Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-Mutant Melanoma
Mené sur 41 patients atteints d'un mélanome présentant des mutations du gène NRAS, cet essai de phase IB/II évalue la dose maximale tolérée du ribociclib en combinaison avec le binimétinib, analyse les caractéristiques pharmacocinétiques et pharmcodynamiques de cette combinaison et évalue son efficacité, du point de vue du taux de réponse globale
Purpose: Enhanced MAPK pathway signaling and cell cycle checkpoint dysregulation are frequent in NRAS-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination. Experimental Design: This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with NRAS-mutant melanoma (NCT01781572). Primary objectives were to estimate the maximum tolerated dose/recommended phase II dose (RP2D) of the combination (phase Ib) and to characterize combination antitumor activity at the RP2D (phase II). Tumor genomic characterization and pharmacokinetic (PK)/pharmacodynamics were also evaluated. Results: Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (n=41) for the selected RP2D (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5% (8/41; 95% CI, 8.8-34.9). The response rate was 32.5% (13/40; 95% CI 20.1-48.0) in patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1. Median progression-free survival was 3.7 months (95% CI 3.5-5.6) and median overall survival was 11.3 months (95% CI 9.3-14.2) for all patients. Common treatment-related toxicities included creatine phosphokinase elevation, rash, edema, anemia, nausea, diarrhea, and fatigue. PK and safety were consistent with single-agent data, supporting a lack of drug-drug interaction. Conclusions: Ribociclib + binimetinib can be safely administered and is clinically active in patients with NRAS-mutant melanoma. Co-mutations of cell cycle genes may define a population with greater likelihood of treatment benefit.