Circulating Tumor HPV-DNA Kinetics in P16+ Oropharyngeal Cancer Patients Undergoing Adaptive Radiation De-Escalation Based on Mid-Treatment Nodal Response

Purpose/Objective(s) Human-papilloma virus-positive (HPV+) OPSCC is known to have an excellent prognosis with a favorable response to CRT. Several studies have shown that de-intensified treatment in select patients (pts) can achieve similar survival outcomes to standard treatment while reducing acute and long-term toxicity. Additionally, rapid clearance of circulating tumor HPV DNA may be useful in predicting the likelihood of disease control. Materials/Methods We evaluated pts enrolled on a phase II institutional clinical trial. Pts with HPV+ OPSCC were included and were treated with definitive CRT with cisplatin. All pts were initially planned to receive standard radiation dose (S-RT) to 70 Gy; those who achieved a favorable mid-treatment response (FMTR) of >40% lymph node shrinkage at week 4 of radiation (RT) received a de-escalated dose (D-RT) to 60 Gy. Blood samples were taken at screening, week 4 of RT, and at follow-up visit after RT and circulating tumor tissue modified viral HPV NDA (TTMV) was qualtified. We define a "substantial TTMV clearance" as either >95% reduction in TTMV from screening to week 4 (screening level >200 copies/ml) or undetectable ctHPVDNA at week 4 (any detectable screening level). Fisher tests were used to evaluate the association of TTMV and treatment group. Results At the time of this analysis, 35 pts were enrolled in the clinical trial with a median age of 60 years at diagnosis (range 38 to 76). 25 pts achieved a FMTR and received D-RT while 10 pts received S-RT. 29 pts (7 S-RT, 18 D-RT) had detectable screening TTMV and week 4 TTMV samples available for analysis. D-RT pts had a significantly higher rate of substantial TTMV clearance at week 4 compared to S-RT: 14.3% (1/7) pts in the S-RT vs. 61.1% (11/18) pts in the D-RT (OR 0.090 [0.002 - 0.105], p=0.036). 6 of 25 pts (24%) had a flare in their TTMV from screening to week 4 including 57.1% (4/7) of the S-RT and 11.1% (2/18) of the D-RT; there was a significantly higher likelihood of TTMV flare in the S-RT group (OR 9.34 [0.898 - 150.960], p=0.032). 24 pts (6 S-RT, 18 D-RT) with initial detectable screening TTMV also had a follow-up TTMV sample available. The median time from screening to follow-up was 81.0 days for all pts (76.5 days for D-RT, 84.0 days for S-RT). 95.7% of pts (83.3% of S-RT, 100%% of D-RT) had complete TTMV clearance at follow-up. Conclusion We report a statistically significant correlation between substantial TTMV clearance and a FMTR of >40% nodal shrinkage. 61.1% of D-RT pts achieved a substantial TTMV clearance compared to 14.3% in the S-RT group. Additionally, we observed that pts who did not achieve a FMTR had a higher likelihood of TTMV flare at week 4. Nearly all pts achieved a complete TTMV clearance by follow-up. Mid-treatment TTMV clearance may help identify pts who may benefit from further de-escalation as well as those who should continue with standard therapy. This study has the ClinicalTrials.gov identifier NCT03215719.