Evolving Management of Advanced-Stage, Resectable Cutaneous Squamous Cell Carcinoma.

e14582 Background: Patients (pts) with advanced-stage, resectable cutaneous squamous cell carcinoma (CSCC) have historically been treated with up-front surgery (US) +/- adjuvant radiotherapy (RT). More recently, the use of neoadjuvant immunotherapy (NEO) has shown promising outcomes. We aimed to describe our institutional experience with these approaches. Methods: We identified 300 pts with stage III (n = 139) or IV (n = 161) resectable CSCC treated 2010-2024 without prior RT. We compared patient characteristics with US (n = 194) vs. NEO (n = 106). Pathologic responses were classified as previously described. Treatment cohort features were compared by Chi-square or Fisher’s exact tests. Event-free survival (EFS) was calculated by the Kaplan-Meier method and defined as time from surgery to disease recurrence or death for US pts and progressive disease without subsequent surgery, recurrence or death for NEO pts. The effect of NEO vs. US was assessed by Log-Rank test. Results: Median age was 71 years (IQR 64-79). Recurrent disease at presentation was similar between cohorts (US-34%, n = 49 vs. NEO-28%, n = 30, p = 0.57). Pts receiving US had lower stage disease (stage III: US-54%, n = 104 vs. NEO-33%, n = 35, p < 0.001) and were more likely to be immunocompromised (US-19%, n = 37 vs. NEO-8%, n = 8, p = 0.008). In the NEO cohort, after a median 3 cycles anti-PD1, 82% (n = 87) of pts proceeded to surgery. Of these, 47 (54%) had a pathologic complete response (pCR), 10 (11%) near-pCR, 8 (9%) pathologic partial response (pPR) and the remaining were pathologic non-responders (pNR). Of the NEO patients who did not have surgery (n = 19, 18%): 11 declined surgery after clinical response, 2 declined surgery after progression, 2 died of other causes and 4 were lost to follow up. Post-op RT was more common after US (72%, n = 141 vs. NEO-26%, n = 28, p = < 0.001). Adjuvant chemotherapy (US-10% vs. NEO-5%) or immunotherapy (US-0% vs. NEO-9%) were infrequently applied. Median follow-up was 33 months for both US (IQR 16-76) and NEO (IQR 18-51). 2-year EFS was greater in the NEO cohort compared to US (90% vs 79%, p = 0.013). Any pathologic response at surgery after NEO (pCR, near-pCR, pPR) was associated with improved outcomes compared to pNR (2-yr EFS 98% vs. 61%, p = < 0.001). Conclusions: In a single-institution, retrospective series, NEO was associated with improved 2-year EFS compared to US. These data support the completion of an ongoing randomized phase 3 trial (NCT06568172) comparing NEO to US.