A Phase 1 Trial of Dose-Escalated Hypofractionated Adaptive Radiation Therapy With Atezolizumab for Advanced Head and Neck Cancers

Purpose: To determine the maximum-tolerated dose (MTD) of dose-escalated hypofractionated adaptive radiation therapy with atezolizumab in patients with head and neck squamous cell carcinomas (HNSCCs) in a phase 1 trial. Methods and Materials: Dose-escalated hypofractionated adaptive radiation therapy was a single-center phase 1 trial. Eligible patients were aged ≥18 years with de novo metastatic HNSCC or localized American Joint Committee on Cancer 8th edition T3-T4 N0-N3, T0-T4 N1-N3 HNSCC meeting one of the following criteria: (1) not candidates for concurrent cisplatin mirroring eligibility for NRG HN-004; (2) refused concurrent cisplatin-based chemoradiation; (3) had unresectable oral cavity cancer; or (4) had recurrent disease after definitive surgical resection alone. Patients received 15 fractions of radiation to escalating total doses of 50, 55, or 60 Gy to gross disease based on a time-to-event continual reassessment methodology. Atezolizumab (1680 mg) was delivered every 4 weeks for up to 1 year after treatment. The primary endpoint of the study was to determine the MTD of radiation. Results: Eighteen patients were enrolled (11 men and 7 women, median age of 74 years [range, 52-89 years]). Five patients were enrolled in radiation dose level 1 (50 Gy in 15 fractions) and received atezolizumab on the first day of radiation. Three of these patients developed Herpes Simplex Virus Type 1 reactivation with excess toxicity. As such, the study was amended to remove the concurrent atezolizumab dose. Thirteen additional patients enrolled and began receiving atezolizumab after radiation. No dose-limiting toxicities were seen after the amendment, and the MTD of radiation was 60 Gy. No loco-regional failures were seen among 7 patients treated to 60 Gy with a 1-year progression-free survival of 71.4%. Conclusions: Radiation dose may be safely escalated to 60 Gy in 15 fractions with adjuvant atezolizumab with no new safety signals. However, concurrent atezolizumab with hypofractionated radiation promoted Herpes Simplex Virus Type 1 reactivation in a previously unreported manner, resulting in excess dose-limiting toxicities.