3608 - The Impact of Circulating Tumor Human Papillomavirus (HPV) DNA Clearance Kinetics on Disease Outcomes during Chemoradiation in Patients with HPV-Associated Oropharyngeal Cancer

S. R. Jhawar¹, C. T. Haring², J. Pan³, J. Ma⁴, E. A. Kubi⁴, P. Bhateja⁵, A. L. Limbach⁴, E. Gogineni⁶, D. L. Mitchell⁶, D. J. Konieczkowski⁶, J. C. Grecula⁶, S. J. Ma⁵, S. Zhu⁷, M. Old², M. Bonomi⁸, J. W. Rocco², D. M. Blakaj⁶, and S. Baliga⁹; ¹Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, ²The Ohio State University Department of Otolaryngology - Head & Neck Surgery, Columbus, OH, ³The Ohio State University Wexner Medical Center, Center for Biostatistics, Columbus, OH, ⁴The Ohio State University Wexner Medical Center, Columbus, OH, ⁵Ohio State University, Columbus, OH, ⁶Department of Radiation Oncology, James Cancer Hospital, The Ohio State University, Columbus, OH, ⁷University of Florida, Gainesville, FL, ⁸Department of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, ⁹Department of Radiation Oncology, The Ohio State University, Columbus, OH

Purpose/Objective(s): Circulating tumor HPV DNA (ctHPVDNA) has emerged as a promising biomarker in human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV-OPSCC). However, the impact of ctHPVDNA kinetics on disease outcomes during chemoradiation (CRT) remains unclear. The objective of this study was to assess ctHPVDNA clearance kinetics during CRT and its relationship with progression in HPV-OPSCC. Materials/

Methods: We retrospectively identified patients diagnosed with AJCC 8^th edition cT1-4, N0-N3, M0, HPV-OPSCC who underwent plasma ctHPVDNA testing before, during and after curative intent CRT between June 2021 to February 2023 (n=82). All patients had pre-, end of, and post-treatment ctHPVDNA collected, while a subset of patients (n=70) also had ctHPVDNA collected during week 4 (mid-treatment) of CRT. Patients with an initial ctHPVDNA of =200 copies/mL and >95% clearance by week 4 were considered favorable risk and those who did not achieve this clearance profile were classified as unfavorable risk. The primary objective was to evaluate the relationship between ctHPVDNA clearance during CRT and its impact on progression free survival (PFS). The association of this clearance status with PFS was evaluated using the Kaplan-Meier estimator.
Results: The median follow up was 14.7 months. Of the 82 patients, 75 (91.4%) had HPV16, 4 (5%) had HPV33, 2 (2.4%) had HPV18, and 1 (1.2%) had HPV35 subtype of disease. Of the 70 patients who had a ctHPVDNA drawn at mid and end of treatment, 31 (37.8%) and 48 (58.5%) completely cleared their ctHPVDNA at those respective time points. At 3 months post CRT, 73 (89%) had complete clearance of their ctHPVDNA. Of the clinical risk factors, only nodal stage was associated with a higher ctHPVDNA score at baseline and the median scores were 128 copies/mL, 778 copies/mL and 1219 copies/mL for patients with N0/1, N2a-b, and N3 disease, respectively (p=0.01). Patients with a favorable risk clearance profile had a trend toward superior PFS compared to those with unfavorable risk disease at 1 (92.9% vs 87.7%) and 2-years (89.3% vs 67.5%) (log-rank,p=0.17). Patients who had persistent ctHPVDNA at the end of CRT had an inferior PFS compared to those who cleared their ctHPVDNA at 1 (95.5% vs 91.7%) and 2 years (85.5% vs 73.2%) (log-rank, p=0.05). There were no loco-regional or distant failures in patients who had =10 pack year smoking history and a favorable risk clearance profile.
Conclusion: Our study demonstrates that rapid clearance of ctHPVDNA during or after CRT predicts excellent disease control for HPV-OPSCC patients, whereas persistent ctHPVDNA post-CRT indicates unfavorable outcomes. Thus, monitoring ctHPVDNA clearance kinetics is a promising approach for adjusting intra-radiation therapy, potentially allowing therapy de-escalation for low-risk patients and escalation for high-risk cases. Prospective clinical trials are necessary to fully assess the utility of ctHPVDNA as a predictive biomarker for treatment stratification.