Case Report: Combined CDK4/6 and MEK Inhibition in Refractory CDKN2A and NRAS Mutant Melanoma.

There are only limited treatment options for metastatic NRAS mutant melanoma patients with resistance to immune checkpoint inhibitors. Besides activation of the mitogen-activated protein (MAP) kinase pathway, they often have additional disturbances in cell cycle regulation. However, unlike BRAF mutant melanoma, no targeted therapy has yet been approved for NRAS mutant melanoma so far. Here we present a NRAS mutant melanoma patient with response to combined binimetinib and ribociclib therapy following characterization of the molecular defects of the tumor by panel sequencing. Next generation sequencing (708 cancer genes) of a soft tissue metastasis revealed a homozygous deletion of CDKN2A in addition to the previously known NRAS mutation, as well as amplification of CCNE1 and CDK6. Immunohistochemical staining of the altered cell cycle genes confirmed loss of p16, reduced expression of p21 and high expression of CDK6 and cyclin D1. As the patient had been progressive on combined immunotherapy, targeted therapy with combined MEK and CDK4/6 inhibition was initiated as recommended by the molecular tumor board. Response to treatment was monitored with PET/CT and liquid biopsy, serum LDH, and S100. In addition, a patient-derived xenograft (PDX) was used to prove the efficacy of the two drugs in combination. Furthermore, senescence-associated beta-galactosidase staining showed that more cells were senescent under the combination treatment of binimetinib and ribociclib. Our case demonstrates how an individualized, molecular-based therapeutic approach could be found based on next-generation sequencing results. Furthermore our report highlights the fruitful and efficient collaboration of dermatooncologists, human geneticists, molecular pathologists, biochemists, radiologists, and nuclear physicians. Further studies are urgently needed to expand the very limited therapeutic landscape of NRAS mutated melanoma.
Competing Interests: AF served as consultant to Roche, Novartis, MSD, BMS, Pierre-Fabre; received travel support from Roche, Novartis, BMS, Pierre-Fabre, received speaker fees from Roche, Novartis, BMS, MSD, and CeGaT outside the submitted work. She reports institutional research grants from BMS Stiftung Immunonkologie outside the submitted work. CS reports institutional grants from Novartis and grants from BMS Stiftung Immunonkologie outside the submitted work. MB served in advisory committees for Bayer, BMS, EISAI, IPSEN, and MSD outside the submitted work. TE reports personal fees from Amgen, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. CG reports personal fees from Amgen, grants and personal fees from NeraCare, grants and personal fees from Novartis, personal fees from Philogen, grants and personal fees from Roche, grants and personal fees from Sanofi, personal fees from BMS, personal fees from MSD, outside the submitted work. IB received speaker fees from Novartis, Bayer and AstraZeneca and honoraria for advisory board participation from BMS and Novartis. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Forschner, Sinnberg, Mroz, Schroeder, Reinert, Gatidis, Bitzer, Eigentler, Garbe, Niessner, Röcken, Roggia, Armeanu-Ebinger, Riess, Mattern, Nann and Bonzheim.)