Purpose: We hypothesize that the addition of the phosphodiesterase-5 inhibitor tadalafil to the PD-1 inhibitor nivolumab, is safe and will augment immune-mediated antitumor responses in previously untreated squamous cell carcinoma of the head and neck (HNSCC).
Patients and methods: We conducted a two-arm multi-institutional neoadjuvant randomized trial in any-stage resectable HNSCC (NCT03238365). Patients were stratified at randomization by human papillomavirus (HPV) status. Patients in both arms received nivolumab 240 mg intravenously on days 1 and 15 followed by surgery on day 28. Those in the combination therapy arm also received tadalafil 10 mg orally once daily for 4 weeks. Imaging, blood, and tumor were obtained pretreatment and posttreatment for correlative analysis.
Results: Neoadjuvant therapy was well-tolerated with no grade 3 to 5 adverse events and no surgical delays. Twenty-five of 46 (54%) evaluable patients had a pathologic treatment response of ≥20%, including three (7%) patients with a complete pathologic response. Regardless of HPV status, tumor proliferation rate was a negative predictor of response. A strong pretreatment T-cell signature in the HPV-negative cohort was a predictor of response. Tadalafil altered the immune microenvironment, as evidenced by transcriptome data identifying enriched B- and natural killer cell gene sets in the tumor and augmented effector T cells in the periphery.
Conclusions: Preoperative nivolumab ± tadalafil is safe in HNSCC and results in more than 50% of the patients having a pathologic treatment response of at least 20% after 4 weeks of treatment. Pretreatment specimens identified HPV status-dependent signatures that predicted response to immunotherapy while posttreatment specimens showed augmentation of the immune microenvironment with the addition of tadalafil.
Recommended CitationLuginbuhl, Adam J.; Johnson, Jennifer; Harshyne,, Larry; Linnenbach, Alban J; Shukla, Sanket Kumar; Alnemri, Angela; Kumar, Gaurav; Cognetti, David; Curry, Joseph; Kotlov, Nikita; Antysheva, Zoya; Degryse, Sandrine; Mannion, Kyle; Gibson, Michael K; Netterville, James; Brown, Brandee; Axelrod, Rita S.; Zinner, Ralph G.; Tuluc, Madalina; Gargano, Stacey; Leiby, Benjamin E; Shimada, Ayako; Mahoney, M G; Martinez-Outshoorn, Ubaldo E.; Rodeck, Ulrich; Kim, Young J; South, Andrew P.; and Argiris, Athanassios, "Tadalafil Enhances Immune Signatures in Response to Neoadjuvant Nivolumab in Resectable Head and Neck Squamous Cell Carcinoma" (2022). Department of Otolaryngology - Head and Neck Surgery Faculty Papers. Paper 62.
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