Data from Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with <i>NRAS</i>-mutant Melanoma

Abstract

<div>AbstractPurpose:<p>Enhanced MAPK pathway signaling and cell-cycle checkpoint dysregulation are frequent in <i>NRAS</i>-mutant melanoma and, as such, the regimen of the MEK inhibitor binimetinib and the selective CDK4/6 inhibitor ribociclib is a rational combination.</p>Patients and Methods:<p>This is a phase Ib/II, open-label study of ribociclib + binimetinib in patients with <i>NRAS</i>-mutant melanoma (NCT01781572). Primary objectives were to estimate the MTD/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 pharmacokinetics/pharmacodynamics were also evaluated.</p>Results:<p>Ten patients (16.4%) experienced dose-limiting toxicities in cycle 1 of phase Ib. Overall response rate in the phase II cohort (<i>n</i> = 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% confidence interval (CI), 8.8–34.9]. The response rate was 32.5% (13/40; 95% CI, 20.1–48.0) in patients with <i>NRAS</i> mutation with concurrent alterations of <i>CDKN2A</i>, <i>CDK4</i>, or <i>CCND1</i>. 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. Pharmacokinetics and safety were consistent with single-agent data, supporting a lack of drug–drug interaction.</p>Conclusions:<p>Ribociclib + binimetinib can be safely administered and is clinically active in patients with <i>NRAS</i>-mutant melanoma. Co-mutations of cell-cycle genes may define a population with greater likelihood of treatment benefit.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-1256" target="_blank">See related commentary by Moschos, p. 2977</a></i></p></div>