Germline <scp><i>MC1R</i></scp> Variant Status and Efficacy of Immune Checkpoint Inhibitors in Patients With Advanced Melanoma

The melanocortin-1-receptor (MC1R) has a key role in melanocyte pigmentation regulation. Certain MC1R germline genetic variants (R alleles) result in deficient melanin production and are associated with red hair, freckling, UV sensitivity, and melanoma susceptibility. We aimed to address whether inherited polymorphisms in MC1R impact the efficacy of immune checkpoint inhibitors (ICI) in patients with metastatic melanoma. Patients with advanced melanoma undergoing ICI treatment were genotyped for MC1R variants. The patients were grouped by their germline MC1R R variants (≥ 1 or 0) and followed for treatment response, progression-free survival (PFS) and overall survival (OS). Of the 103 patients included, 39 (37.9%) had at least one MC1R R allele (MC1R-R-carriers), whereas 64 patients did not harbor any R allele (MC1R-R-non-carriers). The hazard ratio (HR) for PFS in MC1R-R-carriers was 0.60, (95% CI 0.37-0.98, p = 0.043). The HR for OS was 0.63 (95% CI 0.37-1.08, p = 0.091). While MC1R is closely associated with melanoma susceptibility, its impact on ICI efficacy has not been explored previously. MC1R-R-carriers with metastatic melanoma had improved PFS when treated with ICIs. If validated in larger cohorts, MC1R genotyping may serve as a factor helping to predict response to ICIs in melanoma patients.