Phase II Study of Pembrolizumab As First-Line, Single-Drug Therapy for Patients With Unresectable Cutaneous Squamous Cell Carcinomas

<jats:sec><jats:title>PURPOSE</jats:title><jats:p> To evaluate first-line pembrolizumab monotherapy efficacy and safety in patients with unresectable cutaneous squamous cell carcinomas (CSCCs). </jats:p></jats:sec><jats:sec><jats:title>PATIENTS AND METHODS</jats:title><jats:p> Patients, predominantly men, with their CSSCs’ immunohistochemically determined programmed cell death-ligand 1 (PD-L1) status determined (tumor proportion score threshold, 1%), received pembrolizumab (200 mg every 3 weeks). The primary endpoint was the 39-patient primary cohort’s objective response rate at week 15 (ORR<jats:sub>W15</jats:sub>). Secondary objectives were best ORR, overall survival (OS), progression-free survival (PFS), duration of response (DOR), safety, ORR according to PD-L1 status and health-related quality of life using Functional Assessment of Cancer Therapy–General (FACT-G) score. An 18-patient expansion cohort, recruited to power the study to evaluate the ORR<jats:sub>W15</jats:sub> difference between PD-L1+ and PD-L1– patients, was assessed for ORR, disease control rate, and safety, but not survival. </jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p> Median age of all patients was 79 years. The primary cohort’s ORR<jats:sub>W15</jats:sub> was 41% (95% CI, 26% to 58%), including 13 partial and 3 complete responses. Best responses were 8 partial and 8 complete responses. At a median follow-up of 22.4 months, respective median PFS, DOR, and OS were 6.7 months, not reached, and 25.3 months, respectively. Pembrolizumab-related adverse events affected 71% of the patients, and 4 (7%) were grade ≥ 3. One death was related to rapid CSCC progression; another resulted from a fatal second aggressive head and neck squamous cell carcinoma diagnosed 15 weeks postinclusion. ORR<jats:sub>W15</jats:sub> for the entire population was 42%; it was significantly higher for PD-L1+ patients (55%) versus PD-L1– patients (17%; P = .02). Responders’ W15 total FACT-G score had improved ( P = .025) compared with nonresponders. </jats:p></jats:sec><jats:sec><jats:title>CONCLUSION</jats:title><jats:p> First-line pembrolizumab monotherapy exhibited promising anti-CSCC activity, with durable responses and manageable safety. PD-L1 positivity appears to be predictive of pembrolizumab efficacy. </jats:p></jats:sec>