Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor

Kevin B. Kim*, Richard Kefford, Anna C. Pavlick, Jeffrey R. Infante, Antoni Ribas, Jeffrey A. Sosman, Leslie A. Fecher, Michael Millward, Grant A. McArthur, Patrick Hwu, Rene Gonzalez, Patrick A. Ott, Georgina V. Long, Olivia S. Gardner, Daniele Ouellet, Yanmei Xu, Douglas J. DeMarini, Ngocdiep T. Le, Kiran Patel, Karl D. Lewis

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

Purpose BRAF mutations promote melanoma cell proliferation and survival primarily through activation of MEK. The purpose of this study was to determine the response rate (RR) for the selective, allosteric MEK1/MEK2 inhibitor trametinib (GSK1120212), in patients with metastatic BRAFmutant melanoma. Patients and Methods This was an open-label, two-stage, phase II study with two cohorts. Patients with metastatic BRAF-mutant melanoma previously treated with a BRAF inhibitor (cohort A) or treated with chemotherapy and/or immunotherapy (BRAF-inhibitor naive; cohort B) were enrolled. Patients received 2 mg of trametinib orally once daily. Results In cohort A (n = 40), there were no confirmed objective responses and 11 patients (28%) with stable disease (SD); the median progression-free survival (PFS) was 1.8 months. In cohort B (n = 57), there was one (2%) complete response, 13 (23%) partial responses (PRs), and 29 patients (51%) with SD (confirmed RR, 25%); the median PFS was 4.0 months. One patient each with BRAF K601E and BRAF V600R had prolonged PR. The most frequent treatment-related adverse events for all patients were skin-related toxicity, nausea, peripheral edema, diarrhea, pruritis, and fatigue. No cutaneous squamous cell carcinoma was observed. Conclusion Trametinib was well tolerated. Significant clinical activity was observed in BRAF-inhibitor-naive patients previously treated with chemotherapy and/or immunotherapy. Minimal clinical activity was observed as sequential therapy in patients previously treated with a BRAF inhibitor. Together, these data suggest that BRAF-inhibitor resistance mechanisms likely confer resistance to MEK-inhibitor monotherapy. These data support further evaluation of trametinib in BRAF-inhibitor- naive BRAF-mutant melanoma, including rarer forms of BRAF-mutant melanoma.

Original languageEnglish (US)
Pages (from-to)482-489
Number of pages8
JournalJournal of Clinical Oncology
Volume31
Issue number4
DOIs
StatePublished - Feb 1 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Kim, K. B., Kefford, R., Pavlick, A. C., Infante, J. R., Ribas, A., Sosman, J. A., Fecher, L. A., Millward, M., McArthur, G. A., Hwu, P., Gonzalez, R., Ott, P. A., Long, G. V., Gardner, O. S., Ouellet, D., Xu, Y., DeMarini, D. J., Le, N. T., Patel, K., & Lewis, K. D. (2013). Phase II study of the MEK1/MEK2 inhibitor trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. Journal of Clinical Oncology, 31(4), 482-489. https://doi.org/10.1200/JCO.2012.43.5966