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Purpose: Neoadjuvant targeted therapy provides a brief, preoperative ‘window of opportunity’ that can be exploited to individualize cancer care based on treatment response. We investigated whether response to neoadjuvant therapy during the preoperative window confers survival benefit in patients with operable head and neck squamous cell carcinoma (HNSCC). Patients and Methods: A pooled analysis of treatment naïve patients with operable HNSCC enrolled in one of three clinical trials from 2009-2020 (NCT00779389, NCT01218048, NCT02473731). Neoadjuvant regimens consisted of EGFR inhibitors (n=83) or anti-ErbB3 antibody therapy (n=9) within 28 days of surgery. Clinical to pathologic stage migration was compared to disease-free survival (DFS) and overall survival (OS) while adjusting for confounding factors using multivariable Cox regression. Circulating tumor markers validated in other solid tumor models were analyzed. Results: 92 of 118 patients were analyzed; all patients underwent surgery following neoadjuvant therapy. Clinical to pathologic downstaging was more frequent in patients undergoing neoadjuvant targeted therapy compared to a historic cohort without neoadjuvant therapy (P=0.048). Patients with pathologic downstage migration had the highest OS (89.5%, 95% CI 75.7-100) compared to those with no stage change (58%, 95% CI 46.2-69.8) or upstage (40%, 95% CI 9.6-70.4, P=0.003). On multivariable analysis, downstage migration remained a positive prognostic factor for OS (hazard ratio 0.22, 95% CI 0.05-0.90) while adjusting for measured confounders. Downstage migration correlated with decreased circulating tumor markers, SOX17 and TAC1 (P=0.0078). Conclusion: Brief neoadjuvant therapy achieved pathologic downstaging in a subset of patients and was associated with significantly better DFS and OS as well as decreased circulating methylated SOX17 and TAC1. Citation Format: Marco Antonio Mascarella, Tolani Olonisakin, Purva Rumde, Varun Vendra, Melonie Nance, Seungwon Kim, Mark Kubik, Shaum Sridharan, Robert Ferris, Moon Fenton, Daniel Clayburgh, James Ohr, Malabika Sen, Sonali Joyce, James Herman, Jennifer Grandis, Dan Zandberg, Umamaheswar Duvvuri. Response to neoadjuvant targeted therapy in operable head and neck cancer confers survival benefit. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4338.