Randomized Phase III Trial of Postoperative Radiotherapy with or without Cetuximab for Intermediate-Risk Squamous Cell Carcinoma of the Head and Neck (SCCHN): NRG/RTOG 0920

Purpose/Objective(s) The combination of radiotherapy (RT)/cetuximab has demonstrated superiority over RT alone for locally advanced non-operative SCCHN. We performed a definitive randomized trial to test this hypothesis in completely resected, intermediate-risk SCCHN. Materials/Methods Enrolled patients had SCCHN of the oral cavity, oropharynx or larynx (hypopharynx was excluded); complete resection with negative margins and no evidence of nodal extracapsular spread; but one or more risk factors warranting postoperative RT. Patients were randomized 1:1 to IMRT (60-66 Gy) with cetuximab (C) (loading dose 400 mg/m2 pre-RT plus weekly 250 mg/m2 up to 11 total doses) (RT+C) or without C (RT). Patients were stratified by tumor site/ HPV status, clinical T-stage, EGFR expression level, and use of daily IGRT. The primary hypothesis was that RT+C would achieve superior overall survival (OS) in eligible patients. The trial was designed to detect a hazard ratio of 0.74 with 80% power, and 1-sided alpha of 0.025 (372 OS events, target enrollment of 700 patients). Disease-free-survival (DFS) and toxicity were secondary endpoints. Late toxicity was defined as >90 days after start of RT. OS and DFS between arms were compared via stratified log-rank test; toxicity was compared via Fisher's exact test. Locoregional failure was a tertiary/exploratory endpoint. Results The study enrolled 702 pts from 11/2009-3/2018; 627 were randomized, and 577 were eligible (287 RT and 290 RT+C). Most patients (64%) had oral cavity cancer, and 52% had clinical AJCCv6 stage IV(M0) cancer; a large majority (84.6%) had high EGFR expression. Due to substantially lower than expected event (death) rates, the protocol was amended to perform a time-driven analysis with data as of 06/05/2023 (184 OS events). At a median follow-up of 7.2 years, OS was not significantly improved, but DFS was (see table). Grade 3-4 acute toxicity rates were 70.3% (RT+C) versus 39.7% (RT), (p<0.0001), mostly related to skin and/or mucosal effects. Late Grade ≥3 toxicity rate was 33.2% (RT+C) versus 29.0% (RT) (p=0.3101). There were no Grade 5 toxicities in either arm. Conclusion Radiotherapy + cetuximab (RT+C) did not show OS superiority but significantly improved DFS, compared to RT alone for patients with resected, intermediate-risk SCCHN. Acute but not late toxicity was increased with RT+C. RT+C may be considered for this patient population, but it will be critical to identify subgroups achieving benefit from this combined-modality therapy. The combination of radiotherapy (RT)/cetuximab has demonstrated superiority over RT alone for locally advanced non-operative SCCHN. We performed a definitive randomized trial to test this hypothesis in completely resected, intermediate-risk SCCHN. Enrolled patients had SCCHN of the oral cavity, oropharynx or larynx (hypopharynx was excluded); complete resection with negative margins and no evidence of nodal extracapsular spread; but one or more risk factors warranting postoperative RT. Patients were randomized 1:1 to IMRT (60-66 Gy) with cetuximab (C) (loading dose 400 mg/m2 pre-RT plus weekly 250 mg/m2 up to 11 total doses) (RT+C) or without C (RT). Patients were stratified by tumor site/ HPV status, clinical T-stage, EGFR expression level, and use of daily IGRT. The primary hypothesis was that RT+C would achieve superior overall survival (OS) in eligible patients. The trial was designed to detect a hazard ratio of 0.74 with 80% power, and 1-sided alpha of 0.025 (372 OS events, target enrollment of 700 patients). Disease-free-survival (DFS) and toxicity were secondary endpoints. Late toxicity was defined as >90 days after start of RT. OS and DFS between arms were compared via stratified log-rank test; toxicity was compared via Fisher's exact test. Locoregional failure was a tertiary/exploratory endpoint. The study enrolled 702 pts from 11/2009-3/2018; 627 were randomized, and 577 were eligible (287 RT and 290 RT+C). Most patients (64%) had oral cavity cancer, and 52% had clinical AJCCv6 stage IV(M0) cancer; a large majority (84.6%) had high EGFR expression. Due to substantially lower than expected event (death) rates, the protocol was amended to perform a time-driven analysis with data as of 06/05/2023 (184 OS events). At a median follow-up of 7.2 years, OS was not significantly improved, but DFS was (see table). Grade 3-4 acute toxicity rates were 70.3% (RT+C) versus 39.7% (RT), (p<0.0001), mostly related to skin and/or mucosal effects. Late Grade ≥3 toxicity rate was 33.2% (RT+C) versus 29.0% (RT) (p=0.3101). There were no Grade 5 toxicities in either arm. Radiotherapy + cetuximab (RT+C) did not show OS superiority but significantly improved DFS, compared to RT alone for patients with resected, intermediate-risk SCCHN. Acute but not late toxicity was increased with RT+C. RT+C may be considered for this patient population, but it will be critical to identify subgroups achieving benefit from this combined-modality therapy.