Regulatory Decision Summary for COTELLIC

Review decision

The Regulatory Decision Summary explains Health Canada’s decision for the product seeking market authorization. The Regulatory Decision Summary includes the purpose of the submission and the reason for the decision.


Product type:

Drug

Medicinal ingredient(s):

cobimetinib fumarate

Therapeutic area:

Protein Kinase Inhibitor

Type of submission:

New Drug Submission (New Active Substance)

Control number:

182788
What was the purpose of this submission?

 

A New Drug Submission (NDS) was filed to obtain market authorization for Cotellic (cobimetinib), a protein kinase inhibitor, for use in combination with vemurafenib for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600 mutation.

 

Why was the decision issued?

 

Data to support the efficacy and safety of Cotellic (cobimetinib) in combination with vemurafenib for the treatment of adult patients with BRAF V600-mutation positive unresectable or metastatic melanoma were provided from pivotal Phase III Study GO28141 (coBRIM).

Cotellic in combination with vemurafenib showed a statistically significant increase in progression-free survival and objective response rate as compared to placebo in combination with vemurafenib in adult patients with previously untreated BRAF V600 mutation-positive unresectable locally advanced or metastatic melanoma. Median overall survival (OS) had not been reached in either treatment arm at the time of the pre-specified interim OS analysis, and the analysis did not cross the pre-specified boundary for statistical significance. Clinical data supporting the effectiveness of Cotellic in combination with vemurafenib in patients with a BRAF V600K mutation are limited and there are no clinical data for other less common BRAF V600 mutations.

Key clinical harms include the following: left ventricular dysfunction, haemorrhage (including major haemorrhage), serous retinopathy and retinal vein occlusion, hypertension, hepatotoxicity, hypersensitivity, increased serum creatine phosphokinase (CPK) levels and rhabdomyolysis, photosensitivity, and rash. Additional common adverse events that occurred with greater frequency in the Cotellic plus vemurafenib arm were diarrhea, nausea, vomiting, pyrexia, vision blurred, dehydration, hypophosphatemia, hyponatremia, basal cell carcinoma, hyperglycemia, atrial fibrillation, visual impairment, and pneumonitis. Adverse events were monitored for and managed using treatment interruption, dose reduction, and treatment discontinuation.

Although patients with mild hepatic impairment were permitted to enroll into the pivotal study, patients with moderate and severe hepatic impairment were not studied. As cobimetinib is metabolized and eliminated via the liver, patients with hepatic impairment may have increased exposure and increased toxicities. Concomitant use of Cotellic and drugs that strongly or moderately inhibit cytochrome P450 (CYP) enzyme CYP3A can increase cobimetinib exposure. Clinical data in patients using strong CYP3A inhibitors are limited.

Although an exposure-response analysis did not show a clear relationship between systemic exposure and safety in humans, a steep exposure-response was demonstrated in animals. In non-clinical toxicology studies, cobimetinib exhibited high systemic toxicity in animals. Mortality was observed in rats and dogs at plasma exposures below that observed in humans.

A Risk Management Plan (RMP) for Cotellic was submitted by Hoffmann-La Roche Limited to Health Canada. Upon review, the RMP was considered to contain deficiencies that were communicated to the Sponsor. The RMP is designed to describe known and potential safety issues, to present the monitoring scheme and when needed, to describe measures that will put in place to minimize risks associated with the product

The efficacy of Cotellic combined with vemurafenib is supported by a manageable safety profile. Risk mitigation strategies have been incorporated into the Cotellic Product Monograph to communicate key clinical harms that have been observed, provide guidance with regard to monitoring and laboratory tests, and to provide comprehensive guidance with regard to dose modifications associated with adverse events. There is communication with respect to the potential for clinically significant drug-drug interactions with CYP3A inhibitors and the limited data establishing safe use in patients with hepatic impairment.

Based on the data reviewed, the benefit-risk assessment is considered to be positive. Efficacy has been demonstrated and toxicity is considered tolerable and manageable. The combination of Cotellic and vemurafenib represents an effective addition to the currently approved therapeutic options for patients with advanced BRAF-mutated melanoma.

For more information on Health Canadas decision, please view the Summary Basis of Decision.

 

Decision issued

Approved; issued Notice of Compliance in accordance with the Food and Drug Regulations.