Volume 12 Supplement 1
Updated results and correlative FDG-PET analysis of a phase IB study of vemurafenib and cobimetinib (MEK inhibitor [GDC-0973]), in advanced BRAF V600 - mutated melanoma (BRIM7)
© Puzanov et al; licensee BioMed Central Ltd. 2014
Published: 6 May 2014
BRIM7 is a phase 1B study evaluating the safety and efficacy of combined BRAF and MEK inhibition with vemurafenib + cobimetinib. The utility of FDG-PET as an early predictor of clinical benefit was also evaluated in this study.
Materials and methods
Eligible patients (pts) had advanced BRAF V600 -mutated melanoma and ECOG PS 0-1 and were either naïve to BRAF inhibitor (BRAFi-naïve) or had disease progression on vemurafenib (vem-progressor). Pts in the dose-escalation portion received vemurafenib 720 or 960 mg BID continuously and cobimetinib 60, 80, or 100 mg QD 14 days (d) on/14 d off (14/14); 21 d on/7 d off (21/7); or continuously (28/0). Two dose levels were expanded: vemurafenib (720 mg and 960 mg BID) + cobimetinib 60 mg QD 21/7. FDG-PET scans were performed at baseline and on Day 15 of Cycles 1 and 2. Correlation between tumor glucose metabolism changes, baseline tumor burden and target lesion responses were evaluated.
128 pts were treated with vemurafenib + cobimetinib as of 21 June 2013; male 60%, median age 55 y (19-88), stage M1c 76% and BRAFi-naive 49%. Median duration of follow-up in vem-progressor and BRAFi-naïve pts was 3 and 10 months, respectively. Most adverse events (AE) were mild to moderate in severity and vem-progressor pts reported fewer AEs compared to BRAFi-naïve pts. Most common AEs in BRAFi-naïve pts (n=63) were non-acneiform rash (89%), diarrhea (81%), photosensitivity/sunburn (70%), fatigue (67%) and liver test abnormality (59%). Most frequent grade ≥3 AEs in BRAFi-naïve pts were liver test abnormality (19%), non-acneiform rash (13%), arthralgia (11%) and fatigue (10%).
BRAFi-naive pts attained 85% confirmed response rate (RR), including 10% complete responses; median PFS was not reached at 10 months follow-up. Vem-progressor pts attained 15% confirmed RR, stable disease of 43%, and median PFS of 2.8 months. Preliminary FDG-PET analysis showed that the magnitude of reduction in tumor glucose uptake correlated with maximal tumor reduction, but the degree of correlation varied across time and in BRAFi-naïve and Vem-progressor pts.
Vemurafenib + cobimetinib can be safely administered at the respective single-agent MTDs of vemurafenib (960 mg BID) and cobimetinib (60 mg 21/7). Preliminary efficacy of the combination is encouraging in BRAFi-naive patients. FDG-PET is a potentially useful marker of early biologic response to the combination.
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.