Pathologic response rates to neoadjuvant pembrolizumab in locally advanced (LA) resectable cutaneous squamous cell carcinoma (cSCC).
Authors: Florent Amatore, Shaum Sridharan, Arivarasan Karunamurthy, Hong Wang, Ravi Patel, Melissa Pugliano-Mauro, Seungwon Kim, Mohammad Haroon Asif Choudry, James F. Pingpank, Matthew Peter Holtzman, Uma Maheswari Duvvuri, Robert L. Ferris, Jason J. Luke, John M. Kirkwood, Yana G. Najjar, Filippo Pullara, Chakra Chennubhotla, Hassane M. Zarour, Diwakar Davar
Journal: Journal of Clinical Oncology (2024)

9591 Background: Cutaneous squamous cell carcinoma (cSCC) is the second commonest cutaneous malignancy, accounting for 20% of cutaneous malignancies and 75% of non-melanoma skin cancer deaths. Anti-PD-1 is approved in unresectable and metastatic cSCC, and is associated with high rates of pathologic response in resectable locally advanced (LA) cSCC. We conducted a phase II single-arm neoadjuvant trial of pembrolizumab (P) in patients with PD-1 naïve resectable LA cSCC. Methods: Patients with AJCC/UICC ≥T3 (or T2 with ≥2 BWH high-risk features) and/or N+ disease were eligible. Patients received 2 cycles of P (200mg Q3W) prior to definitive surgery, and 15 cycles post-surgery (NCT04808999). The primary endpoint was pathologic complete response (pCR, defined as 0% residual viable tumor, RVT) per independent central pathology review. Key secondary endpoints included incidence of adverse events (AEs), recurrence-free survival (RFS), overall survival (OS), safety and unbiased spatial biomarkers. A selected panel of multiplex immunofluorescence imaging biomarkers were used by PredxBio Inc.’s computational pipeline to reveal spatial intratumor heterogeneity in the tumor microenvironment (TME). Results: Thirty patients were enrolled and received at least 1 cycle of P. The median age was 79 (59-93) years and patients were predominantly male (77%). One patient withdrew consent prior to surgery. Three patients died prior to definitive surgery: 2 from COVID-19, a third from a NSTEMI possibly related to P. Of the 26 response-evaluable patients, AJCC/UICC stage at baseline was high-risk T2, T3, N1, and N2 in 2 (8%), 12 (46%), 9 (34.5%), and 3 (11.5%) patients, respectively. We observed pCR in 15 (57%), pathologic partial response (pPR, 10% &lt; %RVT &lt;50%) in 2 (8%) and pathologic non-response (pNR, &gt;50%RVT) in 8 (31%) patients. One patient is pending surgery. Postoperative radiotherapy (RT) was de-escalated in 54% of the patients (14/15 in pCR). Median RFS was 13 (pCR) versus 10.5 (non-pCR) months. One Grade 5 (NSTEMI) and two Grade 3 (hepatitis, colitis) treatment-related AEs were observed. Computational analysis identifies key spatial interactions between PDL-1+/CD68+ cells implicated in response to P. Conclusions: Neoadjuvant P is efficacious in resectable LA cSCC with a high pCR rate (57%). Three deaths were observed, including 2 unrelated to treatment and 1 possible Grade 5 cardiac irAE, reflecting the inherent risks of perioperative therapy in this patient population. RT was de-escalated in 93% of pCR patients. No relapse events in pCR patients. Spatial interactions between PDL-1+ cells and CD68+ macrophages have a role in therapeutic response and will be detailed along with other spatial analyses of the TME compartment that have an impact on outcomes. Clinical trial information: NCT04808999 .