Aims: Cosibelimab, a high-affinity programmed death ligand-1 (PD-L1)–blocking antibody, is approved by the US Food and Drug Administration (FDA) at 1200 mg every 3 weeks for the treatment of adults with locally advanced (laCSCC) or metastatic cutaneous squamous cell carcinoma who are not candidates for curative radiation or surgery. We present updated safety and efficacy data for patients with laCSCC treated with cosibelimab 800 mg every 2 weeks (Q2W; a similar regimen per FDA criteria) in the pivotal Phase 1 study (NCT03212404). Methodology: Eligible patients were ≥18 years old with unresectable laCSCC not amenable to local therapy. Cosibelimab 800 mg Q2W was administered intravenously until complete response, disease progression, toxicity, or clinical deterioration. Objective response rate (ORR; best overall response: complete or partial) per RECIST V1.1 and duration of response (DOR) based on investigator assessment, and safety data, are presented. Results: As of January 31, 2025, 64 patients with laCSCC (median age [range], 77 [51–95] years; 66% male) received ≥1 dose of cosibelimab 800 mg Q2W, with a median (range) of 29 (2–89) doses over 60 (4–184) weeks. The ORR (95% confidence interval) was 50% (37%–63%; 17 complete, 15 partial). Median DOR was not reached over a median follow-up of 31 (1–59) months. Treatment-emergent adverse events (TEAEs) were reported in 61 (95%) patients and considered treatment-related AEs (TRAEs) in 50 (78%). Grade ≥3 TEAEs were reported in 26 (41%) patients and considered TRAEs in 7 (11%); the only serious TRAE was hypertransaminasemia in 2 (3%) patients. Immune-related AEs (irAEs) were recorded in 22 (34%) patients; Grade ≥3 irAEs (1 [2%] patient) were dermatologic (maculo-papular and pruritic rashes) and considered TRAEs. Conclusion: Response to cosibelimab 800 mg Q2W remained robust and durable with stable ORR after continued follow-up in a larger cohort of patients with laCSCC, with no new safety signals identified.