Survival outcomes following resistance to immune checkpoint inhibition in advanced cutaneous squamous cell carcinoma.

9588 Background: Immune checkpoint inhibitors (ICI) are standard first-line therapy for advanced cutaneous squamous cell carcinoma (cSCC); however, 35% of patients experience disease progression. Evidence guiding optimal second-line management remains limited. We evaluated real-world outcomes of second-line treatment strategies in patients with cSCC resistant to ICI. Methods: A retrospective analysis of patients with unresectable locally advanced or metastatic cSCC treated with ICI monotherapy at two tertiary centres in Brisbane, Australia, was conducted. Patients with progressive disease (PD) were identified and classified as having primary resistance (PD < 4 months) or acquired resistance (PD ≥4 months). Second-line strategies included local therapy (LT - surgery and/or radiotherapy), systemic therapy +/- LT or best supportive care (BSC). Outcomes included progression-free survival from second-line initiation (PFS2), and overall survival (OS) using Kaplan–Meier estimates. Results: Seventy-four patients were identified. Median age was 74 years. Most patients had locoregionally advanced disease (77%), head and neck primary tumours (70%), ECOG performance status 0–1 (76%), and were immunocompetent (70%). Primary resistance occurred in 54% and acquired resistance in 46%, of which 21% progressed after ICI cessation. Locoregional progression was observed in 70% of patients, while 30% progressed with distant disease. Management of ICI resistance included LT (N = 32), systemic therapy +/- LT (N = 16), and BSC (N = 26). An objective response rate of 65% was observed in patients undergoing systemic therapy +/- LT with responses to both ICI rechallenge and/or EGFR targeted therapy (7 of 11 patients). With a median follow up of 46.6m the Median PFS2 was 10.7m. PFS2 was numerically higher in patients undergoing systemic therapy vs LT alone (11.9m vs 8.4m). Of those that underwent LT alone, further PD was seen in 16 patients (50%), with half requiring systemic therapy. Median OS for the overall cohort was 19.0m. OS was numerically reduced in immunocompromised patients (11.6m) and in those with primary ICI resistance (6.9m) vs those who had acquired resistance (22.5m) and progression after ICI cessation (47.1m). Conclusions: Selected patients with advanced cSCC, particularly those with acquired resistance, derive meaningful benefit from second-line therapy following ICI progression. Outcomes remain poor for immunosuppressed patients or those with primary resistance, highlighting a major unmet clinical need and the importance of prospective studies in the post-immunotherapy setting.