While ipilimumab was an important first approval, it only helped about 15-20% of patients and many experienced severe side effects. Since then, several other immunotherapies have been approved that have higher response rates and are generally better tolerated. Keytruda (pembrolizumab) was approved in 2014 for metastatic melanoma patients whose cancer had stopped responding to other treatments. It works by blocking PD-1, another protein that normally helps keep T cells in check. In clinical trials, around 40% of patients saw their tumors shrink or disappear completely in response to Keytruda.

Opdivo (nivolumab) was approved in 2014 as well. Like Keytruda, it also blocks PD-1 to help T cells better attack melanoma cells. Response rates were a bit lower than Keytruda initially at around 30%, but it was generally better tolerated with fewer side effects than ipilimumab. Both pembrolizumab and nivolumab have now been approved as earlier treatments for metastatic melanoma as well. Yervoy (ipilimumab) is still used, often in combination with nivolumab, since the dual immunotherapy approach can provide even higher response rates of around 57%.

Targeted Metastatic Melanoma Therapeutics

For Metastatic Melanoma Therapeutics whose cancer no longer responds to immunotherapy, targeted therapies provide another treatment approach. These drugs target specific genetic mutations that drive melanoma growth and progression. BRAF inhibitors like vemurafenib (Zelboraf) were some of the first targeted therapies approved for metastatic melanoma. About 50% of melanomas have a mutation in the BRAF gene that makes the BRAF protein overactive. Vemurafenib targets and inhibits this mutated BRAF protein to stop tumor growth.

While initial response rates were high at around 48%, resistance often developed within 6-7 months. Combining a BRAF inhibitor with a MEK inhibitor to block downstream signaling helps prevent or delay resistance. Tafinlar (dabrafenib) combined with Mekinist (trametinib) was approved based on improved progression-free survival compared to vemurafenib alone. For patients with the BRAF V600 mutation, this combination provides a median progression-free survival of 9-11 months. Other targeted therapies in development aim to overcome resistance by inhibiting additional genes or pathways.

Combination Approaches Show Promise

Given their different mechanisms of action, combining immunotherapy with targeted therapy has become an active area of investigation. In a key study, treating melanoma with pembrolizumab plus the BRAF/MEK inhibitor combination led to response rates of 69% and median progression-free survival of 14.2 months. Another study found similar benefits from combining nivolumab with the BRAF/MEK inhibitors compared to BRAF/MEK therapy alone. Combining immunotherapies is also being explored, such as combining nivolumab and ipilimumab.

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