Abstract B084: Clinical Outcomes and Biomarker Correlates of Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Treated with Novel Immunotherapies in Phase 1 Trials

Abstract Introduction Immune checkpoint inhibitors (ICIs) have transformed head and neck squamous cell carcinoma (HNSCC) treatment, yet most patients (pts) eventually progress. There is a need for novel immunotherapy (IO) strategies beyond checkpoint blockade. Investigational agents are being tested in early-phase trials, but data in HNSCC remain limited. We evaluated outcomes and biomarkers in HNSCC pts treated with novel IO agents. Methods This is a retrospective cohort study of pts with recurrent/metastatic HNSCC enrolled in phase 1 IO trials at MD Anderson (Jan 2016-May 2025). Kaplan-Meier estimates assessed progression-free survival (PFS) and overall survival (OS). Cox regression identified predictors of survival, and multivariate logistic regression evaluated correlates of clinical benefit rate (CBR), defined as CR, PR or SD ≥6 months. Results Among 158 pts, 70% were <65 years and 86% male. Oropharynx (60%) was the most common primary site, and lymph nodes were the most frequent metastatic site (64%). Median prior systemic therapies: 3; 96% had chemotherapy, 95% radiotherapy, and 80% prior ICIs. HPV-positive tumors comprised 59%. PD-L1 CPS ≥1 in 77% of pts. Genomic profiling (n=127) revealed frequent alterations in TP53 (n=41), PIK3CA (n=24), NOTCH (n=15), and CDKN2A/B (n=12). TP53 mutations were enriched in oral cavity cancers, and PIK3CA in oropharyngeal tumors. Most pts received IO combinations (67%). Common classes included co-stimulatory agonists (n=45), microenvironment modulators (n=37), and bispecific antibodies (n=20), with 4-1BB (n = 19), ICOS (n = 14), and CD40 (n = 13) being the most frequent targets. Median treatment duration was 2.3 months. Treatment-related adverse events (TRAEs) occurred in 54% with grade ≥3 in 15%. Common TRAEs were rash, fatigue, and transaminitis. Grade ≥3 events included febrile neutropenia, lymphopenia, and CRS. ORR was 8%, CBR 16%, and DCR 38%. 2 complete responses were seen, 1 with a bispecific antibody, and 1 with an ICI plus PIK3CA inhibitor. Bispecifics were associated with improved CBR (OR 1.95, p=0.02). PIK3CA mutations correlated with lower benefit (OR 0.03, p=0.04). Median PFS was 2.3 months. In multivariate analysis, adverse PFS predictors included laryngeal cancer (HR 74, p=0.03), TP53 (HR 3.31, p=0.01), PIK3CA (HR 3.31, p=0.01), and >2 metastatic sites (HR 5.31, p=0.001). Lymph node disease predicted improved PFS (HR 0.28, p=0.02). Bispecific antibodies were associated with longer PFS compared to other novel IO agents (log-rank p<0.0001). Median OS was 8.3 months. Poor OS predictors included laryngeal cancer (HR 353, p=0.002), bone metastases (HR 37.5, p=0.002), and CDKN2A/B deletions (HR 318, p<0.001). Improved OS was associated with NOTCH mutations (HR 0.07, p=0.003), combination therapy (HR 0.08, p=0.002), and any-grade TRAEs (HR 0.15, p=0.002). Conclusions Novel IO agents demonstrate manageable toxicity but modest efficacy in pretreated HNSCC. Bispecific antibodies demonstrate encouraging activity. Biomarkers such as PIK3CA, TP53, CDKN2A/B, and NOTCH may inform treatment stratification. Citation Format: Harold N. Tan, Timothy A. Yap, Jordi Rodon, Bettzy Stephen, Ecaterina E. Dumbrava, Sarina Piha-Paul, Siqing Fu, Stephane Champiat, Neal Akhave, Maura Gillison, John V. Heymach, David Hong, Funda Meric-Bernstam, Aung Naing. Clinical Outcomes and Biomarker Correlates of Patients with Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma Treated with Novel Immunotherapies in Phase 1 Trials [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B084.