Immunotherapy and circulating tumor DNA in HPV-positive oropharyngeal cancer: a systematic review and exploratory meta-analysis of survival and surveillance outcomes.

BACKGROUND

Human papillomavirus-positive oropharyngeal squamous cell carcinoma is biologically distinct, yet the effect of immune checkpoint inhibition and the performance of circulating tumor DNA (ctDNA) as a biomarker remain undefined.

METHODS

We searched databases through October 2025 for prospective studies of adults with HPV-positive OPSCC that reported survival after immune checkpoint inhibition or plasma ctDNA/ctHPVDNA as a prognostic or surveillance biomarker. Two reviewers performed selection, extraction, ROBINS-I, and GRADE. Hazard ratios were pooled by inverse variance (common-effect; DerSimonian-Laird sensitivity), the two streams separately.

RESULTS

Six prospective studies (n = 295 HPV-positive patients) were included; none provided an internal immunotherapy-versus-no-immunotherapy contrast. ctDNA was consistently prognostic: across the three with a within-cohort ctDNA-stratified contrast (k = 3, n = 169), pooled hazard ratios were 0.67 (95% CI 0.57-0.80) for progression-free survival and 0.71 (95% CI 0.60-0.85) for overall survival. Whole-evidence-based estimates were 0.70 (95% CI 0.59-0.83) and 0.74 (95% CI 0.63-0.88), with substantial heterogeneity (I² = 63.6% and 67.9%), and are carried by the ctDNA contrasts, holding 89% (PFS) and 81% (OS) of pooled weight. The three studies contributing immunotherapy-associated estimates (k = 3, n = 126) showed no benefit (PFS HR, 0.96; 95% CI, 0.58-1.59; OS HR, 0.90; 95% CI, 0.62-1.32).

CONCLUSIONS

Plasma ctDNA/ctHPVDNA performed consistently as a prognostic and surveillance biomarker, with early clearance predicting better survival within treated cohorts. The evidence for prospective immunotherapy is too sparse and imprecise to demonstrate a survival benefit, and the favorable pooled signal should not be attributed to immunotherapy. Randomized, biomarker-stratified trials are required.