MEK Inhibition in a Patient with Concurrent BRAF- and NRAS-Mutant Malignancies

Vemurafenib, a RAF inhibitor, extends survival in patients with BRAF V600 -mutant melanoma but activates extracellular signal–regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAF V600K -mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP–ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma. SIGNIFICANCE: We show that in a patient with simultaneous RAS-mutant leukemia and BRAF-mutant melanoma, intermittent RAF inhibitor therapy induced a near-complete melanoma response, and addition of a MEK inhibitor prevented RAF inhibitor-induced activation of the RAS-mutant leukemia. Intermittent therapy may permit greater pathway inhibition with less toxicity, avoid chronic relief of pathway feedback, and have enhanced effectiveness compared with chronic administration. Cancer Discov; 4(5); 538–45. ©2014 AACR. See related commentary by Davies, p. 510. Authors’ Affi liations: 1 Human Oncology and Pathogenesis Program, 2 Leukemia Service, 3 Gastrointestinal Oncology Service, 4 Melanoma and Immunotherapeutics Service, Department of Medicine, 5 Molecular Diagnostics Service, Department of Pathology, 6 Department of Radiology, 7 Center for Molecular Oncology, 8 Ludwig Center for Cancer Immunotherapy, and 9 Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center; and 10 Weill Cornell Medical College, New York, New York Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/). Corresponding Author: Paul B. Chapman, Memorial Sloan-Kettering Cancer Center, Room 1007, 300 East 66th Street, New York, NY 10065. Phone: 646-888-4162; Fax: 646-888-4253; E-mail: [email protected] doi: 10.1158/2159-8290.CD-13-1038 ©2014 American Association for Cancer Research. INTRODUCTION Activating mutations at the V600 codon of BRAF are found in 40% to 60% of melanomas. These mutations lead to hyperactivation of the extracellular signal–regulated kinase (ERK) pathway, which causes feedback inhibition of RAS activation and maintains the RAF kinases in a monomeric state. Currently available ATP-competitive RAF inhibitors, such as vemurafenib, bind to BRAF V600E monomer and thus on April 2, 2017. © 2014 American Association for Cancer Research. cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst March 3, 2014; DOI: 10.1158/2159-8290.CD-13-1038