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Advanced melanoma: combination of Cobimetinib and Vemurafenib reduces the risk of disease worsening by half compared to Vemurafenib alone


Data from the coBRIM phase III study were presented at ESMO ( European Society of Medical Oncology ) 2014 Congress.
The results have shown that people with previously untreated BRAF V600 mutation-positive, advanced melanoma who received the MEK inhibitor Cobimetinib plus Vemurafenib ( Zelboraf ) lived significantly longer without their disease worsening or death ( progression-free survival ) compared to Vemurafenib alone.

The combined therapy reduced the risk of disease worsening or death by half ( hazard ratio, HR=0.51, 95% confidence interval [CI] 0.39-0.68; p less than 0.0001 ), with a median progression-free survival of 9.9 months for Cobimetinib plus Vemurafenib compared to 6.2 months with Vemurafenib alone.
The safety profile was consistent with a previous study of the combination. The most common adverse events seen in the combination arm included diarrhea, nausea, rash, photosensitivity, and lab abnormalities.

The coBRIM results were statistically significant across multiple secondary endpoints. The median progression-free survival by independent review committee ( IRC ) was 11.3 months for the combination arm compared to 6.0 months for the control arm ( HR=0.60, 95% CI 0.45-0.79; p=0.0003 ). The objective response rate ( ORR ) was higher in the combination compared to the control arm ( 68 vs. 45%; p less than 0.0001 ).
Overall survival data are not yet mature.

Cobimetinib is designed to selectively block the activity of MEK, one of a series of proteins inside cells that make up a signalling pathway that helps regulate cell division and survival.
Cobimetinib binds to MEK while Vemurafenib binds to mutant BRAF, another protein on the pathway, to interrupt abnormal signalling that can cause tumours to grow.

CoBRIM is an international, randomised, 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 Vemurafenib, compared to 960 mg twice daily of Vemurafenib 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 randomised to receive Vemurafenib 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 progression-free survival was the primary endpoint. In addition to progression-free survival by IRC, ORR and overall survival, secondary endpoints included 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% ), with close to half of these due to lab abnormalities.
Common adverse events ( occurring in more than 20% ) observed at a higher frequency ( all grades ) in the combination arm compared to the Vemurafenib arm included diarrhea ( 57 vs. 28% ), nausea ( 39 vs. 24% ), photosensitivity ( 28 vs. 16% ), lab abnormalities ( increased alanine aminotransferase [ 24 vs. 18% ], increased aspartate aminotransferase [ 22 vs. 13% ], increased creatine phosphokinase [ an enzyme released by muscles, 30 vs. 3% ] ), and vomiting ( 21 vs. 12% ).
Common adverse events observed at a lower frequency in the combination arm included hair loss ( 14 vs. 29% ), thickening of the outer layer of the skin ( 10 vs. 29% ) and joint pain ( 33 vs. 40% ). 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%; all grades ) and keratoacanthomas ( less than 1 vs. 8%; all grades ). Serous retinopathy ( collection of fluid under the retina ) was observed at a higher frequency in the combination arm ( 20 vs. less than 1% ) 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% ).

Melanoma is less common, but more aggressive and deadlier than other forms of skin cancer. BRAF is mutated in approximately half of melanomas. When melanoma is diagnosed early, it is generally a curable disease, but most people with advanced melanoma have a poor prognosis.
More than 232,000 people worldwide are currently diagnosed with melanoma each year and more than 70,000 people worldwide die every year from melanoma and non-melanoma skin cancers. ( Xagena )

Source: Roche, 2014

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