LBA 06 - NRG-HN009 Randomized Phase II/III Trial of RT + Cisplatin Q3 Weeks vs RT + Cisplatin Weekly for Patients with Locoregionally Advanced SCCHN: p16-Negative Phase II Toxicity Results

Purpose/Objective(s): To provide first report of phase II acute toxicity results for the p16-negative cohort of 234 patients from NRG-HN009. The phase II acute toxicity results for the p16-positive cohort of 241 patients were presented at the Multidisciplinary HNC Symposium in Feb 2026.

Materials/Methods: Eligible patients with p16-negative SCCHN were randomly assigned to receive 70 Gy RT + Cis at 100 mg/m2 Q3 weeks (Q3) vs 70 Gy RT + Cis weekly at 40 mg/m2 (Q1). Acute toxicity was measured by T-score, defined as the number of all treatment-related grade 3-4 adverse events during treatment or within six months. To proceed to phase III, the mean T-score ratio (Q1/Q3) from negative binomial regression must be significantly (1-sided p<0.1) < 1 (i.e., Q1 toxicity < Q3 toxicity) and the difference in 6-month locoregional failure estimates (Q1-Q3) must be = 8% (absolute difference). Quality assurance modality reviews for a random sample of cases were performed for radiation and chemotherapy delivery quality.

Results: Between Oct 2021-Sept 2025, 234 patients were randomized, 118 patients to Q3 and 116 to Q1. 91% of patients completed all follow-up up to 6 months. Median age was 60 years; 76% male; 80% white; 58% Zubrod 0; 87% former or current smokers; 70% >10 pack-years smoking history; 57% larynx, 28% oropharynx, 15% hypopharynx; 83% T1-3 tumors and 74% node-positive disease. Mean T-score ratio was 1.11 (90% upper confidence bound 1.33; p=0.77) with mean T-scores of 2.23 (95% confidence interval 1.81, 2.65) for Q3 and 2.48 (95% CI 1.97, 2.99) for Q1. There were absolute differences in acute grade 3-4 rates between arms of = 5% in the following terms as shown in Table 1. The Q3 Cis arm showed higher acute grade 3-4 toxicity rates of nausea, dehydration and acute kidney injury, whereas the Q1 Cis arm showed higher rates of WBC and magnesium decrease. The 6-month locoregional failure rates were 4.6% for Q3 and 9.6% for Q1 [absolute difference 5.0% (95% CI 1.0, 8.9)]. RT reviews were completed for 91% of sampled patients with overall score per protocol or acceptable variation in 81% on Q3 and 94% on Q1. Chemotherapy reviews were completed for 100% of sampled patients with overall score per protocol or acceptable variation in 80% on Q3 and 98% on Q1.

Conclusion: The phase II toxicity results for the p16-negative cohort of NRG-HN009 did not meet criteria for continuing to phase III. Acute grade 3-4 AE rates between arms with = 5% difference varied across the Q3 and Q1 Cis treatment arms as depicted in Table 1. The overall acute toxicity and locoregional control results at 6 months for all 475 patients enrolled on the NRG-HN009 phase II study (p16+ and p16-) will be summarized at presentation.