Immunotherapy Combinations in Advanced Melanoma

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Limited options currently exist for patients with metastatic melanoma who do not have an actionable mutation. In these situations, ipilimumab can be administered as a single-agent, Jeffrey A. Sosman, MD, notes. Additionally, chemotherapy can be administered until a response is achieved followed by a switch to ipilimumab or interleuken-2.

The combination of chemotherapy and interlueken-2, or biochemotherapy, is an effective therapy in patients with aggressive metastatic melanoma, notes Omid Hamid, MD. In some situations, biochemotherapy can be utilized to debulk patients with a large disease burden, Jeffrey S. Weber, MD, PhD, adds. In the future, the combination of nivolumab and ipilimumab could be utilized for patients with metastatic melanoma who do not have actionable mutations, Hamid suggests.

In a phase I study examining the combination of ipilimumab and nivolumab, the 1- and 2-year overall survival rate was 85% and 79%, regardless of BRAF and PD-L1 status. However, the objective response rate was 40%, suggesting that a majority of patients do not respond, Mario Sznol, MD, notes. For patients with BRAF mutations who do not respond, they can receive a combination of a BRAF and MEK inhibitor. Unfortunately, those with BRAF wild-type tumors have few options, Sznol adds.

Combination therapies have generated interest in clinical trials, including the exploration of MEK and CDK4/6 inhibition in patients with NRAS-drive melanoma, Sosman states. Additionally, clinical trials continue to explore the combination of targeted therapies and checkpoint inhibitors. However, in initial studies looking at this strategy, the combination of the BRAF inhibitor vemurafenib with ipilimumab was associated with high-levels of toxicity, Weber notes.

Toxicity differences have emerged between the various BRAF inhibitors, when used in combination with ipilimumab, Sosman notes. To explore these combinations further, a phase I study examined ipilimumab plus dabrafenib with or without trametinib. Dabrafenib plus ipilimumab was well tolerated, without the occurrence of new adverse events. However, the combination of dabrafenib, trametinib, and ipilimumab was associated with a higher rate of grade 3 colitis and perforation.

Combination studies have shifted toward targeted therapies with PD-1 and PD-L1 inhibitors. A phase I/II study is currently looking at the combination of MEDI4736, an anti-PD-L1 antibody, in combination with dabrafenib and trametinib or trametinib alone in patients with advanced melanoma. Additionally, a phase Ib study is exploring the anti-PD-L1 agent MPDL3280A in combination with vemurafenib.