FDA approves first combo therapy for advanced melanoma

January 11, 2014

GSK's Mekinist and Tafinlar combination received accelerated approval after priority review.

FDA has approved trametinib (Mekinist, GlaxoSmithKline) in combination with dabrafenib (Tafinlar, GlaxoSmithKline) to treat patients with advanced melanoma that is unresectable or metastatic.

FDA approved both drugs in May 2013 as single agents to treat patients with unresectable or metastatic melanoma. Melanoma is the most aggressive type of skin cancer and is the leading cause of death from skin disease. According to the Melanoma Research Foundation (http://www.melanoma.org), one in 50 Americans has a lifetime risk of developing melanoma. In the United States in 2009, nearly 63,000 people were diagnosed with melanoma, resulting in approximately 8,650 deaths.

 

Immunotherapy leads

“The most promising aspects of the melanoma pipeline currently are in immunotherapy,” said Tim Turnham, the executive director of the Melanoma Research Foundation. “In 2011, the FDA approved Yervoy [ipilimumab, Bristol-Myers Squibb], a drug that blocks one of the natural braking mechanisms on T-cells, for metastatic melanoma. Two companies are currently working on drugs that attack a different T-cell braking mechanism, and those trials are very promising.  Another company has a virus that is engineered to destroy only tumor cells and to stimulate the immune system against those tumor cells.

“These approaches do not address patients who don’t respond to immunotherapy,” Turnham continued.  “A number of studies of targeted therapies - drugs that address specific mutations found in tumor cells - are under way, but are in earlier stages of development. About half of melanoma patients have mutated BRAF, and two drugs are on the market to treat these tumors. Many patients with cutaneous melanoma and all patients with rarer forms of melanoma, such as uveal, mucosal, and acral, do not benefit from these drugs. Finding better options in the sector of targeted therapy is critical to successfully treating these patients.”

Method of action

Mekinist and Tafinlar are used to block signaling in different sites of the same molecular pathway that promotes cancer-cell growth. They are specifically indicated as a combination therapy for patients with melanoma whose tumors express gene mutations known as BRAF V600E and V600K. The BRAF protein is involved in the regulation of normal cell growth, but it is mutated in approximately half of melanomas arising from the skin.  

Safety and effectiveness

The safety and effectiveness of Mekinist in combination with Tafinlar were demonstrated in a clinical trial of 162 participants with unresectable or metastatic melanoma with the BRAF V600E or V600K mutation, most of whom had not received prior therapy. Patients received either Mekinist in combination with Tafinlar, or Tafinlar as a single agent, until their melanoma progressed or side effects became intolerable.

Results showed that 76% of participants treated with Mekinist in combination with Tafinlar had their cancers shrink or disappear, an objective response lasting an average of 10.5 months. In contrast, 54% of participants treated with Tafinlar as a single agent experienced objective responses for an average of 5.6 months. Clinical trials are ongoing to determine whether Mekinist in combination with Tafinlar improves survival.

 

Side effects

Fever, chills, fatigue, rash, nausea, vomiting, diarrhea, abdominal pain, peripheral edema, cough, headache, joint pain, night sweats, decreased appetite, constipation, and muscle pain were the most common side effects reported by participants receiving Mekinist in combination with Tafinlar. During clinical testing, the incidence and severity of fever increased when Mekinist was used in combination with Tafinlar.

Serious side effects included bleeding, clot formation, heart failure, skin problems, and eye problems. One of the serious side effects of Tafinlar - the development of a new squamous cell carcinoma of the skin - was reduced when the drug was used in combination with Mekinist; this is consistent with the biology of the effects of these two drugs on the targeted molecular pathway. The incidence of squamous cell carcinoma of the skin in this trial was 7% when the drugs were combined, compared to 19% with single agent Tafinlar. Other clinically significant side effects include kidney injury.

Mekinist and Tafinlar can cause birth defects in a developing fetus; women of child-bearing potential should be advised of this risk. Men and women should also be advised that Mekinist and Tafinlar treatment may cause infertility.

FDA approved the combination of Mekinist and Tafinlar under the agency’s accelerated approval program. FDA reviewed this combination of drugs under the agency’s priority review.