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

Schuler M, Zimmer L, Kim KB, Sosman JA, Ascierto PA, Postow MA, De Vos FY, van Herpen CM, Carlino MS, Johnson DB, Berking C, Reddy MB, Harney AS, Berlin JD, Amaria RN (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Clinical Cancer Research American Association for Cancer Research

Book Volume: 28

Pages Range: 3002-3010

Journal Issue: 14

DOI: 10.1158/1078-0432.CCR-21-3872

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.

Authors with CRIS profile

Carola Berking Lehrstuhl für Haut- und Geschlechtskrankheiten

Involved external institutions

Universitätsklinikum Essen DE Germany (DE) California Pacific Medical Center US United States (USA) (US) Northwestern University US United States (USA) (US) Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" IT Italy (IT) Memorial Sloan Kettering Cancer Center US United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Crown Princess Mary Cancer Centre AU Australia (AU) Pfizer, Inc. US United States (USA) (US) Vanderbilt University Medical Center US United States (USA) (US) University of Texas MD Anderson Cancer Center US United States (USA) (US)

How to cite

APA:

Schuler, M., Zimmer, L., Kim, K.B., Sosman, J.A., Ascierto, P.A., Postow, M.A.,... Amaria, R.N. (2022). Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma. Clinical Cancer Research, 28(14), 3002-3010. https://doi.org/10.1158/1078-0432.CCR-21-3872

MLA:

Schuler, Martin, et al. "Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma." Clinical Cancer Research 28.14 (2022): 3002-3010.

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