Phase 1 study of the combination of vemurafenib, carboplatin, and paclitaxel in patients with BRAF-mutated melanoma and other advanced malignancies.

ABSTRACT

BACKGROUND: BRAF inhibitors are effective against selected BRAFV600 -mutated tumors. Preclinical data suggest that BRAF inhibition in conjunction with chemotherapy has increased therapeutic activity. METHODS: Patients with advanced cancers and BRAF mutations were enrolled into a dose-escalation study (3+3 design) to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs). RESULTS: Nineteen patients with advanced cancers and BRAF mutations were enrolled and received vemurafenib (480-720 mg orally twice a day), carboplatin (area under the curve [AUC] 5-6 intravenously every 3 weeks), and paclitaxel (100-135 mg/m2 intravenously every 3 weeks). The MTD was not reached, and vemurafenib at 720 mg twice a day, carboplatin at AUC 5, and paclitaxel at 135 mg/m2 were the last safe dose levels. DLTs included a persistent grade 2 creatinine elevation (n = 1), grade 3 transaminitis (n = 1), and grade 4 thrombocytopenia (n = 1). Non-dose-limiting toxicities that were grade 3 or higher and occurred in more than 2 patients included grade 3/4 neutropenia (n = 5), grade 3/4 thrombocytopenia (n = 5), grade 3 fatigue (n = 4), and grade 3 anemia (n = 3). Of the 19 patients, 5 (26%; all with melanoma) had a partial response (PR; n = 4) or complete response (CR; n = 1); these responses were mostly durable and lasted 3.1 to 54.1 months. Of the 13 patients previously treated with BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors, 4 (31%) had a CR (n = 1) or PR (n = 3). Patients not treated with prior platinum therapy had a higher response rate than those who did (45% vs 0%; P = .045). CONCLUSIONS: The combination of vemurafenib, carboplatin, and paclitaxel is well tolerated and demonstrates encouraging activity, predominantly in patients with advanced melanoma and BRAFV600 mutations, regardless of prior treatment with BRAF and/or MEK inhibitors.