Date: 2015-11-23
Type of information: Presentation of results at a congress
phase: 3
Announcement: presentation of results at the 12th International Congress of the Society for Melanoma Research (SMR) held in San Francisco
Company: Roche (Switzerland) Exelixis (USA - CA)
Product: cobimetinib in combination with Zelboraf® (vemurafenib)
Action
mechanism: kinase inhibitor/serine threonine kinase inhibitor. Cobimetinib (GDC-0973, XL518) was discovered by Exelixis and is being developed in collaboration with Exelixis. The compound is a selective inhibitor of mitogen-activated protein kinase kinase, also known as MEK, a serine/threonine kinase that is a component of the RAS/RAF/MEK/ERK pathway. This pathway mediates signaling downstream of growth factor receptors, and is prominently activated in a wide variety of human tumors. After discovering cobimetinib internally, Exelixis advanced the product to investigational new drug (IND) status. In late 2006, the company entered into its worldwide collaboration with Genentech, under which Exelixis received initial upfront and milestone payments for signing the agreement and submitting the IND. Following the determination of the maximum tolerated dose in phase 1 by Exelixis, Genentech exercised its option to further develop cobimetinib. Under the terms of the collaboration, Exelixis is eligible to receive royalties on sales of cobimetinib outside the United States. In November 2013, Exelixis exercised its option to co-promote cobimetinib, if approved, in the United States. Exelixis is entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and will share equally in the U.S. marketing and commercialization costs. Exelixis is eligible to receive royalties on any sales of the product outside the United States. Zelboraf® (vemurafenib) is a BRAF V600-targeted medicine for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma. The drug was co-developed under a 2006 license and collaboration agreement between Roche and Plexxikon, now a member of the Daiichi Sankyo Group.
Disease: previously untreated BRAF V600 mutation-positive advanced melanoma
Therapeutic area: Cancer - Oncology
Country: Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Hungary, Israel, Italy, The Netherlands, New Zealand, Norway, Russian Federation, Spain, sweden, Switzerland, Turkey, UK, USA
Trial
details: CoBRIM is an international, randomised, double-blind, placebo-controlled Phase III study evaluating the safety and efficacy of cobimetinib in combination with Zelboraf®, compared to Zelboraf® alone, in 495 patients with BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma, previously untreated for advanced disease.6 The primary endpoint for coBRIM is PFS. Secondary endpoints include overall survival, objective response rate, duration of response and other safety, pharmacokinetic and quality of life measures.
The coBRIM study used the Roche cobas 4800 BRAF Mutation Test to determine eligibility of patients for the study. This test identifies people whose tumours carry the BRAF V600 mutation, 7 and therefore, patients who are most appropriate to receive this combination of treatments. (NCT01689519)
Latest
news: * On November 23, 2015, Roche announced data from the pivotal coBRIM study, which showed that Cotellic® (cobimetinib) in combination with Zelboraf® (vemurafenib) helped people with BRAF V600E and V600K mutation-positive unresectable or metastatic melanoma live significantly longer (overall survival; OS) than with Zelboraf® alone. Cotellic® plus Zelboraf® reduced the risk of death by 30 percent compared to Zelboraf® alone and helped people live a median of nearly two years (median OS 22.3 months vs. 17.4 months, hazard ratio [HR]=0.70, 95 percent CI: 0.55–0.90, p=0.005). Ongoing study monitoring did not identify any new safety signals. The final coBRIM OS results were presented during the 12th International Congress of the Society for Melanoma Research (SMR) held in San Francisco, California from 18 – 21 November. * On October 6, 2015, Exelixis announced positive overall survival (OS) results from coBRIM, the phase 3 pivotal trial evaluating cobimetinib in combination with vemurafenib in previously untreated patients with unresectable locally advanced or metastatic melanoma carrying a BRAF V600 mutation. Exelixis’ collaborator Genentech, a member of the Roche Group, informed the company that coBRIM met its secondary endpoint of demonstrating a statistically significant and clinically meaningful increase in overall survival for patients receiving the combination of cobimetinib and vemurafenib, as compared to vemurafenib monotherapy. Ongoing study monitoring did not identify any new safety signals. Long-term safety data are expected later this year. These data will be the subject of a presentation at an upcoming medical meeting. Exelixis announced the first regulatory approval of cobimetinib in Switzerland in August 2015. U.S. and EU regulatory applications sponsored by Genentech and Roche, respectively, are currently under review. In the United States, the Prescription Drug User Fee Act action date is November 11, 2015. In the EU, Roche anticipates a regulatory decision by the end of this year following a positive opinion from the European Committee for Medicinal Products for Human Use announced in late September. * On May 30, 2015, Exelixis announced updated positive results for cobimetinib in combination with vemurafenib for the treatment of patients with previously untreated BRAF V600 mutation-positive advanced melanoma. Updated data from coBRIM (Abstract #9006), the phase 3 pivotal trial conducted by Exelixis’ collaborator Genentech, showed the combination helped patients with previously untreated BRAF V600 mutation-positive advanced melanoma live a median of one year (12.3 months) without disease progression or death, compared to 7.2 months with vemurafenib alone (hazard ratio [HR] = 0.58, 95% confidence interval [CI] 0.46-0.72). Data from a second trial, the phase 1b BRIM7 study (Abstract #9020), showed that treatment with the combination resulted in a median overall survival of more than two years (28.5 months) for patients without prior BRAF inhibitor treatment. Both data sets will be presented at the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO), which is being held this week in Chicago, Illinois. 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 cobimetinib New Drug Application for BRAF V600 mutation-positive advanced melanoma was granted priority review by the FDA and a decision is expected by August 11, 2015. The European Medicines Agency is expected to make a decision on Roche’s marketing authorization application for cobimetinib before the end of this year. * On September 29, 2014, Roche and Genentech have announced positive data from the coBRIM Phase III study. The results showed that people with previously untreated BRAF V600 mutation-positive, advanced melanoma who received the MEK inhibitor cobimetinib plus Zelboraf® (vemurafenib) lived significantly longer without their disease worsening or death (progression-free survival; PFS) compared to Zelboraf alone. The combined therapy reduced the risk of disease worsening or death by half (hazard ratio [HR]=0.51, 95 percent confidence interval [CI] 0.39-0.68; p<0.0001), with a median PFS of 9.9 months for cobimetinib plus Zelboraf® compared to 6.2 months with Zelboraf® alone. The safety profile was consistent with a previous study of the combination. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity, and lab abnormalities. The coBRIM results were statistically significant across multiple secondary endpoints. The median PFS by independent review committee (IRC) was 11.3 months for the combination arm compared to 6.0 months for the control arm (HR=0.60, 95 percent CI 0.45-0.79; p=0.0003). The objective response rate (ORR) was higher in the combination compared to the control arm (68 vs. 45 percent; p<0.0001). Overall survival (OS) data are not yet mature. * On July 14, 2014, Roche announced that the Phase III coBRIM study met its primary endpoint. The study demonstrated that the investigational MEK inhibitor cobimetinib, used in combination with Zelboraf® (vemurafenib), helped patients with previously untreated BRAF V600 mutation-positive advanced melanoma live significantly longer without their disease worsening (progression-free survival; PFS) compared to Zelboraf® alone. Adverse events were consistent with those observed in a previous study of the combination. Data from this pivotal study will be presented at an upcoming medical meeting. Additionally, Roche plans to submit these data to the FDA, EMA, and other health authorities around the world for potential approval.
This final analysis of the OS data from coBRIM showed that with the combination of Cotellic and Zelboraf, 74.5 percent of people with BRAF V600 mutation-positive advanced melanoma in the study were alive at one year and 48.3 percent were alive at two years.The announcement follows the FDA approval of Cotellic® for the treatment of people with BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma in combination with Zelboraf. A decision from the European Commission is expected before the end of 2015. The final OS results are being submitted to both of these health authorities for consideration.
The late-breaking coBRIM data have been presented at ESMO 2014 today during the Presidential Symposium by Professor Grant McArthur, Peter MacCallum Cancer Centre, Australia (Abstract #LBA5_PR, Monday, September 29, 2014, 16:00-17:20 CEST) and are also part of the official press programme. Additionally, the study was published online in the New England Journal of Medicine.
Roche has submitted the coBRIM data to the European Medicines Agency and plans to submit a new drug application to the FDA later this year.
