Phase II study of vemurafenib followed by ipilimumab in patients with previously untreated BRAF-mutated metastatic melanoma

Abstract

Background: Ipilimumab (IPI), an anti-CTLA-4 antibody, and vemurafenib (VEM), a BRAF inhibitor, have distinct mechanisms of action and shared toxicities (e.g., skin, gastrointestinal [GI] and hepatobiliary disorders) that may preclude concomitant administration. Concurrent administration of IPI and VEM previously showed significant dose-limiting hepatotoxicity in advanced melanoma. This single-arm, open-label, phase II study evaluated a sequencing strategy with these two agents in previously untreated patients with BRAF-mutated advanced melanoma.

Methods: This study was divided into two parts. During Part 1 (VEM1-IPI), patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg every 3 weeks for 4 doses (induction), then every 12 weeks (maintenance) beginning at week 24 until disease progression or unacceptable toxicity. During Part 2 (VEM2), patients who progressed after IPI received VEM at their previously tolerated dose. The primary objective was to estimate the incidence of grade 3/4 drug-related skin adverse events (AEs) during VEM1-IPI.

Results: All patients who were initially treated with VEM (n = 46) received IPI induction therapy; 8 received IPI maintenance and 19 were treated during VEM2. During VEM1-IPI, the incidence of grade 3/4 drug-related AEs associated with the skin, GI tract, and hepatobiliary system was 32.6 %, 21.7 %, and 4.3 %, respectively. There were no drug-related deaths. At a median follow-up of 15.3 months, median overall survival was 18.5 months. Median progression-free survival was 4.5 months.

Conclusions: VEM (960 mg twice daily for 6 weeks) followed by IPI 10 mg/kg has a manageable safety profile. The benefits/risks of BRAF inhibitors followed by immunotherapy should be evaluated further in light of continuing developments in treatment options for metastatic melanoma.

Trial registration: ClinicalTrials.gov identifier: NCT01673854 (CA184-240) Registered 24 August 2012.

Keywords: BRAF inhibitor; CTLA-4; Immune checkpoint inhibitor; Immunotherapy; Ipilimumab; Melanoma; Targeted agent; Vemurafenib.

Figures

Fig. 1

This study was divided into two parts: VEM1-IPI and VEM2. During VEM1-IPI, patients received VEM 960 mg twice daily for 6 weeks followed by IPI 10 mg/kg induction and maintenance therapy. During VEM2, patients who progressed after IPI received VEM at their previously tolerated dose (a). Among 70 patients who enrolled in this study, 46 were treated during VEM1 and continued to IPI induction. Eight patients received IPI maintenance therapy. Nineteen patients were treated during VEM2. Reasons for discontinuation of study drug are provided (b). AE = adverse event; BID = twice daily; IPI = ipilimumab; PO = by mouth; PD = progressive disease; Q3W = every 3 weeks; Q12W = every 12 weeks; VEM = vemurafenib

Fig. 2

Kaplan-Meier curves for DOR (a) and DOSD (b) during VEM1-IPI. The median DOR was 23.1 months (95 % CI: 5.03–not evaluable), and the median DOSD was 5.2 months (95 % CI: 3.98–14.75)

Fig. 3

Kaplan-Meier curves for PFS during VEM1-IPI (a) and OS (b). The median PFS was 4.5 months (95 % CI: 4.17–6.57). At a median follow-up of 15.3 months, the median OS was 18.5 months (95 % CI: 11.96–not evaluable)