TY - JOUR
T1 - Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-mutant Melanoma
AU - Schuler, Martin
AU - Zimmer, Lisa
AU - Kim, Kevin B.
AU - Sosman, Jeffrey A.
AU - Ascierto, Paolo A.
AU - Postow, Michael A.
AU - De Vos, Filip Y.F.L.
AU - van Herpen, Carla M.L.
AU - Carlino, Matteo S.
AU - Johnson, Douglas B.
AU - Berking, Carola
AU - Reddy, Micaela B.
AU - Harney, Allison S.
AU - Berlin, Jordan D.
AU - Amaria, Rodabe N.
N1 - Publisher Copyright:
©2022 The Authors; Published by the American Association for Cancer Research
PY - 2022/7/15
Y1 - 2022/7/15
N2 - 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 þ 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 ¼ 41) for the selected RP2D (binimetinib 45 mg twice daily þ 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 þ 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.
AB - 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 þ 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 ¼ 41) for the selected RP2D (binimetinib 45 mg twice daily þ 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 þ 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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U2 - 10.1158/1078-0432.CCR-21-3872
DO - 10.1158/1078-0432.CCR-21-3872
M3 - Article
C2 - 35294522
AN - SCOPUS:85131651373
SN - 1078-0432
VL - 28
SP - 3002
EP - 3010
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -