Dreno, B., Ribas, A., Larkin, J., Ascierto, P. A., Hauschild, A., Thomas, L., Grob, J. J., Koralek, D. O., Rooney, I., Hsu, J. J., McKenna, E. F., McArthur, G. A. (2017) Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. ANNALS OF ONCOLOGY, 28 (5). pp. 1137-1144. ISSN 0923-7534

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Abstract

Background: In the coBRIM phase III trial, the addition of cobimetinib, an MEK inhibitor, to vemurafenib, a BRAF inhibitor, significantly improved progression-free survival [hazard ratio (HR), 0.58; P < 0.0001] and overall survival (HR, 0.70; P = 0.005) in advanced BRAF-mutated melanoma. Here, we report on the incidence, course, and management of key adverse events (AEs) in the coBRIM study. Patients and methods: Patients were randomly assigned 1:1 to receive vemurafenib (960mg twice a day) and either cobimetinib (60mg once a day, 21 days on/7 days off) or placebo. In addition to standard safety evaluations, patients underwent regular ophthalmic, cardiac, and dermatologic surveillance examinations. Results: Of 495 patients recruited to the study, 493 patients received treatment and constituted the safety population (cobimetinib combined with vemurafenib, 247; vemurafenib, 246). At data cut-off (30 September 2015), median follow-up was 18.5 months. Nearly every patient experienced an AE. In patients who received cobimetinib combined with vemurafenib, the frequency of grade >= 3 AEs was higher than in patients who received vemurafenib alone (75% versus 61%). Most AEs, including grade >= 3 AEs, occurred within the first treatment cycle. After the first cycle (28 days), the incidence of common AEs (rash, diarrhoea, photosensitivity, elevated creatine phosphokinase, serous retinopathy, pyrexia, and liver laboratory abnormalities) decreased substantially over time. Most AEs were managed conservatively by supportive care measures, dose modifications of study treatment, and, occasionally, permanent treatment discontinuation. Conclusions: These data indicate that most AEs arising from treatment with cobimetinib combined with vemurafenib generally occur early in the treatment course, are mild or moderate and are manageable by patient monitoring, dose modification and supportive care.

Item Type:	Article
Authors (ICR Faculty only):	Larkin, James
All Authors:	Dreno, B., Ribas, A., Larkin, J., Ascierto, P. A., Hauschild, A., Thomas, L., Grob, J. J., Koralek, D. O., Rooney, I., Hsu, J. J., McKenna, E. F., McArthur, G. A.
Additional Information:	ISI Document Delivery No.: ET4VQ Times Cited: 0 Cited Reference Count: 16 Dreno, B. Ribas, A. Larkin, J. Ascierto, P. A. Hauschild, A. Thomas, L. Grob, J. -J. Koralek, D. O. Rooney, I. Hsu, J. J. McKenna, E. F. McArthur, G. A. F. Hoffmann-La Roche Ltd. This work was supported by F. Hoffmann-La Roche Ltd. No grant numbers applied. 0 OXFORD UNIV PRESS OXFORD ANN ONCOL
Uncontrolled Keywords:	cobimetinib MEK inhibition melanoma safety MEK INHIBITORS MELANOMA BRAF TRIAL
Research teams:	ICR divisions > Clinical Studies > Melanoma and Kidney Cancer Clinical Units > Renal & Melanoma Unit
Depositing User:	Barry Jenkins
Date Deposited:	23 May 2017 14:47
Last Modified:	23 May 2017 14:47
URI:	http://publications.icr.ac.uk/id/eprint/15941

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