Exelixis Announces Positive Overall Survival Results from Phase 3 Pivotal Trial of Cobimetinib in Combination with Vemurafenib in Patients with BRAF V600 Mutation-Positive Advanced Melanoma

“Exelixis, Inc.EXEL, -1.02% today announced positive overall survival (OS) results from coBRIM, the phase 3 pivotal trial evaluating cobimetinib, a specific MEK inhibitor discovered by Exelixis, 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.”


Cobimetinib and Vemurafenib Combination Treatment Is Highly Active in BRAF+ Melanoma

“Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced follow-up data from two studies of the investigational MEK inhibitor cobimetinib in combination with Zelboraf® (vemurafenib). Updated data from the pivotal coBRIM Phase III study showed the combination helped people with previously untreated BRAF V600 mutation-positive advanced melanoma live a median of one year (12.3 months) without their disease worsening or death (progression-free survival; PFS) compared to 7.2 months with Zelboraf alone (hazard ratio [HR]=0.58, 95 percent confidence interval [CI] 0.46-0.72).1

“ ‘The combination of cobimetinib and Zelboraf extended the time people lived without their disease getting worse to a year,’ said Sandra Horning, M.D., Chief Medical Officer and Head of Global Product Development. ‘These results are exciting because they underscore the importance of combining medicines that target the signals, which cause about half of all melanomas to grow.’ “


Roche Gets FDA Priority Review for Cancer Treatment

“Roche Holding AG said Thursday one of its skin cancer treatments had been granted a priority review by the U.S. Food and Drug Administration, cutting the time the drug might take to become available to patients.

“Basel-based Roche said the FDA would make an accelerated decision on its cobimetinib drug when used with another medication, Zelboraf, to treat a serious form of skin cancer known as BRAF V600 mutation-positive melanoma. The drug is being developed by Genentech, part of the Roche Group, and Exelixis, Inc. which is a biopharmaceutical company.

“In a late stage trial of the drug, cobimetinib raised the median length of time patients experienced no worsening of their disease to 9.9 months when used with Zelboraf, up from 6.2 months for Zelboraf alone, Roche said.

“The priority review cuts the FDA decision time to six months from the standard 10 months.”


New Drug Combo Might Soon Be an Option for People with Advanced Melanoma with BRAF V600 Mutation

The gist: A combination of the drugs cobimetinib and vemurafenib (aka Zelboraf) might soon become a new treatment option for U.S. patients with advanced melanoma whose tumors have a V600 mutation in the BRAF gene. The drug company Genentech submitted a New Drug Application to the U.S. Food and Drug Administration (FDA) asking for FDA approval of the combo. In a clinical trial, Genentech researchers found that patients who take cobimetinib along with vemurafenib do better than patients who take vemurafenib alone. Both drugs are targeted therapies.

“Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), today announced the company has submitted a New Drug Application (NDA) for cobimetinib to the U.S. Food and Drug Administration (FDA) for treatment, in combination with Zelboraf® (vemurafenib), for people with BRAF V600 mutation-positive advanced melanoma. The submission is based on results of the coBRIM Phase III study, which showed people who received the MEK inhibitor cobimetinib plus Zelboraf lived significantly longer without their disease worsening or death (progression-free survival; PFS) compared to Zelboraf alone.

” ‘In the past several years we have made significant progress in treating advanced melanoma, but it remains a serious and difficult to treat cancer that affects more people each year,’ said Sandra Horning, M.D., chief medical officer and head of Global Product Development. ‘We look forward to working with the FDA as they review the NDA and hope the combination of cobimetinib and Zelboraf will soon become a new option for people with BRAF mutation-positive advanced melanoma.’

“In the coBRIM study, cobimetinib and Zelboraf 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 Grade 3 or higher adverse events in the combination arm included liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity and lab abnormalities. The most common Grade 3 or higher adverse events in the combination arm included liver lab abnormalities, elevated creatine phosphokinase (CPK, an enzyme released by muscles) and diarrhea.”


New Standard in Melanoma: Combo of BRAF and MEK Inhibitors

The gist: Two new, similar melanoma treatments have been tested in clinical trials—research studies with volunteer patients. Both of the trials are focused on people with advanced melanoma whose tumors have mutations in the BRAF gene. Such patients are often treated with a targeted therapy called a BRAF inhibitor, but their tumors often become resistant and keep growing. In these two trials, the researchers hope that combining BRAF inhibitors with other targeted drugs known as MEK inhibitors might help patients avoid resistance. One of the trials tested a combination of the drugs vemurafenib and cobimetinib. The other trial combined dabrafenib and trametinib. In both trials, patients treated with the combination treatment fared better than patients treated with just a BRAF inhibitor alone.

“For patients with advanced melanoma that isBRAF-mutation positive, the combination of a BRAF and MEK inhibitor works better than a BRAF inhibitor alone. The data come from 2 phase 3 trials presented here at the presidential session of the European Society for Medical Oncology (ESMO) Congress 2014.

“Experts here say that such combinations should be the new standard of care in this patient population, which accounts for about 40% of all melanoma.

“At present, the first-line treatment for these patients is a BRAF inhibitor used alone, but while these drugs can elicit dramatic responses, they do not last, and after about 5 or 6 months, patients relapse. The tumor develops resistance to the drug via the MAPK pathway, and this is blocked by a MEK inhibitor. Adding a MEK inhibitor to the BRAF inhibitor from the beginning of treatment blocks this resistance pathway and improves outcomes.

“The 2 new trials are known as COMBI-v and coBRIM.

“Both studies used vemurafenib (Zelboraf, Roche/Plexxikon) as the single BRAF inhibitor, but each used a different combination of BRAF and MEK inhibitor.”


Roche Drugs Shown Effective in Breast and Skin Cancers

The gist: Drug company giant Roche is mixing drugs in new combinations to provide melanoma and breast cancer patients with potential new treatments. This article outlines the company’s endeavors.

“Mixing drugs in various combinations has given Roche Holding AG (ROG) effective new treatments for skin and breast cancer strains.

“Combining Zelboraf, a melanoma drug now on the market, with experimental cobimetinib showed significant improvement over Zelboraf alone, according to data presented today at the European Society for Medical Oncology’s annual meeting in Madrid.

“Roche said yesterday that a combination of two breast cancer drugs, plus chemotherapy, could add almost 16 months to the lives of a class of patients. Roche today also reported data from an early-stage study of its MPDL3280A immune therapy treatment in bladder cancer which showed a 52 percent response rate. If successfully developed, the drug will be the first new treatment for bladder cancer in 30 years, the Basel, Switzerland-based company said.

“ ‘This is a good meeting for Roche,’ said Asthika Goonewardene, an analyst with Bloomberg Intelligence. ‘They’re firing in three different areas.'”


ESMO 2014 Press Release: New Data on Combination Treatments for Melanoma

The gist: Researchers tested a new melanoma treatment in a clinical trial—a research study with volunteer patients. The treatment combines the targeted drugs vemurafenib and cobimetinib. All of the patients who participated in the trial had melanoma tumors with mutations in the BRAF gene, as detected by molecular testing. The combination treatment proved more beneficial for these patients than vemurafenib alone.

“Combination therapy with both BRAF inhibitor vemurafenib and MEK inhibitor cobimetinib achieves greater progression-free survival and response rates than vemurafenib plus placebo in BRAF-mutation positive melanoma, according to phase III data presented at the ESMO 2014 Congress in Madrid, Spain.

“ ‘Before the results of this study, we knew that cobimetinib plus vemurafenib could be safely delivered together with highly promising rates of tumour shrinkage; however until the performance of a scientifically rigorous randomised trial the potential magnitude of this benefit could not be measured,’ says lead author Dr Grant McArthur, head of the Cancer Therapeutics Program at the Peter MacCallum Cancer Centre, Melbourne, Australia.

“The ongoing CoBRIM study enrolled 495 treatment-naive patients with BRAFV600-mutation-positive unresectable locally advanced or metastatic melanoma. Patients were randomised to received a 28-day treatment cycle of vemurafenib (960 mg, twice daily), and either cobimetinib or placebo (60 mg daily from days 1-21), with a primary end-point of progression-free survival.

“Patients in the combination arm of the study showed a significantly improved median progression-free survival of 9.9 months, compared to 6.2 months in the placebo arm, and a 49% reduction in the risk of progression. Researchers observed a response rate of 68% in the combination arm and 45% in the control arm, including a complete response in 10% of patients treated with combination therapy compared to 4% of patients treated with vemurafenib alone.”


Combined MEK, BRAF Inhibitors Promising in Melanoma

The gist: Researchers have conducted a clinical trial with volunteer patients to test a new melanoma treatment that combines the drugs cobimetinib and vemurafenib. The participants all had melanoma tumors with BRAFV600 mutations. People with BRAFV600 mutations often become resistant to treatment if they take a “BRAF inhibitor” like vemurafenib. The hope is that drugs like cobimetinib can be given alongside vemurafenib to circumvent resistance. The researchers found that the combination treatment was safe for these patients, and there was some promising evidence that the treatment was effective, but more follow-up will be needed.

“Combined treatment of BRAFV600-mutated melanoma with the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib was safe and tolerable, according to the results of a phase Ib study.

“Based on the promising antitumor activity seen with the combination, researchers led by Antoni Ribas, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues recommended further clinical development and testing of this combination.

“According to background information published with the study in Lancet Oncology, patients with BRAFV600-mutated metastatic melanoma often develop resistance to treatment with a BRAF inhibitor, ‘which frequently reactivates the MAPK pathway through MEK.’ Prior research has shown that sequential treatment with a MEK inhibitor after this progression does not result in meaningful antitumor activity.”


UPDATE 1-Roche Skin Cancer Drug Meets Main Goal in Combination Study

“An experimental drug from Roche helped people with an advanced form of skin cancer live longer without their disease worsening when used in combination with another treatment, the Swiss drugmaker said on Monday.

“Pharmaceutical companies are looking to combination therapy to yield better results and drug cocktails are expected to be crucial as oncologists seek to block cancer on multiple fronts.

“Cobimetinib, which is being developed in collaboration with Exelixis Inc, is designed to be used with another Roche drug called Zelboraf for patients with tumors that have a mutation in a gene known as BRAF that allows melanoma cells to grow.”

Editor’s note: Cobimetinib is meant to be used in combination with the targeted therapy Zelboraf (vemurafenib) to treat people with melanoma whose tumors have a mutation in the BRAF gene. Oncologists can use a method called molecular testing to figure out whether a patient has a BRAF mutation.