Surrogate Endpoints in p16-Positive Squamous Cell Carcinoma of the Oropharynx

Purpose/Objective(s) The increased incidence of HPV-related cancers has motivated efforts to optimize treatment paradigms for these excellent-prognosis patients. Validation of surrogates for overall survival (OS) could expedite the evaluation of new therapies. We sought to validate candidate intermediate clinical endpoints (ICE) in trials assessing definitive treatment of p16-positive oropharyngeal cancer with (chemo)radiation. Materials/Methods A retrospective review of five multicenter randomized trials (NRG/RTOG 9003, 0129, 0234, 0522, 1016) was performed. Eight ICEs were considered as potential surrogates for OS: freedom from local progression (FLP), freedom from regional progression (FRP), freedom from distant metastasis (FDM), freedom from locoregional progression (FLRP), freedom from any progression (FFP), locoregional progression-free survival (LRPFS), progression-free survival (PFS), and distant metastasis-free survival (DMFS). A two-stage meta-analytic framework was used to evaluate the ICEs, with R2 ≥0·7 as criteria for clinically relevant surrogacy. Results In total, 1,373 patients with p16-positive oropharyngeal cancer were analyzed. Median follow-up was four years. For the first condition, correlating the ICE with OS at the individual and trial level, FDM and the three composite endpoints LRPFS, DMFS, and PFS were highly correlated with OS at the patient level (Kendall's τ > 0·85) and at the trial arm level (R2 >0·75). For the second condition, correlating treatment effects of the ICE and OS, the composite endpoints LRPFS, DMFS, and PFS met criteria with R2 of 0·89, 0·97, and 0·92, respectively. Treatment effects on the remaining ICEs were less highly correlated and did not meet surrogacy validation criteria for OS for the second criterion. Conclusion LRPFS, DMFS, and PFS are validated surrogates for OS in p16-positive oropharyngeal cancers treated with (chemo)radiation and may serve as clinical trial endpoints.