Reference Detail

Ref Type

Journal Article

PMID

(35294522)

Authors

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

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research			2022 Mar 16	3002-3010	Clin Cancer Res

URL

Abstract Text

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.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.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.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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS Q61X	melanoma	sensitive	Binimetinib + Ribociclib	Phase Ib/II	Actionable	In a Phase Ib/II trial, Kisqali (ribociclib) plus Mektovi (binimetinib) was well tolerated in NRAS-mutant melanoma patients and resulted in an overall response rate (ORR) of 19.5% (8/41; all PR), disease control rate of 70.7% (29/41), median duration of response of 10.3 months, median progression-free survival of 3.7 months, and median overall survival (OS) of 11.3 months in the phase II cohort, and a response rate of 22.9% (16/70) in patients with an NRAS Q61 mutation overall (PMID: 35294522; NCT01781572).	35294522
NRAS act mut	melanoma	predicted - sensitive	Binimetinib + Ribociclib	Phase Ib/II	Actionable	In a Phase Ib/II trial, Kisqali (ribociclib) plus Mektovi (binimetinib) was well tolerated in NRAS-mutant melanoma patients and resulted in an overall response rate of 19.5% (8/41; all PR), disease control rate of 70.7% (29/41), median duration of response of 10.3mo, median progression-free survival of 3.7mo, and median overall survival of 11.3mo in phase II, and a response rate of 22.9% (16/70) in patients with an NRAS Q61 mutation, and 12.5% (1/8) with NRAS G12/G13 mutation (PMID: 35294522; NCT01781572).	35294522