Therapeutic implications of a novel driver classification system for cutaneous and unknown primary melanomas.

Abstract

9539 Background: Cutaneous and “unknown primary” melanomas frequently harbor alterations that activate the Mitogen Activated Protein Kinase (MAPK) pathway, and are often classified as BRAF, NRAS, NF1 mutant, or “triple wild type.” Multigene sequencing may identify additional oncogenic drivers, but the clinical impact of this information is unknown. Methods: Patients with BRAF inhibitor naïve melanoma underwent prospective tumor molecular profiling using a targeted capture-based assay (MSK-IMPACT), and demographic and treatment data were collected. Time to treatment failure was assessed for patients who received frontline PD-1 monotherapy or nivolumab plus ipilimumab. Results: 576 patients were successfully sequenced. 533 samples (96%) harbored a known or presumed oncogenic mutation in 1 of 28 genes in the RTK-RAS-MAPK pathway. 187 tumors (32%) had two or more drivers in this pathway, and the rates of driver co-alterations varied widely by specific driver. A hierarchical classification of 9 driver groups (BRAF V600E; V600K/R/M; BRAF non-V600; NRAS Q61; Other RAS; NF1; KIT; Other driver; Unknown driver) was significantly associated with tumor mutational burden, primary melanoma site, and patient age. Time to treatment failure varied by driver class and site of primary melanoma for PD-1 monotherapy but not nivolumab plus ipilimumab. 150 patients with BRAF V600 wild-type melanoma required systemic therapy after progression on checkpoint blockade. 21 were given genomically matched therapy, and 5/21 had clinical benefit for ≥6 months. Complete and durable responses were observed with TRK and ROS1 inhibitors in patients with NTRK1/2/3 and ROS1 fusion positive tumors. Conclusions: Oncogenic alterations in the RTK-RAS-MAPK pathway can be detected using targeted capture NGS in the vast majority of cutaneous and unknown primary melanomas. A hierarchical classification of 9 driver groups revealed clinically relevant melanoma subsets with varying clinical outcomes to PD-1 monotherapy. Select patients with oncogenic kinase fusions can achieve durable therapeutic benefit with targeted inhibitors of these rare drivers.