LBA03 - Interim Futility Results of NRG-HN005, A Randomized, Phase II/III Non-Inferiority Trial for Non-Smoking p16+ Oropharyngeal Cancer Patients

S. S. Yom¹, J. Harris², J. J. Caudell³, J. L. Geiger⁴, J. Waldron⁵, M. Gillison⁶, R. M. Subramaniam⁷, M. Yao⁸, C. Xiao⁹, N. Kovalchuk¹⁰, R. Martino¹¹, R. Jordan¹, C. Henson¹², M. Echevarria³, C. E. Lominska¹³, J. A. Dorth¹⁴, W. A. Stokes¹⁵, J. Chan¹⁶, M. F. Gensheimer¹⁷, and Q. T. Le¹⁸; ¹University of California San Francisco, San Francisco, CA, ²American College of Radiology, Philadelphia, PA, ³H. Lee Moffitt Cancer Center and Research Institute, Department of Radiation Oncology, Tampa, FL, ⁴Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, ⁵Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, ⁶The University of Texas MD Anderson Cancer Center, Houston, TX, ⁷University of Notre Dame, Sydney, Australia, ⁸University Hospitals Cleveland Medical Center, Cleveland, OH, ⁹Yale University, Orange, CT, ¹⁰Department of Radiation Oncology, Stanford University, Stanford, CA, ¹¹Krembil Research Institute, University Health Network, Toronto, ON, Canada, ¹²University of Oklahoma Health Sciences Center, OKLAHOMA CITY, OK, ¹³Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, KS, ¹⁴Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, ¹⁵Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, ¹⁶University of California San Francisco, Department of Radiation Oncology, San Francisco, CA, ¹⁷Radiation Oncology, Stanford University, Stanford, CA, ¹⁸Stanford University, Stanford, CA

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.