Prospective Phase II Trial of Definitive Chemoradiation and Concurrent Nivolumab in Locally Advanced p16+ Oropharynx...

We conducted a prospective, single-institution phase II trial to test the hypothesis that the addition of nivolumab to definitive chemoradiation would improve the progression-free survival (PFS) among patients with high-risk p16+ oropharyngeal squamous cell carcinoma (OPSCC).

Patients with previously-untreated locoregionally advanced, p16+ OPSCC (clinical T4/N3, matted lymph nodes, and/or retropharyngeal lymphadenopathy) were enrolled. Patients received a priming dose of nivolumab, concurrent nivolumab and chemoradiation (70 Gy to PTVhigh, 56 Gy to PTVlow, weekly carboplatin/paclitaxel), and 4 cycles of adjuvant nivolumab over 12 weeks. The primary endpoint was 2-year PFS compared to an institutional historic control of 68%. Exploratory endpoints included associations between survival and circulating tumor DNA kinetics during treatment and pretreatment/midtreatment ¹⁸F-fluorodeoxyglucose positron-emission tomography with computed tomography and magnetic resonance imaging metrics (gross tumor volume, low blood volume tumor subvolume, low apparent diffusion coefficient tumor subvolume, and metabolic tumor volume ≥50% of maximum standardized uptake value).

Twenty-six patients were enrolled prior to an interim analysis; 65% cT4, 46% with matted nodes, with a median total gross tumor volume of 60 cc (range, 36-165). Estimated 2-year PFS was 65% (2-sided 90% CI, 46%-79%) and 2-year distant metastasis-free survival was 84% (66%-93%). The majority (69%) did not complete the full course of nivolumab because of toxicity, and 54% experienced grade ≥3 acute dysphagia. Statistical analyses showed that increasing values of imaging-defined primary tumor subvolumes were significant associated with inferior PFS (eg, midtreatment low apparent diffusion coefficient: HR, 5.61; P = .05) and distant metastasis-free survival (eg, pretreatment metabolic tumor volume ≥50% of maximum standardized uptake value: HR, 2.97; P = .05). Midtreatment circulating tumor DNA kinetics were not associated with survival endpoints.

Concurrent and adjuvant nivolumab did not improve PFS in locoregionally advanced Human papillomavirus+ OPSCC and was associated with significant toxicity. Physiological magnetic resonance imaging and ¹⁸F-fluorodeoxyglucose positron-emission tomography with computed tomography imaging markers are potential biomarkers to guide future therapy escalation strategies in high-risk oropharynx cancer.