FDA Approves Cobimetinib as Part of Combination Treatment for Advanced Melanoma

Combination of cobimetinib and vemurafenib demonstrates greater benefit than vemurafenib alone in BRAF mutation-positive melanoma

On 10 November, 2015 the US Food and Drug Administration (FDA) approved cobimetinib (Cotellic) to be used in combination with vemurafenib to treat patients with advanced melanoma (metastatic disease or that can’t be removed by surgery) whose tumours express BRAF V600E or V600K mutation.

“As we continue to advance our knowledge of tumor biology, we have learned that cancer cells have a remarkable ability to adapt and become resistant to targeted therapies. Combining two or more treatments addressing different cancer-causing targets may help to address this challenge,” said Dr Richard Pazdur, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Cobimetinib is a MEK inhibitor. Vemurafenib, marketed in the US as Zelboraf, is a BRAF inhibitor that affects a different part of the same signaling pathway and was approved in 2011 to treat patients with metastatic melanoma or disease that cannot be removed by surgery, whose tumours express BRAF V600E mutation, as detected by an FDA approved test.

Health care providers should confirm the presence of BRAF V600 E or V600K mutation in their patients’ tumour specimens using one of the available FDA approved tests prior to starting treatment with cobimetinib in combination with vemurafenib.

The safety and efficacy of cobimetinib taken in combination with vemurafenib were demonstrated in a randomised phase III clinical study (coBRIM) of 495 patients with previously untreated, BRAF V600 mutation-positive melanoma that is advanced or cannot be removed by surgery. All study participants received vemurafenib and were then randomly selected to also take either cobimetinib or a placebo.

A median progression-free survival (PFS) was 12.3 months for cobimetinib plus vemurafenib compared to 7.2 months with vemurafenib alone (HR=0.56, p < 0.001). An interim analysis also showed the combination of cobimetinib and vemurafenib improved overall survival than vemurafenib alone (HR=0.63; p = 0.0019). The objective response rate was higher with cobimetinib plus vemurafenib compared to vemurafenib alone (70 vs. 50%; p < 0.001), as was the complete response rate (16 vs. 11%).

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

Cobimetinb may cause severe side effects including cardiomyopathy, rhabdomyolysis, new primary cutaneous malignancies, retinal detachment, severe skin rash, hepatotoxicity, hemorrhage and severe skin rash due to increased photosensitivity.

People taking cobimetinib should avoid sun exposure, wear protective clothing, and a broad spectrum ultraviolet A/ultraviolet B sunscreen to protect against sunburn. Women taking cobimetinib should use effective contraception, as the medication can cause harm to a developing foetus.

Cobimetinib was reviewed under the FDA’s priority review programme that provides for an expedited six-month review of drugs that, at the time the application was submitted, have the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. Cobimetinib also received orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for orphan drug exclusivity to assist and encourage the development of drugs for rare diseases.

Cotellic and Zelboraf are both marketed by Genentech of San Francisco, California.