The NRG Oncology NRG-HN005 phase II/III clinical trial has revealed that standard radiotherapy combined with cisplatin remains the most effective treatment for patients with p16-positive (p16+) oropharyngeal cancer. The trial, which sought to determine if de-intensified treatment regimens could offer non-inferior outcomes, failed to meet its non-inferiority criteria in the phase II portion, thus not proceeding to phase III.
The study compared two experimental treatment arms against a control arm consisting of standard dose, slightly accelerated intensity modulated radiotherapy (IMRT) and two cycles of cisplatin chemotherapy. The experimental arms explored lower doses of IMRT with either the same cisplatin schedule or slightly accelerated IMRT with six cycles of nivolumab, an immunotherapy drug, administered before, during, and after radiation.
Trial Design and Patient Population
The NRG-HN005 trial enrolled 384 patients with p16+ oropharyngeal squamous cell carcinoma and a smoking history of ≤ 10 pack-years. Participants were stratified by Zubrod Performance Status and randomly assigned to one of three treatment arms:
- Arm 1 (Control): 70 Gy of radiation in 6 weeks, 6 fractions per week, with cisplatin every 3 weeks.
- Arm 2: 60 Gy of radiation over 6 weeks in 5 fractions per week with cisplatin.
- Arm 3: 60 Gy of radiation in 5 weeks and 6 fractions per week with nivolumab starting 1 week before radiation and given every 2 weeks.
Futility Analysis and Results
Futility analyses for Treatments 1 and 2, and Treatments 1 and 3 were conducted after 11 progression-free survival (PFS) events. At a median follow-up of 2.2 years, the 2-year PFS estimates were:
- Control Arm: 98.1% (95% CI 95.4, 100)
- Lower Dose Radiation and Cisplatin Arm: 88.6% (95% CI 82.4, 94.7)
- Lower Dose Radiation and Nivolumab Arm: 90.3% (95% CI 84.5, 96.1)
The high PFS rate in the control arm was a significant factor in the failure of the experimental arms to demonstrate non-inferiority.
Implications for Clinical Practice
"This study, despite the overall failure of the experimental arms, is extremely important as an affirmation that this group of patients achieves genuinely outstanding outcomes with traditional chemoradiation," stated Sue S. Yom, MD, Ph.D., of the University of California San Francisco and the lead author of the NRG-HN005 abstract. She further noted that the study sets "a new very high bar for deintensification studies in the future," given the excellent prognosis observed in the control arm.
The control arm's regimen was based on findings from the RTOG 1016 clinical trial, which established radiotherapy and cisplatin as the standard of care for p16-positive oropharyngeal cancer. The NRG-HN005 trial reinforces this standard, suggesting that current attempts to reduce treatment intensity may compromise outcomes for this patient population.
