The treatment of metastatic melanoma has been revolutionized in the past decade because of the development of immunotherapies and targeted therapies.,Despite these developments, there is still an unmet clinical need for more advanced combination therapies for the subset of patients who remain resistant to immunotherapy or targeted therapy alone.,To our knowledge, no reports have been published on combinations of PD-1 blockades and c-KIT inhibitors in melanoma patients.,Furthermore, data are limited regarding the safety and efficacy of this combination in patients harboring KIT mutations.,We report a case of an 82-year-old female with metastatic melanoma who was found to have double KIT mutations at V559 and N822I.,She was treated with a combination of c-KIT inhibitor and PD-1 blockade after being resistant to anti-PD-1 monotherapy.,Patient developed two episodes of grade 2 liver toxicity requiring treatment breaks followed by a dose reduction.,Her transaminitis eventually resolved and patient remained on combination treatment for almost two years with good control of her disease prior to progression.,Treatment options for patients who progress after PD-1 inhibitors are very limited; therefore, there is a high unmet clinical need for this patient population.,Combining Imatinib with checkpoint inhibitors may be efficacious in patients with metastatic melanoma and KIT mutations.,This novel combination can cause additional toxicities which seem to be overall manageable.
Knowledge of key drivers and therapeutic targets in mucosal melanoma is limited due to the paucity of comprehensive mutation data on this rare tumor type.,To better understand the genomic landscape of mucosal melanoma, here we describe whole genome sequencing analysis of 67 tumors and validation of driver gene mutations by exome sequencing of 45 tumors.,Tumors have a low point mutation burden and high numbers of structural variants, including recurrent structural rearrangements targeting TERT, CDK4 and MDM2.,Significantly mutated genes are NRAS, BRAF, NF1, KIT, SF3B1, TP53, SPRED1, ATRX, HLA-A and CHD8.,SF3B1 mutations occur more commonly in female genital and anorectal melanomas and CTNNB1 mutations implicate a role for WNT signaling defects in the genesis of some mucosal melanomas.,TERT aberrations and ATRX mutations are associated with alterations in telomere length.,Mutation profiles of the majority of mucosal melanomas suggest potential susceptibility to CDK4/6 and/or MEK inhibitors.,Mucosal melanomas are challenging to treat partly because so little is known about the genetic drivers underpinning them.,Here, the authors perform a genomic landscape analysis of samples collected from three continents, revealing a potential role for CDK4/6 or MEK inhibition in the treatment of the disease.