Phase Ib/II Trial of Ribociclib in Combination with Binimetinib in Patients with NRAS-Mutant Melanoma
Schuler, Martin; Zimmer, Lisa; Kim, Kevin B; Sosman, Jeffrey A; Ascierto, Paolo A; Postow, Michael A; De Vos, Filip; van Herpen, Carla M L; Carlino, Matteo S; Johnson, Douglas B; Berking, Carola; Reddy, Micaela B; Harney, Allison S; Berlin, Jordan D; Amaria, Rodabe N
(2022) Clinical cancer research : an official journal of the American Association for Cancer Research, volume 28, issue 14, pp. 3002 - 3010
(Article)
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 þ binimetinib in patients
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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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Keywords: Oncology, Cancer Research, Journal Article
ISSN: 1078-0432
Publisher: American Association for Cancer Research Inc.
Note: Funding Information: M. Schuler reports personal fees from Amgen, BIOCAD, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Merck Serono, Novartis, Roche, Sanofi, and Takeda, as well as grants and personal fees from AstraZeneca and Bristol Myers Squibb outside the submitted work. L. Zimmer reports grants, personal fees, and other support from Novartis, as well as personal fees and other support from Pierre Fabre during the conduct of the study. L. Zimmer also reports grants, personal fees, and other support from Novartis, as well as personal fees and other support from Pierre Fabre, Bristol Myers Squibb, MSD, Sanofi, and Sun Pharma outside the submitted work. K.B. Kim reports personal fees and other support from Array Pharmaceuticals outside the submitted work. P.A. Ascierto reports grants and personal fees from Bristol Myers Squibb, Roche-Genentech, Sanofi, and Pfizer/Array, as well as personal fees from MSD, Novartis, Merck-Serono, Pierre-Fabre, AstraZeneca, Sun Pharma, Idera, Sandoz, Immunocore, 4SC, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regen-eron, Daiichi Sankyo, Oncosec, Nouscom, Lunaphore, Seagen, iTeos, and Medicenna outside the submitted work. M.A. Postow reports personal fees from RGenix, Infinity, Array BioPharma, Incyte, NewLink Genetics, Aduro, Eisai, and Pfizer; grants and personal fees from Bristol Myers Squibb, Merck, and Novartis; and grants from AstraZeneca outside the submitted work. F.Y.F.L. De Vos reports other support from Pfizer during the conduct of the study; F.Y.F.L. De Vos also reports other support from AbbVie, Bristol Myers Squibb, Novartis, Vaximm, BioClin Therapeutics, and EORTC, as well as grants from Foundation STOPbraintumors outside the submitted work. C.M.L. van Herpen reports grants from Bayer, Ipsen, MSD, AstraZeneca, Merck, Novartis, and Sanofi outside the submitted work. M.S. Carlino reports personal fees from MSD, Bristol Myers Squibb, Amgen, Ideaya, OncoSec, Pierre Fabre, QBiotics, Regeneron, Roche, Sanofi, Eisai, and Merck outside the submitted work. D.B. Johnson reports other support from Pfizer and Novartis during the conduct of the study, as well as other support from Bristol Myers Squibb, Catalyst, Iovance, Janssen, Merck, Mosaic ImmunoEngineering, Novartis, Pfizer, Oncosec, and Targovax outside the submitted work. C. Berking reports personal fees from Bristol Myers Squibb, MSD, Roche, Novartis, Sanofi, Regeneron, Immunocore, Pierre Fabre, Almirall Hermal, InflaRx, and Leo Pharma outside the submitted work. A.S. Harney reports personal fees from Pfizer during the conduct of the study, as well as personal fees from Array Biopharma outside the submitted work. J.D. Berlin reports grants from Novartis during the conduct of the study. J.D. Berlin also reports grants and personal fees from EMD Serono, Bayer, and Karyopharm; personal fees from AstraZeneca, QED, Ipsen, Clovis, Mirati, Insmed, Oxford Biotech, and Novocure; Funding Information: We thank the patients and their families, as well as the participating study teams, for making this study possible. This study was sponsored by Array BioPharma in collaboration with Novartis. Array BioPharma was acquired by Pfizer in July 2019. Editorial/medical writing assistance was provided by JD Cox, PhD, of Mayville Medical Communications and Tracey Lonergan, PhD of Caudex, both funded by Pfizer Inc. M.A. Postow would like to acknowledge NIH/NCI Cancer Center Support Grant P30 CA008748. Publisher Copyright: ©2022 The Authors; Published by the American Association for Cancer Research
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