Checkpoint inhibitor (preferred)
Preferred PD-1 inhibitors Cemiplimab (NCCN Category 1; EMPOWER-CSCC-1) Pembrolizumab (NCCN Category 1) Alternative checkpoint inhibitor Cosibelimab-ipdl (FDA-approved; CK-301-101) Consider when PD-1 inhibitors are unsuitable or when access, tolerability, or other patient-specific factors influence treatment selection Updated data presented at ASCO 2026 (Abstract 9585) demonstrated that responses with cosibelimab 800 mg every 2 weeks remained robust and durable, with a stable objective response rate (ORR) after longer follow-up in a larger cohort of patients with locally advanced cSCC and no new safety signals.
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Response?
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CR/PR → Continue IO ± RT
Continuation of PD-1 therapy in responders aligns with how pivotal PD-1 trials administered treatment until progression/toxicity and with guideline-based principles for ongoing systemic therapy. Adding RT for consolidation/symptom control is supported mainly by guideline practice patterns and extrapolation rather than definitive randomized evidence specific to this exact sequencing in cSCC.
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SD/PD → Add RT or Change Therapy
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Second-line: Cetuximab / Chemotherapy / Trial (Category 2A)
After progression on PD-1 therapy, evidence for EGFR inhibitors and cytotoxic chemotherapy is less robust (mostly non-randomized/retrospective or older phase II data), and guidelines commonly prioritize clinical trial enrollment while listing cetuximab and chemotherapy as options for selected patients.