response to programmed cell death-1 protein (PD-1) monotherapy across multiple cancer types. In skin cancers, as high TMB is mostly because of ultraviolet (UV) exposure, we hypothesized a correlation between the primary melanoma cutaneous location according to sun exposure and response to anti-PD-1 monotherapy. METHODS: The aim of this study was to analyze, in advanced melanoma, the relationship between TMB, locations according to sun exposure, and response to PD-1 inhibitors. We conducted a prospective multicentric analysis, by sequencing the most recent metastatic sample before PD-1 inhibitors using FoundationOne assay. RESULTS: One hundred two patients were included, with TMB available for 94 cases. In univariate and multivariate linear regression, TMB was significantly associated with sun-exposed areas of the primary melanoma location and with age (coefficients of the association with log-TMB: non-UV location, -1.05; chronic sun-exposed area, 1.12; P value for the location, < 10-5; age, 0.021 per year, P value for age, .002). Molecular UV signature present on the metastatic site was associated with higher TMB (P = .003). Melanomas bearing a high TMB had a higher probability of response to PD-1 inhibitors compared with melanomas with a low TMB, with a dose-dependent effect following an exponential curve and a negative odds ratio of 0.40 (95% CI, 0.20 to 0.72, P = .004) between log-TMB and 6-month progression. CONCLUSION: Cumulative sun exposure related to skin location and molecular UV signature present on the metastatic site appear to be relevant biomarkers directly linked to TMB. Because TMB is not yet available to all for routine clinical use, the location of the primary melanoma in a sun-exposed area may play an important role in clinical decisions regarding therapeutic choice.

Dramatic response of refractory metastatic squamous cell carcinoma of the skin with cetuximab/pembrolizumab.

Cutaneous squamous cell carcinoma (cSCC) accounts for 20% of skin cancers. At an advanced stage the prognosis is poor, making cSCC the second leading cause of death from skin cancer. In cases of metastatic or unresectable disease, anti-programmed cell death 1 (anti-PD1) treatment has shown promising results in a recent phase II study. Although anti-PD1 treatment now offers higher response rates, the responses remain inconsistent and may lead to therapeutic impasses. Preclinical data have suggested synergy between anti-epidermal growth factor receptor (anti-EGFR) and immunotherapy. We report the case of a patient with metastatic cSCC that proved refractory first to anti-EGFR/carboplatin and then to immunotherapy, but who showed a complete and durable response with cetuximab/pembrolizumab combination. This response could reflect synergy of the two treatments.

Simultaneous long-lasting regression of multiple nevi and melanoma metastases after ipilimumab therapy.

We report a case of major regression of multiple atypical melanocytic nevi with a vitiligoid reaction in a patient with metastatic melanoma who achieved long-lasting complete remission after ipilimumab therapy. In 2008, a 54-year-old man presented with a dysplastic nevus syndrome. The patient was diagnosed with a scalp ulcerated melanoma (Breslow index 5.1 mm and Clark level IV), which was removed surgically. Four years later in April 2012, the patient was diagnosed with a right parietal skin metastasis, brain, lymph nodes, and bilateral lung metastases. The patient was first treated with vemurafenib, which had to be stopped because of renal toxicity. Disease stabilization was achieved after the second line of treatment with immunotherapy (ipilimumab, four infusions). However, 6 months later, the lung metastases had progressed. The patient was treated with pulmonary stereotactic radiotherapy associated with a second cycle of ipilimumab. After 6 months, he achieved complete remission. Simultaneously, the patient presented a generalized regression of his nevi with a vitiligoid reaction, or halo nevus, associated with a vitiligo located on the hands and inguinal areas. Vitiligo is a frequent immune-related adverse event of immunotherapy. Immunotherapy-induced halo nevus reaction is much less frequent than vitiligo. It was associated in the two case reports from the literature and in our patient with a quick and long-lasting complete remission of nodes and visceral metastases. Therefore, it might correspond to a stronger antimelanocyte immune reaction, associated with a favorable prognosis. The generalized halo nevi reaction in our patient could be more important because of the two cycles of ipilimumab compared with a single one. In conclusion, this case report suggests that a major regression of multiple nevi on ipilimumab might be associated with immunotherapy response.