On May 10, 2018 Exelixis, Inc. (Nasdaq:EXEL) reported that IMblaze370, the phase 3 pivotal trial of atezolizumab (TECENTRIQ), an anti-PDL1 antibody discovered and developed by Genentech, a member of the Roche Group, and cobimetinib (COTELLIC), an Exelixis-discovered MEK inhibitor, did not meet its primary endpoint (Press release, Exelixis, MAY 10, 2018, View Source;p=RssLanding&cat=news&id=2348344 [SID1234526398]). Genentech, Exelixis’ collaborator and sponsor of the IMblaze370 trial, informed the company that the combination of atezolizumab and cobimetinib did not deliver an improvement in overall survival (OS) versus regorafenib. The IMblaze370 trial evaluated the combination in patients with difficult-to-treat, locally advanced or metastatic colorectal cancer (CRC) whose disease had progressed or who were intolerant to at least two systemic chemotherapy regimens.
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The safety profile for the combination appeared consistent with the known safety profile of each individual medicine, and no new safety signals were identified with the combination. Genentech will further examine results from IMblaze370 and plans to present the data at an upcoming medical meeting.
"We are disappointed that the IMblaze370 trial did not reach a positive conclusion," said Michael M. Morrissey, Ph.D., President and Chief Executive Officer of Exelixis. "Metastatic colorectal cancer is an aggressive and difficult-to-treat disease, and patients and clinicians would be well served by additional treatment options. We will continue to work with Genentech on the evaluation of cobimetinib’s potential in other tumor types, including in melanoma, in which there are two ongoing phase 3 pivotal trials. Separately, Exelixis remains focused on and committed to maximizing the potential of the cabozantinib franchise through our commercial activities and ongoing clinical development program evaluating the compound alone, or in combination with immune checkpoint inhibitors, across numerous tumor types."
Other ongoing late-stage clinical trials of cobimetinib include: IMspire150 TRILOGY, a fully enrolled study of cobimetinib, vemurafenib, and atezolizumab in previously untreated patients with BRAF V600-positive metastatic melanoma; and IMspire170, which is evaluating cobimetinib and atezolizumab in BRAF V600-wild type metastatic melanoma.
About the IMblaze370 Phase 3 Pivotal Trial
In early June 2016, shortly before the initial presentation of data from the phase 1b clinical trial of cobimetinib and atezolizumab at the 2016 Annual Meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper), Genentech initiated IMblaze370, a phase 3 pivotal trial of cobimetinib plus atezolizumab and atezolizumab monotherapy versus regorafenib in patients with locally advanced or metastatic CRC who had received at least two prior regimens of chemotherapy. The trial enrolled 363 patients who were randomized 2:1:1 to receive cobimetinib plus atezolizumab, atezolizumab alone, or regorafenib.
Patients in the combination arm received cobimetinib on days 1 to 21 plus atezolizumab on day 1 and day 15 in a 28-day cycle. Patients in the experimental monotherapy arm received atezolizumab on day 1 of each 21-day cycle. Patients in the control arm received regorafenib on days 1 to 21 in a 28-day cycle. All patients continued to receive study drug until clinical benefit was no longer observed.
The primary endpoint of IMblaze370 is OS; key secondary endpoints include progression-free survival, objective response rate, and duration of response. IMblaze370 completed enrollment in the first quarter of 2017. More information about IMblaze370 is available at www.clinicaltrials.gov.
About the Cobimetinib Development Collaboration
Exelixis discovered cobimetinib internally and advanced the compound to investigational new drug (IND) status. In late 2006, Exelixis entered into a worldwide collaboration agreement 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 entitled to an initial equal share of U.S. profits and losses, which will decrease as sales increase, and shares U.S. commercialization costs. Outside of the United States, Exelixis is eligible to receive royalties on any sales.
Cobimetinib is now approved in multiple countries, including the U.S., European Union, Switzerland, Canada, Australia and Brazil, to treat specific forms of BRAF mutation-positive unresectable or metastatic melanoma, in combination with vemurafenib (ZELBORAF). The trade name for cobimetinib is COTELLIC. Cobimetinib is also the subject of a clinical development program aimed at evaluating its potential in combination with a variety of investigational and approved therapies in disease settings including metastatic melanoma, triple-negative breast cancer and colorectal carcinoma.
Important: If a patient’s healthcare provider prescribes ZELBORAF (vemurafenib), the patient should also read the Medication Guide that comes with ZELBORAF.
COTELLIC Indication
COTELLIC is a prescription medicine that is used with the medicine ZELBORAF 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
that has a certain type of abnormal "BRAF" gene.
A patient’s healthcare provider will perform a test to make sure that COTELLIC is right for the patient. It is not known if COTELLIC is safe and effective in children under 18 years of age.
Important Safety Information
Before taking COTELLIC, patients should tell their healthcare provider about all of their medical conditions, including if they:
have skin problems or history of skin problems, other than melanoma
have bleeding problems, any medical conditions and/or on any medications that increase the risk of bleeding
have heart problems
have eye problems
have liver problems
have muscle problems
are pregnant or plan to become pregnant. COTELLIC can harm an unborn baby.
Females who are able to become pregnant should use effective birth control during treatment with COTELLIC, and for two weeks after the final dose of COTELLIC.
Patients should talk to their healthcare provider about birth control methods that may be right for them.
Patients should tell their healthcare provider right away if they become pregnant or think they are pregnant during treatment with COTELLIC.
are breastfeeding or plan to breastfeed. It is not known if COTELLIC passes into breast milk. Patients should not breastfeed during treatment with COTELLIC and for two weeks after the final dose of COTELLIC. Patients should talk to their healthcare provider about the best way to feed their baby during this time.
Patients should tell their healthcare provider about all the medicines they take, including prescription and over-the-counter medicines, vitamins and herbal supplements. Certain medicines may affect the blood levels of COTELLIC.
Patients should know the medicines they take and keep a list of them to show their healthcare provider and pharmacist when they get a new medicine.
How should patients take COTELLIC?
Patients should take COTELLIC exactly as their healthcare provider tells them. Patients should not change their dose or stop taking COTELLIC unless their healthcare provider tells them to.
Patients should take COTELLIC one time a day for 21 days, followed by seven days off treatment, to complete a 28-day treatment cycle.
Patients can take COTELLIC with or without food.
If a patient vomits after taking their dose of COTELLIC, they should not take an additional dose.
If a patient misses a dose of COTELLIC, they should take their next dose as scheduled.
What should patients avoid during treatment with COTELLIC?
Patients should avoid sunlight during treatment with COTELLIC. COTELLIC can make a patient’s skin sensitive to sunlight. They may burn more easily and get severe sunburns. To help protect against sunburn:
When a patient goes outside, they should wear clothes that protect their skin, including their head, face, hands, arms and legs.
They should use lip balm and a broad-spectrum sunscreen with SPF 30 or higher.
What are the possible side effects of COTELLIC?
COTELLIC may cause serious side effects, including:
Risk of new skin cancers. COTELLIC may cause new skin cancers (cutaneous squamous cell carcinoma, keratoacanthoma or basal cell carcinoma).
Patients should check their skin regularly and tell their healthcare provider right away if they have any skin changes including:
new wart
skin sore or reddish bump that bleeds or does not heal
change in size or color of a mole
A patient’s healthcare provider should check the patient’s skin before they start taking COTELLIC, and every two months during treatment with COTELLIC. A patient’s healthcare provider may continue to check the patient’s skin for six months after the patient stops taking COTELLIC.
A patient’s healthcare provider should also check for cancers that may not occur on the skin. Patients should tell their healthcare provider about any new symptoms that develop during treatment with COTELLIC.
Bleeding problems. COTELLIC can cause serious bleeding problems.
Patients should call their healthcare provider and get medical attention right away if they get any signs of bleeding, including:
red or black stools (looks like tar)
blood in their urine
headaches
cough up or vomit blood
stomach (abdominal) pain
unusual vaginal bleeding
dizziness or weakness
Heart problems. A patient’s healthcare provider should do tests before and during treatment to check the patient’s heart function. Patients should tell their healthcare provider if they get any of these signs and symptoms of heart problems:
persistent coughing or wheezing
shortness of breath
swelling of their ankles and feet
tiredness
increased heart rate
Severe rash. Patients should tell their healthcare provider right away if they get any of these symptoms:
a rash that covers a large area of their body
blisters
peeling skin
Eye problems. Patients should tell their healthcare provider right away if they get any of these symptoms:
blurred vision
partly missing vision or loss of vision
see halos
any other vision changes
A patient’s healthcare provider should check the patient’s eyes if the patient notices any of the symptoms above.
Liver problems. A patient’s healthcare provider should do blood tests to check the patient’s liver function before and during treatment. Patients should tell their healthcare provider right away if they get any of these symptoms:
yellowing of their skin or the white of their eyes
dark or brown (tea color) urine
nausea or vomiting
feeling tired or weak
loss of appetite
Muscle problems (rhabdomyolysis). COTELLIC can cause muscle problems that can be severe. Treatment with COTELLIC may increase the level of an enzyme in the blood called creatine phosphokinase (CPK) and may be a sign of muscle damage. A patient’s healthcare provider should do a blood test to check the patient’s levels of CPK before and during treatment. Patients should tell their healthcare provider right away if they get any of these symptoms:
muscle aches or pain
muscle spasms and weakness
dark, reddish urine
Skin sensitivity to sunlight (photosensitivity). Skin sensitivity to sunlight during treatment with COTELLIC is common and can sometimes be severe. Patients should tell their healthcare provider if they get any of these symptoms:
red, painful, itchy skin that is hot to touch
sun rash
skin irritation
bumps or tiny papules
thickened, dry, wrinkled skin
See "What should patients avoid during treatment with COTELLIC?" for information on protecting the skin during treatment with COTELLIC.
The most common side effects of COTELLIC include:
diarrhea
nausea
fever
vomiting
A patient’s healthcare provider will take blood tests during treatment with COTELLIC. The most common changes to blood tests include:
increased blood levels of liver enzymes (GGT, ALT or AST)
increased blood level of enzyme from muscle (creatine phosphokinase)
decreased blood level of phosphate, sodium or potassium
increased blood level of liver or bone enzyme (alkaline phosphatase)
decreased blood level of a type of white blood cell (lymphocyte)
These are not all the possible side effects of COTELLIC. Patients should call their doctor for medical advice about side effects. Patients may report side effects to FDA at (800) FDA-1088 or www.fda.gov/medwatch. Patients may also report side effects to Genentech at (888) 835-2555.
Please see Full COTELLIC Prescribing Information and Patient Information for additional Important Safety Information at www.COTELLIC.com.
TECENTRIQ (atezolizumab), COTELLIC (cobimetinib) and ZELBORAF (vemurafenib) are registered trademarks of Genentech, a member of the Roche Group