A prospective trial of single-dose neoadjuvant PD-1 blockade with or without a CD40 agonist in HPV-negative HNSCC.

Abstract

6087 Background: Neoadjuvant PD-1 blockade is approved for resectable locally advanced HPV-negative HNSCC, but major pathologic response rates are <10%, underscoring the need for effective combination strategies. Agonists of the TNF receptor superfamily member CD40 can reverse dendritic cell dysfunction, a key mediator of immune resistance, and may combine with PD-1 blockade to enhance anti-tumor T cell recruitment. We investigated the safety and immunologic effects of combination neoadjuvant PD-1 blockade with CD40 agonism. Methods: We enrolled 20 patients with resectable HPV-negative HNSCC; 10 received a single intravenous dose of PD-1 inhibitor (LVGN3616, 300mg), and 10 received a PD-1 inhibitor (LVGN3616, 300mg) in combination with a CD40 agonist (LVGN7409, 1mg/kg), administered prior to surgical resection (window, 4-28 days). Pre-treatment biopsies, post-treatment surgical specimens, and peripheral blood samples were collected. The primary endpoint was safety, with secondary endpoints including pharmacodynamic immune changes and pathologic responses. Results: Median age was 65 years (range, 39-79); 16 (80%) were male; 16 (80%) were White; 18 (90%) had oral cavity cancer (2 larynx); and 17 (85%) had PD-L1 CPS ≥1. Baseline demographics and PD-L1 were well-balanced between arms. Neoadjuvant immunotherapy was administered a median of 9 days (range, 5-19) before surgery, with no surgical delays observed. Treatment was well tolerated; grade 3/4 events occurred in 12/20 patients, nearly all attributable to post-surgical complications and unrelated to study drug. The only treatment-related grade 3/4 events were transient elevations in liver enzymes seen in two patients in the PD-1+CD40 arm. With a minimum of 6 months' follow-up, 3/20 patients (1 in PD1 arm, 2 in PD1+CD40 arm) had progressed. Serum analyses revealed that combined PD-1 and CD40 agonist therapy induced significant increases in multiple cytokines including IL-15 (p=0.0084), IP-10 (p=0.0379), MCP-1 (p=0.0002), MDC (p<0.0001), and MIG (p=0.0178) at 24 hours, indicating enhanced immune activation. A biomarker-driven inflammatory score based on baseline LCN2 and SAA levels predicted pathological response with 85% accuracy, 71.4% sensitivity, and 92.3% specificity (Fisher’s exact p=0.0072). Pathologic tumor response (pTR) was observed in 3/10 patients in the PD-1 arm (pTR1, 10-49%) and 4/10 patients in the PD-1+CD40 arm (including one pTR2 with 85% regression. Multiplex IHC was performed on tissue samples using CD3, Ki67, PD-L1, CD8, FOXP3, CD68, and panCK markers; quantitative spatial analyses are ongoing and results will be presented. Conclusions: Single-dose neoadjuvant PD-1 blockade combined with a CD40 agonist for HPV-negative HNSCC was safe, did not delay surgery, and produced modestly improved pathologic regressions that correlated with a cytokine-based baseline inflammatory score. Clinical trial information: NCT06159621 .