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- Updated results from coBRIM phase 3 pivotal trial show median progression-free survival of one year for patients with BRAF V600 mutation-positive advanced melanoma –
- Additional data from phase 1b BRIM7 study showed 61 percent of patients who had not been previously treated with a BRAF inhibitor were alive after two years -
- Cobimetinib for use in combination with vemurafenib is the subject
of pending U.S. and European regulatory applications, with U.S. PDUFA
“The updated results for the combination of cobimetinib and vemurafenib,
including a median progression-free survival of one year in patients
with previously untreated BRAF V600 mutation-positive advanced melanoma,
are encouraging,” said
The updated results from coBRIM also showed higher response rates with cobimetinib and vemurafenib compared to vemurafenib alone. Objective response rate, a secondary endpoint of the trial, was 70% (16% compete response [CR], 54% partial response [PR]) with the combination compared to 50% (11% CR, 40% PR) with vemurafenib alone. The CR rate with the combination has increased from 10% to 16% with further follow-up as some patients who had an initial PR achieved a CR after more than one year of treatment. The safety profile of the combination was consistent with data previously reported. The most common adverse events in the combination arm include diarrhea, rash, nausea, fever, sun sensitivity, liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and vomiting.
Follow-up data from BRIM7, the phase 1b study that provided the rationale for the coBRIM pivotal trial, demonstrated that the combination of cobimetinib and vemurafenib resulted in a median overall survival of 28.5 months, with 61% of BRAF inhibitor-naive patients remaining alive after two years. The safety profile from the BRIM7 trial was consistent with previous analyses, and the incidence of serous retinopathy, cardiomyopathy and cutaneous squamous cell carcinoma were similar to those previously reported.
The coBRIM data will be presented in an oral session today by Dr.
The cobimetinib New Drug Application for BRAF V600 mutation-positive
advanced melanoma was granted priority review by the
About the coBRIM Study
The coBRIM trial is an international, randomized, double-blind, placebo-controlled Phase III study evaluating the safety and efficacy of 60 mg once daily of cobimetinib in combination with 960 mg twice daily of vemurafenib, compared to 960 mg twice daily of vemurafenib alone. In the study, 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma (detected by the cobas® 4800 BRAF Mutation Test) and previously untreated for advanced disease, were randomized to receive vemurafenib every day on a 28-day cycle plus either cobimetinib or placebo for days 1-21. Treatment was continued until disease progression, unacceptable toxicity or withdrawal of consent. Investigator-assessed PFS is the primary endpoint. Secondary endpoints include PFS by independent review committee, overall response rate, overall survival, duration of response and other safety, pharmacokinetic and quality of life measures.
The most common adverse events reported in patients taking cobimetinib in combination with vemurafenib (≥ 20%) were diarrhea, rash, nausea, fever, sun sensitivity, liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and vomiting. Serous retinopathy (collection of fluid under the retina) was observed at a higher frequency in the combination arm (26% vs. 3%) with most of these events either Grade 1 or 2, asymptomatic, and temporary in nature. Some adverse events, including cutaneous squamous cell carcinomas and keratoacanthomas, were reported less frequently in the combination arm.
About the BRIM7 Study
BRIM7 is a Phase 1b study of 129 patients evaluating the safety and tolerability of cobimetinib in combination with vemurafenib in people with BRAF V600 mutation-positive unresectable or metastatic melanoma who had either not been previously treated with a BRAF inhibitor or had shown disease progression following treatment with a BRAF inhibitor. The primary endpoint of the BRIM7 study focused on safety, tolerability, and the identification of an optimal dose. The secondary outcome measures focused on efficacy. Patients in the dose-escalation stage of the study received cobimetinib 60, 80 or 100 mg once daily given on a schedule of 14 days on/14 days off; 21 days on/7 days off; or continuously for 28 days, and vemurafenib 720 or 960 mg twice daily continuously. Following the dose-escalation stage, two dose levels were selected for further investigation: cobimetinib 60 mg once daily for 21 days on/7 days off and vemurafenib (720 mg or 960 mg twice daily).
The most common adverse events were mild to moderate in severity, and the overall frequency of adverse events with an extended median follow-up of up to 21 months have remained consistent without new safety signals.
About the Cobimetinib Development Collaboration
About the Cobimetinib and Vemurafenib Combination
Cobimetinib is a selective inhibitor that blocks the activity of MEK, a protein kinase that is part of a key pathway (the RAS-RAF-MEK-ERK pathway) that promotes cell division and survival. This pathway is frequently activated in human cancers including melanoma, where mutation of one of its components (BRAF) causes abnormal activation in about 50% of tumors. Tumors with BRAF mutations may develop resistance and subsequently progress after treatment with a BRAF inhibitor. In preclinical melanoma models, co-treatment with a BRAF inhibitor and a MEK inhibitor may delay the emergence of resistant tumors. In addition to the combination with vemurafenib in melanoma, cobimetinib is also being investigated in combination with several investigational medicines, including an immunotherapy, in several tumor types, including non-small cell lung cancer, colorectal cancer, triple-negative breast cancer and melanoma.
About Melanoma and its BRAF V600 Mutation-Positive Form
Melanoma is the less common, but more serious category of skin cancer
that starts in the skin’s pigment producing cells known as melanocytes.
According to the
This press release contains forward-looking statements, including,
without limitation, statements related to: the continued development and
clinical, therapeutic and commercial potential of cobimetinib for use in
combination with vemurafenib; future potential regulatory approvals of
cobimetinib; data presentations for the coBRIM phase 3 pivotal trial and
the phase 1b BRIM7 study; Exelixis’ co-promotion efforts with Genentech
in the event of regulatory approval; the plan of Genentech
and Exelixis to share U.S. profits and losses for cobimetinib and U.S.
marketing and commercialization costs for cobimetinib;
Exelixis’ potential receipt of royalties on sales of cobimetinib
products outside the
Susan Hubbard, 650-837-8194
Investor Relations and Corporate Communications
For Exelixis, Inc.
Hal Mackins, 415-994-0040