Interim Futility Results of NRG-HN005, A Randomized, Phase II/III Non-Inferiority Trial for Non-Smoking p16+ Oropharyngeal Cancer Patients

Abstract

Purpose/Objective(s)

NRG-HN005 was a phase II/III randomized study comparing each of two experimental arm(s) against a control arm from RTOG 1016, in patients with p16+, non-smoking associated, locoregionally advanced oropharyngeal cancer. The phase II primary endpoint was non-inferiority (NI) of progression-free survival (PFS). The phase III trial would have included the experimental arm(s) found to be NI in phase II, with co-primary endpoints of NI PFS and superior quality of life.

Materials/Methods

Eligible patients had p16+ stage T1-2N1M0 or T3N0-N1M0 (AJCC 8^th edition) oropharyngeal squamous cell carcinoma and ≤10 pack-year smoking history. Patients were stratified by Zubrod performance status and randomized (1:1:1) to 70 Gy of intensity modulated radiation therapy (IMRT) over 6 weeks + Cisplatin at 100 mg/m² every 3 weeks (Arm 1) vs 60 Gy IMRT over 6 weeks + Cisplatin at 100 mg/m² every 3 weeks (Arm 2) vs 60 Gy IMRT over 5 weeks with nivolumab (Arm 3). For trial design, the assumed 9-month PFS was 96.5% and the lower threshold for Arms 2 and 3 was 91.8% (absolute NI margin 4.7%), for a hazard ratio (HR) boundary HR < 2.4 required for noninferiority. With one-sided type I error rate of 10% per test and 80% power, a log-rank test required 22 events from 266 patients per comparison (requiring 133 patients per arm and a total sample size of 399). In phase II, a futility analysis would be triggered for each comparison after 50% of the PFS events (11/22) had been reported. If the observed HR exceeded the NI margin, accrual would be discontinued. All randomized patients were included in analysis.

Results

Phase II accrued from 7/10/19 to 11/8/23. Accrual was suspended from 2/3/23 to 5/25/23, to discontinue Arm 2, after which randomization continued (1:1) to Arms 1 and 3 to complete the new phase II sample size of 382 patients. The median age was 60 years, 90.6% were male, 87.5% were White, and 84.9% had stage I disease. The first futility analysis was conducted after 11 PFS events (Arm 1: 2, Arm 2: 9) were reported, at a median follow-up of 1.1 years. The estimated HR was 4.34 (1-sided 90% upper confidence limit 11.83). The second futility analysis was triggered after 11 PFS events (Arm 1: 2, Arm 3: 9) were reported, at a median follow-up of 1.7 years. The estimated HR was 4.51 (1-sided 90% upper confidence limit 12.29). Accrual would have stopped but phase II had already completed. At present (median follow-up 2.2 years), 2-year PFS estimates are 98.1% (95% CI 95.4, 100) for Arm 1, 88.6% (95% CI 82.4, 94.7) for Arm 2, and 90.3% (95% CI 84.5, 96.1) for Arm 3. The 2-year overall survival estimates are 99.0% (95% CI 97.0, 100), 98.0% (95% CI 95.2, 100), and 96.1% (95% CI 92.3, 99.9), respectively.

Conclusion

The failure of the experimental arms to satisfy non-inferiority is due in part to the highly favorable outcome for the RTOG 1016 regimen, which demonstrated a 98% PFS rate through 2 years. A phase III trial will not proceed.