47 Early molecular response kinetics to induction chemotherapy and anti-PD1 immunotherapy in HPV-positive head and neck squamous cell carcinoma (HNSCC) patients

<h3>Background</h3> In recurrent/metastatic HPV+ HNSCC, chemotherapy with anti-PD1 immunotherapy improves overall survival more than chemotherapy alone^{1 2} Recent studies suggest anti-PD1 may also benefit treatment of locally-advanced (LA) tumors.^{3 4} Tumor tissue-modified viral HPV (TTMV) DNA is a sensitive, specific biomarker for HPV+ HNSCC that may help assess treatment efficacy and risk of recurrence.^5-8 However, TTMV responses to chemotherapy and anti-PD1 in LA HPV+ HNSCC patients have not been described. <h3>Methods</h3> Patients with LA HPV+ HNSCC with high-risk features (ECE, T4, &gt;=N2c) or deemed unresectable were treated with 3 cycles of induction chemotherapy (IC) only (docetaxel-cisplatin-fluorouracil, or TPF) or with anti-PD1 (docetaxel-cisplatin-Cemiplimab, or TP-PD1) based on clinical trial participation (NCT02945631 and NCT05376553, respectively). TPF patients were followed by standard (sd, 70Gy) or reduced dose (rd, 56Gy) chemoradiation (CRT) based on IC response. TP-PD1 patients were followed by sdCRT and six months of adjuvant Cemiplimab. TTMV testing was done pre-treatment, after each IC cycle, during CRT, and at follow-ups during standard surveillance. <h3>Results</h3> This analysis included 28 subjects treated between 6/2020–5/2024 with available pre- and post-IC TTMV data. 21 patients received TPF (19 TPF, 2 TP); seven received TP-PD1. 6/21 TPF and 7/7 TP-PD1 patients were smokers. Mean pre-treatment TTMV was 5580 (27-90770) in TPF patients and 12671 (89-50186) in TP-PD1 patients (table 1). 7/21 TPF patients were rapid responders (RR) with full TTMV clearance after one IC cycle, 9/21 were slow responders (SR) with clearance after 2-3 cycles, 4/21 were missing data (unknown), and 1/21 remained TTMV-positive throughout IC (figure 1). 3/7 TP-PD1 patients were RR, 3/7 SR, and 1/7 unknown (no testing during IC, but TTMV-negative at sdCRT start). All patients were TTMV-negative post-CRT. Within one year following IC initiation, 4/21 TPF patients developed recurrent HPV+ HPSCC (figure 1); 3/4 were SR and 1/4 unknown. 3/4 failures were confirmed TTMV+ and PET+ (1 locoregional, 2 metastatic); 1/4 was TTMV+ but PET-negative and is being followed. No TP-PD1 patients developed TTMV+ or PET+ recurrence within the same period (figure 2). <h3>Conclusions</h3> In this small study set, all recurrences occurred in the TPF cohort and predominantly in patients with delayed TTMV responses. TTMV clearance was consistent with one-year disease-free survival in TP-PD1 patients, suggesting its potential for anti-PD1 surveillance. Our study describes early TTMV kinetics in TPF vs. TP-PD1 patients but lacks statistical power to demonstrate associations with clinical outcomes. Future studies may examine TTMV dynamics in larger cohorts to guide HPV+ HNSCC treatment. <h3>Trial Registration</h3> The study includes data from clinical trials NCT02945631 and NCT05376553. <h3>References</h3> Huang Y, Lan Y, Zhang Z, Xiao X, Huang T. An Update on the Immunotherapy for Oropharyngeal Squamous Cell Carcinoma. <i>Front Oncol</i> 2022;<b>12</b>:800315. Burtness B, Harrington KJ, Greil R, <i>et al</i>. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. <i>Lancet Lond Engl</i> 2019;<b>394</b>(10212):1915-1928. Wang HL, Yue K, Wu YS, Duan YS, Jing C, Wang XD. Phase II clinical trial of PD-1 inhibitor combined with chemotherapy for locally advanced resectable oral squamous cell carcinoma. <i>Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi</i> 2024;<b>59</b>(4):335-342. Wu WJ, Liu Q, An PG, <i>et al</i>. Neoadjuvant tislelizumab combined with chemotherapy in locally advanced oral or oropharyngeal squamous cell carcinoma: a real-world retrospective study. <i>Front Immunol</i> 2023;<b>14</b>:1282629. Ferrandino RM, Chen S, Kappauf C, <i>et al</i>. Performance of liquid biopsy for diagnosis and surveillance of human papillomavirus-associated oropharyngeal cancer. <i>JAMA Otolaryngol Neck Surg</i>. 2023;<b>149</b>(11):971-977. Hanna GJ, Roof SA, Jabalee J, <i>et al.</i> Negative predictive value of circulating tumor tissue modified viral (TTMV)-HPV DNA for HPV-driven oropharyngeal cancer surveillance. <i>Clin Cancer Res Off J Am Assoc Cancer Res</i>. 2023;<b>29</b>(20):4306-4313. Cao Y, Haring CT, Brummel C, <i>et al</i>. Early HPV ctDNA kinetics and imaging biomarkers predict therapeutic response in p16+ oropharyngeal squamous cell carcinoma.<i> Clin Cancer Res Off J Am Assoc Cancer Res</i>. 2022;<b>28</b>(2):350-359. Chera BS, Kumar S, Beaty BT, <i>et al</i>. Rapid clearance profile of plasma circulating tumor HPV type 16 DNA during chemoradiotherapy correlates with disease control in HPV-associated oropharyngeal cancer. <i>Clin Cancer Res</i> 2019;<b>25</b>(15):4682-4690.