Hypothesis: Hypofractionated radiation therapy (HFRT) in combination with checkpoint blockade may modulate the tumor microenvironment to induce favorable antitumor immune responses and enhance surgical resection.

Purpose: The purpose of this first-in-human phase Ib clinical trial was to test the safety and immunologic effects of neoadjuvant immunoradiotherapy prior to surgery in patients with head and neck squamous cell carcinoma (HNSCC) (NCT03247712).

Methods: Patients with previously untreated stage I-III (AJCC 8th Ed) p16 positive squamous cell carcinoma of the oropharynx (OPSCC) or cervical lymph nodes from an unknown primary (SCCUP) were eligible to enroll. Neoadjuvant treatment consisted of sandwich nivolumab in combination with HFRT to gross tumor volume in one of two dose-finding cohorts of 8Gy x5 (Monday-Friday) or 8Gy x3 (Monday-Wednesday-Friday), followed five weeks later by definitive surgical resection. The primary endpoint was < 33% unplanned surgical delay; secondary endpoint was pathologic response. Surgical complications were assessed using the Clavien-Dindo scale, a validated scoring tool for surgical complications, applied for 90 days postoperatively. Serial blood and tissue specimens were obtained longitudinally for immunogenomic changes over time.

Results: 10 patients (stage: T0N1M0, N=3; T1N1M0, N=1; T2N1M0, N=6) enrolled and underwent neoadjuvant immunoradiotherapy prior to surgery with curative intent, which consisted of selective neck dissection (level II-IV) and transoral robotic assisted oropharyngectomy for patients with mucosal disease. Surgery was safely performed in all patients without delay, thus meeting the primary endpoint. 7 patients demonstrated a partial radiologic response (PR) by RECIST criteria prior to surgery and 3 patients had stable disease (SD). The pathologic complete response rate (pCR) was 90% (8GyX5 cohort=5/5; 8GyX3 cohort=4/5) with the remaining patient achieving a major pathologic response (MPR; <10% viable tumor cells). All patients were successfully downstaged prior to surgery (ypT0N0M0=9; ypT0N1M0=1) and no patient required adjuvant radiation or chemoradiation. Grade 3 surgical complications as assessed by Clavien-Dindo occurred in 3/5 patients in the 8Gy X5 cohort, but there were no grade 3 or 4 complications in in the 8Gy X3 cohort. All patients are alive without evidence of disease (median follow-up <1 year).

Conclusions: Neoadjuvant HFRT in combination with nivolumab is safe, does not delay definitive surgical resection, and results in significant downstaging with major pathologic response. A lower toxicity profile favors a radiation dose of 8Gy x3 for future development in both human papilloma virus (HPV)-related and HPV-unrelated HNSCC.

Citation Format: R. Bryan Bell, Rom Leidner, Marcus Couey, Ashish Patel, Amber Watters, Hong Ziao, Carlo Bifulco, Brian Piening, George Morris, Lessli Rushforth, Dawn Brucker, Shoren Nemeth, Kristina Young, Michael Gough, Marka Crittenden. Surgical outcomes following neoadjuvant hypofractionated radiation in combination with nivolumab: High rate of pathologic complete response in patients with p16+ head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr B01.