Novel Therapies in Metastatic Melanoma

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The FDA approval of ipilimumab in 2011 set off a chain reaction that culminated in the current explosion of novel therapies for patients with metastatic melanoma. From the immune point of view, these novel therapies include PD-1 and PD-L1 antibodies, which have demonstrated 30-40% response rates for long durations, notes Jeffrey S. Weber, MD, PhD.

For targeted therapies, the BRAF inhibitor vemurafenib was approved in 2011 as a treatment for BRAF-mutated metastatic melanoma. The efficacy of the BRAF/MEK combination remains questionable; however, in the long run, Weber believes that the combination will show superiority once more clinical trial data is available.

Given the level of efficacy seen in patients with metastatic disease, the next phase for these novel agents will be the adjuvant setting, believes Weber. In a pilot study, Weber notes that he has seen promising results for adjuvant nivolumab. Moreover, results have been demonstrated for adjuvant ipilimumab; albeit, at a larger dose than is approved in the United States.

Despite the explosion of new therapies, there remains a role for standard high-dose IL-2 as a treatment for patients with melanoma, believes Omid Hamid, MD. The PD-1/PD-L1 therapies have shown impressive responses with low toxicity; however, they have not yet demonstrated response rates of 100%, warranting the use of other drugs. IL-2 and chemotherapy should still have a role when there are limited other options, believes Hamid.

The landscape for patients with BRAF-mutated metastatic melanoma has been changing rapidly in recent years, notes Jeffrey A. Sosman, MD. For testing, Sosman uses a CLIA approved test developed at his laboratory. This picks up BRAF, KIT, and other mutations using a multiplex assays. However, with all of the emerging therapies, a next-generation sequencing approach should be considered, Sosman believes.

With all of the newly approved therapies, the next major question facing researchers will be the discovery of an optimal sequence, notes Sosman. Whether to begin with a BRAF/MEK combination or a checkpoint inhibitor will be addressed by an upcoming ECOG study. This study is comparing trametinib plus dabrafenib followed by ipilimumab plus nivolumab to the reverse sequence in patients with advanced BRAF-mutated melanoma (NCT02224781). This study will hopefully provide more information on an optimal sequence, Sosman notes.