3426 - Real-Time Circulating Tumor HPV DNA Kinetics to Guide Adaptive Radiotherapy De-Escalation in HPV-Associated Oropharyngeal Cancer: Interim Results of a Phase II Trial
Presenter(s)
E. Gogineni1, S. R. Jhawar2, C. T. Haring3, J. Pan4, D. L. Mitchell1, J. C. Grecula1, D. J. Konieczkowski1, S. Zhu5, S. J. Ma6, N. Seim3, K. VanKoevering6, A. Agrawal3, E. Ozer7, A. L. Limbach8, E. A. Kubi8, P. Bhateja8, J. W. Rocco3, M. Bonomi8, D. M. Blakaj1, and S. Baliga9; 1Department of Radiation Oncology, James Cancer Hospital/Wexner Medical Center, The Ohio State University, Columbus, OH, 2Department of Radiation Oncology, The James Cancer Center, Ohio State University Wexner Medical Center, Columbus, OH, 3The Ohio State University Department of Otolaryngology - Head & Neck Surgery, Columbus, OH, 4The Ohio State University Wexner Medical Center, Center for Biostatistics, Columbus, OH, 5University of Florida, Gainesville, FL, 6The Ohio State University, Columbus, OH, 7Ohio State University Comprehensive Cancer Center, Columbus, OH, 8The Ohio State University Wexner Medical Center, Columbus, OH, 9Department of Radiation Oncology, James Cancer Hospital, The Ohio State University Medical Center, Columbus, OH
Purpose/Objective(s): Definitive chemoradiation to 70 Gy with cisplatin remains the standard of care for locally advanced Human Papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma (HPV-OPSCC), yet long term toxicity remains substantial. We hypothesized that rapid mid-treatment clearance of circulating tumor tissue modified viral HPV-DNA (TTMV) identifies a subgroup of HPV-OPSCC patients suitable for biologically guided radiation dose de-escalation without compromising disease control. We report the planned interim analysis of a prospective Phase II trial evaluating the clinical efficacy of TTMV guided radiation dose de-escalation.
Materials/Methods: We enrolled patients with non-metastatic T0-T2, N1-2 or T3-T4, N0-N2 HPV-OPSCC with an initial TTMV score of >200 viral particles/mL and =10 pack year smoking history. Patients who had a rapid decline in TTMV levels during mid-radiotherapy (>95% by fraction 20) received radiotherapy dose reduction to 53 Gy in 25 fractions with concurrent weekly cisplatin (40 mg/m2) or carboplatin/paclitaxel (AUC1/30mg/m2). Patients without rapid TTMV clearance received 69.96 Gy with chemotherapy. The primary endpoint was 3-month complete metabolic response (CR) by Hopkins PET/CT criteria (score 1–2), chosen as an early surrogate endpoint to evaluate whether biomarker-guided dose reduction preserved disease control compared with historical outcomes. A Simon two-stage design (target N=25) provided 90% power to exclude a =20% decrement in CR rate compared with historical controls. A pre-specified interim futility boundary required =8 CRs among the first 12 de-escalated patients to proceed.
Results: Of the first 15 patients enrolled in the trial, 12 (80%) had a rapid decline in TTMV during mid-RT (>95% by week 20). The mean age was 59 years, and all de-escalated patients received the protocol prescribed dose of 53 Gy in 25 fractions. Median follow up time was 1.1 years. Eight patients were Stage I (66.7%) and four patients (33.3%) were Stage II. The median pre-treatment, mid-treatment, end of treatment, and three-month post treatment TTMV were 1361.3, 12.7, 1.8 and 0, respectively. All 12 patients achieved a CR by Hopkins criteria at 3 months post-treatment. There were no loco-regional failures and only one distant failure (Distant failure in lung currently treated with pembrolizumab). The median MDADI score before treatment, end of treatment, and 3 months post treatment was 92.6 (range 79-100), 69.8 (47.4-92.6) and 86.4 (55.8-100). Only 1 of 12 patients (8.3%) were gastrostomy tube dependent at 3 months post-CRT.
Conclusion: In a planned interim analysis of this prospective Phase II trial, circulating tumor DNA guided biological radiation dose de-escalation achieved excellent early metabolic response, disease control, and functional swallowing outcomes. These findings support the feasibility of a biomarker driven de-escalation strategy in HPV-OPSCC and warrants continued enrollment and longer follow-up to confirm long term efficacy.