Beyond Checkpoint Inhibition: Keeping Therapeutic Options Open.

Combination immune checkpoint inhibitor therapy (ICI) with ipilimumab (anti-cytotoxic T-lymphocyte-associated protein 4) + nivolumab (anti-PD-1) in untreated, metastatic melanoma has achieved a ten-year melanoma-specific survival of 52%. However, approximately 40%-55% of patients with metastatic melanoma have primary resistance and do not initially respond to anti-PD-1, and an additional 25% of patients develop secondary resistance, exhibiting an initial response followed by disease progression. In PD-1-refractory melanoma, treatment options are limited. Addition of ipilimumab, relatlimab (anti-LAG3), or lenvatinib (VEGFR TKI) has minimal to modest efficacy. Switching to targeted BRAF/MEK inhibition improves survival for BRAF-mutant disease. MEK and KIT inhibitors have limited activity in NRAS- and KIT-mutant metastatic melanoma, respectively. Recently, personalized, autologous tumor-infiltrating lymphocyte therapy has become a US Food and Drug Administration-approved second-line option; lifileucel demonstrates durable response (approximately 30%) in heavily pretreated, metastatic melanoma. Emerging therapeutics that show promising clinical benefit in ongoing clinical trials include novel engineered oncolytic viral and human leukocyte antigen (HLA)-restricted immune-mediated T-cell therapies. As a therapy which is limited to patients who are HLA-A*02:01, T-cell receptor (TCR) engineered T cells (TCR-T) iterates on personalized adoptive cell transfer, and immune mobilizing monoclonal TCRs against cancer are CD3 bispecifics that bind glycoprotein 100 (tebentafusp, approved for metastatic uveal melanoma) or PRAME to activate T cells. Finally, in patients at high risk for immune-related adverse events (irAEs), ICI should still be considered. ICI may be given with modified immunosuppression in patients with autoimmune disease or previous organ transplantation. Cumulative data support safe administration in older patients and in ICI rechallenge for patients with previous irAE.