Clinical outcomes and management following progressive disease with anti-PD-(L)1 therapy in patients with advanced cutaneous squamous cell carcinoma

Aim Anti-programmed death-1/ligand-1 (anti-PD-(L)1) therapies are effective for advanced cSCC. This international study examines response patterns and subsequent management strategies following anti-PD-(L)1 therapy. Method This retrospective cohort study involved 10 centres across 6 countries. Key outcomes included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS) for anti-PD-(L)1 and subsequent therapy. Results One-hundred and fifty-nine patients with advanced cSCC who received anti-PD-(L)1 were evaluated. At median follow-up of 19.3 months (95% CI; 17.5 – 22.2), ORR was 67%. The 12-month and 24-month PFS rates were 62% (95% CI: 55 - 70) and 55% (95% CI: 47 - 64), while 12-month and 24-month OS rates were 81% (95% CI: 75- 88) and 71% (95% CI: 63 – 80). Disease progression occurred in 47 patients (30%); 11% who progressed within 6 weeks of receiving anti-PD-(L)1 therapy, 55% with primary resistance, 28% with secondary resistance, 6% with late progression. Among 21 patients who received subsequent systemic therapies; 8 received cetuximab monotherapy (ORR 50%, DOR 8.5 months [95% CI; 6.9 - NR]) and 5 received anti-PD-(L)1 rechallenge (ORR 20%, one responder with response duration of 3.2 months). In multivariate analysis, a head and neck primary tumour site was associated with higher ORR, and prolonged PFS. Conclusion Our real-world findings reinforce the efficacy of anti-PD-(L)1 therapy in patients with advanced cSCC, with outcomes influenced by primary tumour location. The heterogeneity of subsequent treatments highlights an unmet need in the management of patients who progress on these therapies.