Evaluation of progression-free status at 24 months as a surrogate endpoint for overall survival in patients with human papillomavirus-positive oropharyngeal cancer: a retrospective cohort study.

Abstract

There is minimal evidence supporting the use of early clinical endpoints to evaluate the activity of initial treatment in human papillomavirus (HPV)-positive oropharyngeal cancer in the context of contemporary therapeutic approaches. The aim of this study was to assess progression-free status at 24 months as a potential surrogate endpoint for overall survival at the patient level, within a large, retrospective cohort of patients with HPV-positive oropharyngeal cancer. In this retrospective cohort study, we included all consecutive patients aged 18 years or older with newly diagnosed, non-metastatic, HPV-positive oropharyngeal cancer who underwent radiotherapy (dose ≥50 Gy [relative biological effectiveness]) at Memorial Sloan Kettering Cancer Center (New York, NY, USA). Post-radiotherapy follow-up consisted of a clinical evaluation 8-12 weeks after treatment, then surveillance every 3 months for 2 years and every 6-12 months thereafter, incorporating imaging and physical examination to assess response and detect disease recurrence. The primary dichotomous outcome was progression-free status at 24 months after initiating radiotherapy. Overall survival outcomes were compared with those of age-matched, sex-matched, and calendar year-matched general populations sourced from US Life Tables, using expected survival estimates and standardised mortality ratios (SMRs). Between Jan 11, 2013, and Dec 27, 2022, 1245 patients with HPV-positive oropharyngeal cancer treated with radiotherapy were included in the analysis (median age 61 years [IQR 55-68]; 1093 [87·8%] male patients and 152 [12·2%] female patients). Median follow-up from the start of radiotherapy was 63·3 months (IQR 40·4-91·3). 5-year overall survival was 89·3% (95% CI 87·4-91·2). 1183 patients had follow-up data for 24-month progression-free status assessment with 1044 (88·3%) progression-free at 24 months after initiating radiotherapy. The SMR after reaching 24-month progression-free status was 1·2 (95% CI 1·0-1·6; p=0·090). The 5-year subsequent overall survival of patients who reached 24-month progression-free status was 93·1% (95% CI 91·1-95·1), similar to the expected 5-year overall survival of 92·7% in the matched US general population. In patients with disease progression within 24 months, 5-year subsequent overall survival was 33·5% (25·4-44·2), versus an expected 5-year overall survival of 91·1% in the matched US general population, with a corresponding SMR of 17·9 (14·3-22·2; p<0·0001). Progression-free status at 24 months was a strong prognostic marker for overall survival at the patient level in HPV-positive oropharyngeal cancer and future trial-level analysis is now warranted. The adoption of this endpoint has the potential to accelerate therapeutic development by enabling earlier evaluation of treatment activity, thereby facilitating the timely introduction of novel therapies to this patient population before the availability of mature overall survival data. This research was funded in part through the US National Institutes of Health, National Cancer Institute Cancer Center Support Grant P30 CA008748.