NRG-HN002: A Randomized Phase II Trial for Patients With p16-Positive, Non-Smoking-Associated, Locoregionally Advanced Oropharyngeal Cancer

Purpose/Objective(s): NRG-HN002 was designed to select the arm(s) achieving acceptable progression-free survival (PFS) without unacceptable swallowing-related quality of life [MD Anderson Dysphagia Inventory (MDADI)] in patients with p16+, non-smoking-associated, locoregionally advanced oropharyngeal cancer. Materials/Methods: Eligible patients had stage T1-2N1-N2bM0 or T3N0-N2bM0 (AJCC 7th edition) oropharyngeal squamous cell carcinoma and ≤10 pack-year smoking history. p16 immunohistochemistry was centrally confirmed. Patients were stratified by unilateral vs bilateral radiation and randomized (1:1) to either 60 Gy of intensity modulated radiation therapy over 6 weeks + Cisplatin (IMRT+C) at 40 mg/m2 weekly vs 60 Gy of modestly accelerated IMRT alone over 5 weeks. For the expected 2-year PFS of 91%, assuming a binomial distribution, 140 randomized eligible patients per arm were required for 80% power and 10% 1-sided type I error rate. For swallowing acceptability, the required mean 1-year MDADI composite score was ≥ 60. Results: NRG-HN002 accrued 10/2014-2/2017. Of 316 patients enrolled, 306 were randomized and eligible. Among randomized eligible patients, 84.0% were male, 52.6% had tonsil primary, 62.4% had T2-3 disease, 75.5% had N2 disease, and 80.1% had bilateral IMRT. 97.7% completed 60 Gy IMRT. Of 157 patients receiving Cisplatin, 80.9% had ≥5 cycles and 72.6% had ≥200 mg/m2. There were 15.1% grade 4 and 64.5% grade 3 acute (≤ 180 days after the end of treatment) toxicities on the IMRT+C arm as compared to 2.0% grade 4 and 50.3% grade 3 on the IMRT arm. There were 1.3% grade 4 and 20.0% grade 3 late toxicities on the IMRT+C arm as compared to 1.4% grade 4 and 16.7% grade 3 on the IMRT arm. There was no grade 5 toxicity reported. Nine patients withdrew consent and 5 did not have 2-year assessments, leaving 292 patients analyzable for PFS. At 2.6 years of median follow-up, the 2-year PFS estimate for the IMRT+C arm was 90.5% (95% CI 84.5-94.7%) with p=0.0350 thus rejecting the null hypothesis of 2-year PFS ≤ 85%. For IMRT, the 2-year PFS was 87.6% (95% CI 81.1-92.5%) with p=0.2284 thus failing to reject the null hypothesis. At 1 year, useable and timely MDADI completion rates were 77.1% and 71.1% in the IMRT+C and IMRT arms, respectively. Both arms passed the MDADI threshold, with 1-year means of 85.30 (95% CI 82.53-88.07) and 81.76 (95% CI 78.98-84.54) in the IMRT+C and IMRT arms, respectively. Estimated 2-year OS rates were 96.7% (95% CI 93.9-99.5%) for IMRT+C and 97.3% (95% CI 94.6-99.9%) for IMRT. Conclusion: The IMRT+C arm met the acceptability criteria for both 2-year PFS and 1-year MDADI. The IMRT alone arm did not meet the PFS acceptability criterion. Higher rates of grade ≥3 acute toxicity were reported for IMRT+C. Rates of late grade ≥3 toxicity and estimated 2-year OS rates were similar. Author Disclosure: S.S. Yom: Research Grant; Genentech, Merck, Bristol-Myers Squibb, BioMimetix. book royalty; Springer. chapter royalty; UpToDate. Honoraria; ASTRO. Consultant; Galera. Appropriate Use Criteria Committee; American Radium Society; American Society for Radiation Oncology, American Radium Society. P. Torres-Saavedra: None. J.J. Caudell: None. J.N. Waldron: None. M. Gillison: None. M. Truong: Travel Expenses; American Board Radiology. R. Jordan: None. R. Subramaniam: None. M. Yao: None. C. Chung: None. J.L. Geiger: Drug company-sponsored clinical trial of which I am institutional PI.; Regeneron. J. Chan: None. B. O'Sullivan: None. D.M. Blakaj: None. L.K. Mell: None. W.L. Thorstad: None. C.U. Jones: None. R.N. Banerjee: Independent Contractor; University of Calgary. C.E. Lominska: None. Q. Le: Research Grant; Amgen, NIH, Redhill. Travel Expenses; BMS. Stock; Aldea; Head and Neck Cancer International Group (HNCIG). Chair of head and neck committee- design clinical trial; RTOG NRG Cooperative group. president elect; American Radium Society.