Purpose: The development and place in therapy of vemurafenib and ipilimumab for the treatment of metastatic melanoma are reviewed.
Summary: Vemurafenib is an adenosine triphosphate-competitive, reversible, and highly selective BRAF kinase inhibitor targeted at BRAF-V600E and is a first-line option for patients with BRAF-mutation-positive disease. Vemurafenib has clinically significant antitumor activity in metastatic melanoma, and response rates and overall and progression-free survival rates are improved when compared with dacarbazine. Responses also occur quickly, often within days to weeks of starting treatment. Disadvantages of vemurafenib include the short duration of response; significant skin toxicities, including skin cancers and severe photosensitivity; the need for long-term daily administration; and the potential for drug interactions. Ipilimumab is a fully human monoclonal antibody that binds to the cytotoxic T-lymphocyte-associated antigen 4 to enhance and prolong T-cell responses to elicit antitumor activity. Clinical trials have demonstrated the superiority of ipilimumab in terms of overall survival when compared with an immune stimulator and placebo. While the rate of response to ipilimumab is low, responses tended to be more durable than those achieved with vemurafenib. A disadvantage of ipilimumab is that a response may require months, making ipilimumab inappropriate as monotherapy for patients with symptomatic disease. Additional disadvantages are the adverse-effect profile and the requirement of enrollment in the risk evaluation and mitigation strategy program.
Conclusion: Vemurafenib and ipilimumab are important advances in the treatment of metastatic melanoma. Benefit is typically short lived for vemurafenib and uncommon for ipilimumab. Neither agent is curative, and clinical trials remain an alternative first-line treatment option.