Treating BRAF-Mutated Melanoma: Tough Choices for Clinicians and Patients

Where there were no treatment options for metastatic melanoma patients in the past, there are now several. Prior to 2010, only two treatments were approved: the chemotherapy drug dacarbazine and recombinant human interleukin 2 (IL-2) immunotherapy. Neither was effective in providing durable responses or led to an improvement in overall survival.

But now, the immunotherapy antibody ipilimumab and the targeted oral therapy vemurafenib, a BRAF inhibitor, have been shown to improve overall survival. Both were approved by the Food and Drug Administration (FDA) in 2011.

More targeted agents and immunotherapies are coming down the pike. Another oral BRAF inhibitor, dabrafenib, as well as an oral MEK inhibitor, trametinib, were filed with the FDA as monotherapies in 2012 and will likely be approved this year. Combination trials of the MEK and BRAF inhibitors dabrafenib plus trametinib are now underway. Several anti-PD1 immunotherapy antibodies are also in late-stage trials.

For the 50% of metastatic melanoma patients whose tumors harbor an activating mutation in the BRAF gene, the V600 mutation, treatment choices are now more complicated. A patient could receive ipilimumab or another experimental immunotherapy as a first-line treatment followed by a BRAF inhibitor or could be treated with the BRAF-inhibitor first.

Researchers Sekwon Jang, MD and Michael Atkins, MD, of the Georgetown University School of Medicine in Washington, DC, have reviewed the most recent clinical trial data to help guide both initial treatment choice and subsequent treatment options for patients with BRAFV600-positive melanoma (see: Jang S, Atkins S. Which drug, and when, for patients with BRAF-mutant melanoma? The Lancet Oncology,2013;14:e60-9).

Patients will soon have a choice of targeted therapies: vemurafenib, dabrafenib, or trametinib. Patients taking vemurafenib in a phase III, randomized trial had a 63% lower risk of dying from melanoma compared with patients taking chemotherapy (p < .0001) at a median follow up of 3.75 months. With a longer, 6.2-month follow-up, vemurafenib-treated patients had a 56% lower risk of dying compared to those taking chemotherapy.

The BRAF inhibitor dabrafenib showed similar survival results in a phase III trial. Patients in the dabrafenib trial had a 37% lower risk of dying compared to those taking chemotherapy. The lower survival benefit in the dabrafenib trial was not a reflection of the efficacy of dabrafenib, but was due to the ability of patients in the chemotherapy group to be treated with dabrafenib after progression of their disease. Also, about one-quarter of patients taking vemurafenib experience skin toxicity in the form of removable cutaneous squamous cell carcinomas and have high sun sensitivity. Skin toxicities are less frequent with dabrafenib.

The MEK inhibitor trametinib has also improved survival for patients, as shown in a phase III clinical trial. However, most clinicians see the combination of a MEK and a BRAF inhibitor becoming the standard of care in several years. Dr. Atkins tells Cancer Commons that he does not see a role for trametinib monotherapy for the majority of BRAF-positive melanoma patients.

“[Currently], a BRAF inhibitor is preferred and following cancer progression [on a BRAF inhibitor], trametinib has little if any activity,” Atkins says. He believes most patients are likely to be able to tolerate a BRAF inhibitor and trametnib is more likely to have side effects compared to either dabrafenib or vemurafenib.

“Data to guide treatment choices, including prospective data, are scarce,” according to Jang and Atkins. Available data suggests that ipilimumab may be a more optimal first treatment option, as disease progression is often rapid after development of resistance to vemurafenib. Such a period of rapid tumor growth is likely not an optimal time to start treatment with immunotherapy, which takes longer to kick in. A randomized, prospective trial led by the U.S. Intergroup will test which treatment sequence is optimal for patients.

Whether the combination of a BRAF and a MEK inhibitor confers better progression-free and overall survival remains to be seen. Two ongoing, phase III trials are comparing the combination with either dabrafenib or vemurafenib alone. Other clinical trials are testing vemurafenib together with ipilimumab and other immunotherapies.

“Combinations of BRAF inhibitor plus immunotherapy would likely omit a MEK inhibitor, as it is more likely to have negative effects on the immune system,” Atkins says. For now, optimal dosing for the targeted therapy–immnotherapy combinations and drug sequence are still being worked out.

According to Atkins, the main treatment option question for BRAF-mutated melanoma patients is whether to use a molecular targeted agent or an immunotherapy for initial treatment.

“We desperately need a trial to address this fundamental question—and not just for patients with melanoma,” he says.