Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma

Abstract

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.

Patients and methods: 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 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.

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% confidence interval (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. Pharmacokinetics 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. See related commentary by Moschos, p. 2977.

©2022 The Authors; Published by the American Association for Cancer Research.

Figures

Figure 1.

Study design. BID, twice daily; BINI, binimetinib; PR, partial response; QD, once daily; RIBO, ribociclib.

Figure 2.

Kaplan–Meier estimates of (A) PFS in phase Ib dose escalation and phase II dose expansion and (B) OS in phase II dose expansion. CI confidence interval; OS, overall survival; PFS, progression-free survival.

Figure 3.

Tumor change from baseline by presence of cell-cycle alterations. Waterfall plot of best change from baseline (%) tumor in evaluable patients (top). Dark gray bars = no cell-cycle gene alterations; light gray bars = cell-cycle gene alterations. Oncoprint of cell-cycle gene alteration (16) by patient (bottom). Red rectangles are amplification, blue rectangles are loss of copy, and purple squares are short variants. The biomarker analysis set consisted of all patients who provided a biomarker sample for DNA sequencing and had at least one reported result, even if the result was that no gene alteration was found. PD, progressive disease; PR, partial response; SD, stable disease; UN, unknown.