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 results were presented at the European Society of Medical Oncology
(ESMO) 2014 Congress and published in the New England Journal of
Medicine. Roche has already submitted the coBRIM data to the
European Medicines Agency.
About the coBRIM study
CoBRIM 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 Zelboraf,
compared to 960 mg twice daily of Zelboraf 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 Zelboraf every day on a 28-day cycle plus either
cobimetinib or placebo on days 1-21. Treatment was continued until
disease progression, unacceptable toxicity or withdrawal of consent.
Investigator-assessed PFS was 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.
There was a higher overall frequency of Grade 3 or higher adverse events
in the combination arm (65 vs. 59 percent), with close to half of these
due to lab abnormalities (mainly increased blood levels of liver enzymes
and CPK). Common adverse events (occurring in more than 20 percent)
observed at a higher frequency (all grades) in the combination arm
compared to the Zelboraf arm included diarrhea (57 vs. 28 percent),
nausea (39 vs. 24 percent), photosensitivity (28 vs. 16 percent), lab
abnormalities (increased alanine aminotransferase [ALT, 24 vs. 18
percent], increased aspartate aminotransferase [AST, 22 vs. 13 percent],
increased CPK [30 vs. 3 percent]) and vomiting (21 vs. 12 percent).
Common adverse events observed at a lower frequency in the combination
arm included hair loss (14 vs. 29 percent), thickening of the outer
layer of the skin (10 vs. 29 percent) and joint pain (33 vs. 40
percent). Most instances of each common adverse event were Grade 1 or 2
in severity.
Other select adverse events that were lower in the combination arm
included cutaneous squamous cell carcinomas (3 vs. 11 percent; all
grades) and keratoacanthomas (<1 vs. 8 percent; all grades). Serous
retinopathy (collection of fluid under the retina) was observed at a
higher frequency in the combination arm (20 vs. <1 percent) with most of
these events either Grade 1 or 2 and temporary in nature. Specific
adverse events leading to withdrawal from treatment were similar in both
study arms, as was the overall discontinuation rate from treatment (13
vs. 12 percent).
About melanoma
Melanoma is less common, but more aggressive and deadlier than other
forms of skin cancer. When melanoma is diagnosed early, it is generally
a curable disease, but most people with advanced melanoma have a poor
prognosis. The American Cancer Society estimates there will be more than
76,100 new cases of melanoma and approximately 9,700 melanoma deaths
this year in the United States. In recent years, there have been
significant advances in treatment for metastatic melanoma and people
with the disease have more options. However, it continues to be a
serious health issue with a high unmet need and a steadily increasing
incidence over the past 30 years.
About the cobimetinib and Zelboraf combination
Cobimetinib is designed to selectively block the activity of MEK, one of
a series of proteins inside cells that make up a signaling pathway that
helps regulate cell division and survival. Cobimetinib binds to MEK
while Zelboraf binds to mutant BRAF, another protein on the pathway, to
interrupt abnormal signaling that can cause tumors to grow.
About cobimetinib
Cobimetinib (GDC-0973, XL518) was discovered by Exelixis Inc. and is
being developed in collaboration with Exelixis. Cobimetinib is also
being investigated in combination with several investigational
medicines, including an immunotherapy, in several tumor types such as
non-small cell lung cancer, colorectal cancer, triple-negative breast
cancer and melanoma.
About Zelboraf
Zelboraf is a prescription medicine used to treat a type of skin cancer
called melanoma that has spread to other parts of the body or cannot be
removed by surgery, and has a certain type of abnormal “BRAF” gene. BRAF
is mutated in approximately half of melanomas. A patient’s healthcare
provider will perform a test to make sure that Zelboraf is right for the
patient. Zelboraf is not used to treat melanoma with a normal BRAF gene.
It is not known if Zelboraf is safe and effective in children under 18
years of age.
Zelboraf is now approved in more than 80 countries and has been used to
treat more than 11,000 patients worldwide. Zelboraf was co-developed
under a 2006 license and collaboration agreement between Roche and
Plexxikon, now a member of the Daiichi Sankyo Group.
Important Safety Information
Zelboraf can cause serious side effects, including risk of cancers.
Zelboraf may cause a type of skin cancer called cutaneous squamous
cell carcinoma (cuSCC). New melanoma lesions have occurred in people who
take Zelboraf. Zelboraf may also cause another type of cancer called
non-cutaneous squamous cell carcinoma (SCC). Patients must talk with
their healthcare provider about their risk for these cancers. Patients
must check their skin and tell their doctor about skin changes including
a new wart, a sore or bump that bleeds or does not heal, or a mole that
changes size or color.
A patient’s healthcare provider should also check for cancers that may
not occur on the skin. Patients must tell their healthcare provider
about any new symptoms that they get while taking Zelboraf.
While taking Zelboraf, patients should avoid sunlight. When they go
outside, patients must wear clothes that protect their skin, including
their head, face, hands, arms and legs. Patients must use lip balm and a
broad-spectrum sunscreen with SPF 30 or higher.
Possible serious side effects of Zelboraf include severe allergic
reactions, severe skin reactions, potentially life-threatening changes
in the electrical activity of the heart called QT prolongation, liver
injury and eye problems. Patients must tell their doctor if they are
pregnant or plan to become pregnant, as Zelboraf can harm a patient’s
unborn baby.
Common side effects of Zelboraf include joint pain, rash, hair loss,
tiredness, sunburn or sun sensitivity, nausea, itching or warts.
Patients must tell their doctor if they have any side effect that
bothers them or does not go away. These are not all of the possible side
effects of Zelboraf. For more information about side effects, patients
should ask their doctor or pharmacist.
Report side effects to the FDA at (800) FDA-1088 or http://www.fda.gov/medwatch.
Report side effects to Genentech at (888) 835-2555.
Patients should read the full Prescribing Information and Medication
Guide for additional Important Safety Information at http://www.zelboraf.com.
About Genentech
Founded more than 35 years ago, Genentech is a leading biotechnology
company that discovers, develops, manufactures and commercializes
medicines to treat patients with serious or life-threatening medical
conditions. The company, a member of the Roche Group, has headquarters
in South San Francisco, California. For additional information about the
company, please visit http://www.gene.com.
Copyright Business Wire 2014