Temozolomide overcoming resistance to immune checkpoint inhibitors in relapsed/refractory metastatic melanoma? Insights from a single center series

There is a need to develop more effective salvage therapies for patients with relapsed melanoma of the skin. Research has shown that chemotherapy-induced cancer cell death may increase immunogenic antigen exposure, or upregulation of co-inhibitory ligands such as PD-L1, thereby augmenting immune checkpoint inhibitor (ICI) efficacy. In addition, chemotherapy preconditioning may lead to depletion of Tregs, known to suppress immune anti-melanoma responses. As a result, regimens including both chemotherapy and ICI constructs are currently successfully employed in the 1^st line therapy of many solid tumors. We report a series of three patients with metastatic melanoma, refractory to ICI treatment, who responded to salvage therapy with temozolomide (TMZ) in combination with PD-1 inhibitors, with or without CTLA-4 inhibitors. The responses were durable, each lasting more than 12 months. In two patients, complete responses are ongoing at 13 and 15 months, respectively. Randomized clinical trials with TMZ plus ICIs for patients with relapsed or refractory malignant melanoma seem warranted.