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  5. Drug Trials Snapshots: COTELLIC
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Drug Trials Snapshots: COTELLIC

HOW TO USE THIS SNAPSHOT
The information provided in Snapshots highlights who participated in the clinical trials that supported the FDA approval of this drug, and whether there were differences among sex, race and age groups. The “MORE INFO” bar shows more detailed, technical content for each section. The Snapshot is intended as one tool for consumers to use when discussing the risks and benefits of the drugs.

LIMITATIONS OF THIS SNAPSHOT:
Do not rely on Snapshots to make decisions regarding medical care. Always speak to your health provider about the risks and benefits of a drug. Refer to the COTELLIC Prescribing Information for complete information.

COTELLIC(cobimetinib)
Co-TELL-ic
Genentech, Inc.
Approval date: November 10, 2015


DRUG TRIALS SNAPSHOT SUMMARY:

What is the drug for?

COTELLIC is a drug which is to be used with another drug, vemurafenib, to treat a type of skin cancer called melanoma. COTELLIC is only to be used in patients with melanoma with a specific abnormal gene (called BRAF V600E or V600K mutation) that has spread to other parts of the body (advanced melanoma) or cannot be removed by surgery.

How is this drug used?

COTELLIC is a tablet that is taken by mouth once daily for 21 days, followed by a 7-day rest period (no drug), to make a 28-day cycle.

What are the benefits of this drug?

Compared to patients taking vemurafenib alone, patients taking COTELLIC plus vemurafenib had a delay in the amount of time it took for the disease to worsen (approximately 12.3 months after starting treatment) compared to approximately 7.2 months after starting treatment for patients taking vemurafenib only.

In addition, patients taking COTELLIC alone:

  • lived longer (65% of patients were alive 17 months after starting treatment compared to 50% of patients taking vemurafenib only).
  • experienced complete or partial shrinkage of their tumors more often (70% of patients) compared to 50% of patients taking vemurafenib only.

What are the benefits of this drug (results of trials used to assess efficacy)?

The table below summarizes efficacy results for the clinical trial.

Table 2. Efficacy Results from the Clinical Trial

 COTELLIC + Vemurafenib (n=247)Placebo + Vemurafenib (n=248)
Progression-free Survival (Investigator-Assessed)
Number of Events (%)143 (58%)180 (73%)
Progression131169
Death1211
Median PFS, months (95% CI)12.3 (9.5, 13.4)7.2 (5.6,7.5)
Hazard Ratio (95% CI)0.56 (0.45, 0.70)
p-value (stratified log-rank test)<>
Overall Survival
Number of Deaths (%)79 (32%)109 (44%)
Median OS, months (95% CI)NE (20.7, NE)17.0 (15.0, NE)
Hazard Ratio (95% CI)0.63 (0.47, 0.85)
p -value (stratified log-rank test)0.0019
Objective Response Rate
Objective Response Rate70%50%
(95% CI)(64%, 75%)(44%, 56%)
Complete Response16%10%
Partial Response54%40%
P-value<>
Median Duration of Response, months (95% CI)13.0 (11.1, 16.6)9.2 (7.5, 12.8)

CI=Confidence Interval; NE=Not Estimable
aStatistical significance depending on the comparison to the allocated alpha of 0.019 for this interim analysis
COTELLIC Prescribing Information, Table 5

Were there any differences in how well the drug worked in clinical trials among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: COTELLIC worked similarly in men and women.
  • Race: COTELLIC worked similarly in whites and non-whites.
  • Age: The majority of patients were below the age of 65. Differences in response to COTELLIC in patients below and above age 65 could not be determined.

Were there any differences in how well the drug worked in clinical trials among sex, race, and age groups?

The table below summarizes efficacy results by subgroup.

Figure 4. Progression-Free Survival Results in Demographic Subgroups (Intent to Treat Population)

Table summarizes efficacy results by subgroup trial.

FDA Review

What are the possible side effects?

The most common side effects of treatment with COTELLIC in combination with vemurafenib are diarrhea, sensitivity to ultraviolet (UV) light (photosensitivity reaction), nausea, fever, and vomiting.

COTELLIC may cause severe side effects including damage to the heart muscle or to other muscles, new skin tumors, eye disease (retinal detachment), severe skin rash, liver damage, bleeding throughout the body because of a ruptured blood vessel (hemorrhage), and severe skin rash due to increased sensitivity to sunlight. People taking COTELLIC should avoid sun exposure, and wear protective clothing and a broad spectrum ultraviolet A/ultraviolet B sunscreen to protect against sunburn. Women taking COTELLIC should use effective birth control methods, as the medication can cause harm to a developing fetus.

What are the possible side effects (results of trials used to assess safety)?

The table below summarizes adverse drug reactions in the clinical trial.

Table 3. Incidence of Adverse Drug Reactions Occurring in ≥10% (All Grades) of Patients Receiving COTELLIC with Vemurafenib and at a Higher Incidence* than Patients Receiving Vemurafenib in the Clinical Trial

Adverse ReactionsCOTELLIC + Vemurafenib
(N=247)
Placebo +
Vemurafenib
(N=246)
All Gradesa
(%)
Grades
3–4
(%)
All Grades
(%)
Grades
3–4
(%)
GASTROINTESTINAL DISORDERS
Diarrhea606311
Nausea411251
Vomiting241131
Stomatitisb14180
SKIN AND SUBCUTANEOUS TISSUE DISORDERS
Photosensitivity reactionc464350
Acneiform dermatitis162111
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
Pyrexia282230
Chills10050
VASCULAR DISORDERS
Hypertension15482
Hemorrhaged1317<>
EYE DISORDERS
Vision impairede15<>40
Chorioretinopathy13<><>0
Retinal detachmentf122<>0

* ≥5% for All Grades or ≥2% for Grades 3–4 incidence in patients receiving COTELLIC with vemurafenib compared with patients receiving vemurafenib as a single agent
a NCI CTCAE, v4.0.
b Includes stomatitis, apthous stomatitis, mouth ulceration, and mucosal inflammation
c Includes solar dermatitis, sunburn, photosensitivity reaction
d Includes hemorrhage, rectal hemorrhage, melena, hemorrhoidal hemorrhage, gastrointestinal hemorrhage, hematemesis, hematochezia, gingival bleeding, metrorrhagia, uterine hemorrhage, hemorrhagic ovarian cyst, menometrorrhagia, menorrhagia, vaginal hemorrhage, hemoptysis, pulmonary, cerebral, subarachnoid hemorrhage, subgaleal hematoma, hematuria, epistaxis, contusion, traumatic hematoma, ecchymosis, purpura, nail bed bleeding, ocular, eye, conjunctival, and retinal hemorrhage
e Includes vision blurred, visual acuity reduced, visual impairment
f Includes retinal detachment, detachment of retinal pigment epithelium, detachment of macular retinal pigment epithelium
COTELLIC Prescribing Information, Table 3

Were there any differences in side effects among sex, race and age?

Subgroup analyses were conducted for sex, race and age.

  • Sex: The risk of side effects was similar in men and women.
  • Race: The majority of patients were white. It could not be determined whether there were differences in whites and non-whites.
  • Age: Certain adverse events, called serious adverse events and Grade 3 adverse events, were more common in patients 65 years of age and older.

Were there any differences in side effects of the clinical trials among sex, race, and age groups?

Table 4. Per-patient Incidence of Serious Adverse Events and Adverse Events of ≥Grade 3 by Age and Sex Group (Safety Population)

EventAge/SexPlacebo + VemurafenibCOTELLIC + Vemurafenib
Serious adverse event (N)n (%)(N)n (%)
 <>9324(26)11231 (28)
 <>7912 (15)7720 (26)
 ≥ 65/M4017 (43)3920 (51)
 ≥ 65/F2711 (41)2613 (50)
Grade ≥ 3 adverse event
 <>9353 (57)11273 (65)
 <>7940 (51)7748 (62)
 ≥ 65/M4029 (73)3931 (79)
 ≥ 65/F2724 (89)2624 (92)

FDA Clinical Review

WHO WAS IN THE CLINICAL TRIALS?

Who participated in the clinical trials?

The FDA approved COTELLIC based on evidence from one clinical trial of 495 patients with melanoma containing the BRAF V600 mutation that was advanced or could not be removed by surgery. The trial was conducted at 133 sites in 19 countries including those in North America, Europe, and Australia.

Figure 1 summarizes how many men and women were enrolled in the clinical trial used to evaluate efficacy.

Figure 1. Baseline Demographics by Sex

Pie chart summarizing how many men and women were enrolled in the clinical trial used to evaluate efficacy of the drug COTELLIC.  In total, 286 men (58%) and 209 women (42%) participated in the clinical trial used to evaluate efficacy of the drug COTELLIC.

Clinical Trial Data

Figure 2 and Table 1 summarize the percentage of patients by race enrolled in the clinical trial used to evaluate efficacy.

Figure 2. Baseline Demographics by Race

Pie chart summarizing the percentage of patients by race enrolled in the COTELLIC clinical trial. In total, 462 Whites (93%) and 33 Non-white (7%) participated in the clinical trial.

Clinical Trial Data

Table 1. Baseline Demographics by Race

RaceNumber of PatientsPercentage
White46293%
Non-White337%

Clinical Trial Data

The figure below summarizes the percentage of patients by age enrolled in the clinical trial.

Figure 3. Baseline Demographics by Age (years)

Pie chart summarizing how many individuals of certain age groups were enrolled in the COTELLIC clinical trial.  In total, 362 participants were below 65 years old (73%) and 133 participants were 65 and older (27%).

Clinical Trial Data

Who participated in the trials?

The table below summarizes baseline demographics for patients in the trial.

Table 5. Baseline Demographics for the Clinical Trial

 COTELLIC +
Vemurafenib
N=247
n (%)
Placebo + Vemurafenib
N=248
n (%)
Total
N=495
n (%)
Sex
Male146 (59)140 (56)286 (58)
Female101 (41)108 (44)209 (42)
Race
White227 (92)235 (95)462 (93)
Non-white20 (8)13 (5)33 (7)
Age
<65>183 (74)179 (72)362 (73)
≥65 years64 (26)69 (28)133 (27)

Clinical Trial Data

How were the trials designed?

The benefits and side effects of COTELLIC taken in combination with vemurafenib were evaluated in a clinical trial in patients with previously untreated advanced melanoma containing a certain type of abnormal gene (called BRAF V600E or V600K mutation) and that spread to other parts of the body or that could not be removed by surgery. All patients received vemurafenib and were then randomly selected to also take either COTELLIC or a placebo.

Treatment continued until the disease progressed or there were unacceptable side effects.

How were the trials designed?

The safety and efficacy of COTELLIC was established in a multicenter, randomized (1:1), double-blinded, placebo-controlled trial conducted in patients with previously untreated, BRAF V600 mutation-positive, unresectable or metastatic, melanoma. The presence of BRAF V600 mutation was detected using the cobas® 4800 BRAF V600 mutation test. All patients received vemurafenib 960 mg orally twice daily on days 1–28 and were randomized to receive COTELLIC 60 mg or matching placebo orally once daily on days 1–21 of an every 28-day cycle. Randomization was stratified by geographic region (North America vs. Europe vs. Australia/New Zealand/others) and disease stage (unresectable Stage IIIc, M1a, or M1b vs. Stage M1c). Treatment continued until disease progression or unacceptable toxicity. Patients randomized to receive placebo were not offered COTELLIC at the time of disease progression.

The major efficacy outcome was investigator-assessed progression-free survival (PFS) per RECIST v1.1. Additional efficacy outcomes were investigator-assessed confirmed objective response rate, overall survival, PFS as assessed by blinded independent central review, and duration of response.

GLOSSARY

CLINICAL TRIAL: Voluntary research studies conducted in people and designed to answer specific questions about the safety or effectiveness of drugs, vaccines, other therapies, or new ways of using existing treatments.
COMPARATOR: A previously available treatment or placebo used in clinical trials that is compared to the actual drug being tested.
EFFICACY: How well the drug achieves the desired response when it is taken as described in a controlled clinical setting, such as during a clinical trial.
PLACEBO: An inactive substance or “sugar pill” that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.
SUBGROUP: A subset of the population studied in a clinical trial. Demographic subsets include sex, race, and age groups.

PRESCRIBING INFORMATION

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