Phase I Dose-Escalation and -Expansion Study of the BRAF Inhibitor Encorafenib (LGX818) in Metastatic BRAF -Mutant Melanoma

• Published in: Clinical cancer research 2017-09, Vol.23 (18), p.5339-5348
• Main Authors: Delord, Jean-Pierre, Robert, Caroline, Nyakas, Marta, McArthur, Grant A, Kudchakar, Ragini, Mahipal, Amit, Yamada, Yasuhide, Sullivan, Ryan, Arance, Ana, Kefford, Richard F, Carlino, Matteo S, Hidalgo, Manuel, Gomez-Roca, Carlos, Michel, Daniela, Seroutou, Abdelkader, Aslanis, Vassilios, Caponigro, Giordano, Stuart, Darrin D, Moutouh-de Parseval, Laure, Demuth, Tim, Dummer, Reinhard
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - therapeutic use; Antitumor activity; Cancer; Carbamates - administration & dosage; Carbamates - adverse effects; Carbamates - pharmacokinetics; Carbamates - therapeutic use; Confidence intervals; Disease Models, Animal; Drug Evaluation, Preclinical; Drug Monitoring; Expansion; Experimental design; Female; Humans; Inhibitors; Kaplan-Meier Estimate; Male; Maximum Tolerated Dose; Melanoma; Melanoma - drug therapy; Melanoma - genetics; Melanoma - mortality; Melanoma - pathology; Metastases; Metastasis; Mice; Molecular Targeted Therapy; Mutation; Myalgia; Nausea; Neoplasm Staging; Patients; Pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - adverse effects; Protein Kinase Inhibitors - pharmacokinetics; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Sulfonamides - therapeutic use; Toxicity; Treatment Outcome; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-16-2923

Encorafenib, a selective BRAF inhibitor (BRAFi), has a pharmacologic profile that is distinct from that of other clinically active BRAFis. We evaluated encorafenib in a phase I study in patients with BRAFi treatment-naïve and pretreated -mutant melanoma. The pharmacologic activity of encorafenib was first characterized preclinically. Encorafenib monotherapy was then tested across a range of once-daily (50-700 mg) or twice-daily (75-150 mg) regimens in a phase I, open-label, dose-escalation and -expansion study in adult patients with histologically confirmed advanced/metastatic -mutant melanoma. Study objectives were to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D), characterize the safety and tolerability and pharmacokinetic profile, and assess the preliminary antitumor activity of encorafenib. Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of V600E-mutant melanoma models. In the dose-escalation phase, 54 patients (29 BRAFi-pretreated and 25 BRAFi-naïve) were enrolled. Seven patients in the dose-determining set experienced dose-limiting toxicities. Encorafenib at a dose of 300 mg once daily was declared the RP2D. In the expansion phase, the most common all-cause adverse events were nausea (66%), myalgia (63%), and palmar-plantar erythrodysesthesia (54%). In BRAFi-naïve patients, the overall response rate (ORR) and median progression-free survival (mPFS) were 60% and 12.4 months [95% confidence interval (CI), 7.4-not reached (NR)]. In BRAFi-pretreated patients, the ORR and mPFS were 22% and 1.9 months (95% CI, 0.9-3.7). Once-daily dosing of single-agent encorafenib had a distinct tolerability profile and showed varying antitumor activity across BRAFi-pretreated and BRAFi-naïve patients with advanced/metastatic melanoma. .