Systemic Treatment Options for CSCC and Mechanism of Action

Dr. Zeitouni describes how FDA approval of 3 immune checkpoint inhibitors has fundamentally transformed the management of advanced CSCC. Prior to these approvals, available options were limited to EGFR inhibitors, targeted therapies, and platinum-based chemotherapy with modest outcomes. The current era of checkpoint inhibitor availability has enabled multidisciplinary co-management, with dermatologists and Mohs surgeons now actively partnering with medical oncologists through staging, imaging, and ongoing follow-up alongside systemic therapy.

She explains the mechanistic differences between PD-1 and PD-L1 inhibition. PD-1 inhibitors (cemiplimab, pembrolizumab) bind to the PD-1 receptor on T cells, preventing interaction between tumor-expressed PD-L1 and T-cell PD-1, thereby restoring T-cell activation through the adaptive immune system. Cosibelimab, an anti-PD-L1 agent, binds PD-L1 on tumor cells and similarly prevents this inhibitory interaction, also restoring adaptive immune T-cell function.

Cosibelimab additionally has a multifaceted mechanism. By binding PD-L1, it relieves inhibition of antigen-presenting cells, enhancing their interaction with T cells. Through its Fc domain, cosibelimab can also bind and activate natural killer cells, triggering antibody-dependent cellular cytotoxicity via release of cytotoxic granules, engaging the innate immune system in addition to adaptive immunity. Importantly, cosibelimab preserves PD-L2 signaling, which helps maintain immune tolerance and may reduce immune-mediated adverse events compared with PD-1 inhibition.

Dr. Hamid emphasizes this last point: PD-L2 is expressed in stress-related tissue-protective contexts, and preserving its signaling, a function lost with PD-1 inhibition, may have practical implications for patients at higher toxicity risk. He notes that although no head-to-head comparisons between these agents exist, mechanistic differences may meaningfully inform agent selection for specific patient profiles. Real-world data will be important given that clinical trial populations tend to include more ECOG 0 to 1 patients than those encountered in everyday practice, where ECOG 2 patients with more comorbidities are common.