Ribociclib–binimetinib combo safe, effective in NRAS-mutant melanoma

Treatment with the combination of ribociclib plus binimetinib appears to be well tolerated and delivers a modest clinical activity in patients with locally advanced or metastatic melanoma harbouring NRAS mutation, according to the results of a phase Ib/II study.

The study included 61 patients in the dose-escalation phase (Ib) and 41 (mean age 64 years, 36.6 percent female) in the dose-expansion phase (II). In the dose-escalation phase, 29 patients (mean age 58.5 years, 41.4 percent female) were treated in the 28-day treatment cycle and 32 (mean age 60.6 years, 43.8 percent female) in the 21-day treatment cycle. In the dose-expansion phase, patients were treated with binimetinib 45 mg twice daily plus ribociclib 200 mg once daily on the 28-day schedule.

In phase Ib, dose-limiting toxicities occurred in 10 patients (16.4 percent). In phase II, the overall response rate for the selected recommended phase II dose (binimetinib 45 mg twice daily + ribociclib 200 mg once daily, 21 days on/7 days off) was 19.5 percent (95 percent confidence interval [CI], 8.8–34.9).

The response rate was 32.5 percent (95 percent CI, 20.1–48.0) in the subgroup of patients with NRAS mutation with concurrent alterations of CDKN2A, CDK4, or CCND1.

For all patients, median progression-free survival was 3.7 months (95 percent CI, 3.5–5.6) while median overall survival was 11.3 months (95 percent CI, 9.3–14.2).

Common treatment-related toxicities were creatine phosphokinase elevation, rash, oedema, anaemia, nausea, diarrhoea, and fatigue. Pharmacokinetics and safety data support an absence of drug–drug interaction.

The findings indicate that patients with melanomas harbouring NRAS mutations and comutations of genes acting in the D-cyclin-CDK4/6-INK4a-Rb pathway at the G₁ cell-cycle checkpoint may represent a population who are likely to derive greater benefit from combined treatment with ribociclib plus binimetinib.