Combination Therapies for Metastatic Melanoma

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There is a scientific rationale for immune checkpoint inhibitor combinations in the treatment of advanced melanoma, with the ultimate goal of improving efficacy while maintaining tolerability. While the combination of dabrafenib and ipilimumab proved far too toxic, clinical trial results for nivolumab and ipilimumab are very impressive. In fact, preclinical studies in mice have shown the additive potential for triple immunotherapy with CTLA-4, PD-1, and PD-L1 blockade, says Howard Kaufman, MD.

In general, combinations are associated with increased toxicity, with it still remaining unclear whether a triplet therapy of 3 checkpoint inhibitors would be tolerable, adds Kaufman. However, with some of the less toxic agents, like talimogene laherparepvec and granulocyte-macrophage colony-stimulating factor, it might be possible to think about 3- and 4-drug combinations.

Radiation therapy is taking on an increased role based on evidence of the “abscopal effect” in combination with immunotherapy. According to Richard Joseph, MD, it is reassuring that the addition of radiation therapy can improve tumor response without adding further toxicity. Joseph adds that it’s more than just the abscopal effect that he’s seen with the combination of ipilimumab and radiation therapy; for example, systemic ipilimumab can be administered concurrently with localized treatment for isolated metastases.

The concurrent administration of stereotactic radiotherapy and ipilimumab can be utilized effectively in patients with brain metastases, explains Robert Andtbacka, MD. When utilizing radiation therapy, it is important to initiate treatment with immunotherapy as early as possible to try to achieve the abscopal effect. Significant responses can be achieved with the combination in patients with brain metastases, Omid Hamid, MD, agrees.

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