Cell-Free HPV DNA Kinetics Predicted by Radiographic Response in Locoregional Viral-Associated Oropharyngeal Cancer Receiving Response-Adaptive Treatment – Exploratory Analysis of a Prospective Trial

Abstract

<h3>Purpose/Objective(s)</h3> Human papillomavirus (HPV) associated oropharyngeal cancer (HPV+OPC) has a favorable prognosis. Current response-adapted strategies utilize RECIST to guide therapy. In the present study, we examined the utility of cell-free HPV DNA (cfHPV DNA) kinetic responses as an additional parameter to track therapy efficacy in de-escalation strategies. Here, we report a comparison of cfHPV DNA kinetics by RECIST and tumor volume (TV) from a prospective response-adaptive de-escalation trial. <h3>Materials/Methods</h3> Patients enrolled on the prospective phase II OPTIMA 2 (NCT03107182) de-escalation trial with available cfHPV DNA information were included for analysis. OPTIMA 2 enrolled locoregionally advanced HPV+OPC including low and high risk patients. High risk patients were defined as T4, N2c-N3 (AJCC 7^th edition), > 20 pack year smoking history, or non-HPV16 subtype. Neck CT or MRI as well as cfHPV DNA was obtained at baseline and following induction chemoimmunotherapy. Target lesions were assessed via RECIST 1.1 at baseline and post-induction therapy per protocol; patients with ≥ 50% response by RECIST received de-escalated radiation dose and volume. cfHPV DNA was detected and quantified using a CLIA-certified cfHPV sequencing assay (HPV-SEQ, Sysmex Inostics, Inc.). For this analysis, target lesions were delineated post hoc to obtain TV metrics. Linear regression was used to examine correlation between cfHPV DNA, RECIST, and TV response. Receiver Operating Characteristic (ROC) analysis was used to identify an optimal TV response to predict ≥ 95% cfHPV DNA response. <h3>Results</h3> 39 patients of which 31 had follow up cfHPV DNA information were evaluable. Median RECIST was 4.9 cm at baseline and 2.0 cm at follow up. Median TV was 29 cm³ at baseline and 6 cm³ at follow-up. 39 (100%) patients had detectable cfHPV DNA at baseline, with median 180 [IQR: 15, 966] copy number/mL. Of 31 patients with paired cfHPV DNA information at baseline, 29 (94%) had a ≥ 95% cfHPV DNA reduction. Of those, cfHPV DNA was undetectable in 21 (71%) cases. Baseline TV was associated with cfHPV DNA (p=0.04), and the median cfHPV DNA / TV ratio was 5.5 (copy number / cm³). No differences were observed between low and high-risk cohorts with respect to cfHPV DNA or radiographic metrics. RECIST was not associated with cfHPV DNA metrics. When adjusting for risk, TV response predicted cfHPV DNA response (p = 0.003). ROC analysis identified a TV response of 63% (AUC 0.88) to predict ≥ 95% cfHPV DNA response; 74% of patients had a TV response ≥ 63%. <h3>Conclusion</h3> cfHPV DNA kinetics were more pronounced than radiographic response to systemic therapy in both high and low risk groups. cfHPV DNA was predicted by TV response to chemoimmunotherapy, but was not predicted by traditional RECIST dynamics. We identified potential TV responses to predict cfHPV DNA response. This represents the first direct correlation of circulating tumor DNA levels to tumor volume and has implications for response assessment in the neoadjuvant setting as well as in other solid tumors.