Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma

Jean Pierre Delord, Caroline Robert, Marta Nyakas, Grant A. McArthur, Ragini Kudchakar, Amit Mahipal, Yasuhide Yamada, Ryan Sullivan, Ana Arance, Richard F. Kefford, Matteo S. Carlino, Manuel Hidalgo, Carlos Gomez-Roca, Daniela Michel, Abdelkader Seroutou, Vassilios Aslanis, Giordano Caponigro, Darrin D. Stuart, Laure Moutouh-De Parseval, Tim DemuthReinhard Dummer

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40 Scopus citations

Abstract

Purpose: 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 BRAF-mutant melanoma. Experimental Design: 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 BRAF-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. Results: Preclinical data demonstrated that encorafenib inhibited BRAF V600E kinase activity with a prolonged off-rate and suppressed proliferation and tumor growth of BRAF 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). Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)5339-5348
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number18
DOIs
StatePublished - Sep 15 2017
Externally publishedYes

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Delord, J. P., Robert, C., Nyakas, M., McArthur, G. A., Kudchakar, R., Mahipal, A., Yamada, Y., Sullivan, R., Arance, A., Kefford, R. F., Carlino, M. S., Hidalgo, M., Gomez-Roca, C., Michel, D., Seroutou, A., Aslanis, V., Caponigro, G., Stuart, D. D., Moutouh-De Parseval, L., ... Dummer, R. (2017). Phase I dose-escalation and -expansion study of the BRAF inhibitor encorafenib (LGX818) in metastatic BRAF-mutant melanoma. Clinical Cancer Research, 23(18), 5339-5348. https://doi.org/10.1158/1078-0432.CCR-16-2923