Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial

Summary Background The incidence of human papillomavirus ( HPV)- positive oropharyngeal cancer, a disease affecting younger patients, is rapidly increasing. Cetuximab, an epidermal growth factor receptor inhibitor, has been proposed for treatment de-escalationin this setting to reduce the toxicity of standard cisplatintreatment, but no randomised evidence exists for the efficacy of this strategy. Methods We did an open-label randomised controlled phase 3 trial at 32 head and neck treatment centres in Ireland, the Netherlands, and the UK, in patients aged 18 years or older with HPV-positive low-risk oropharyngeal cancer (non-smokers or lifetime smokers with a smoking history of 2 on days 1, 22, and 43 of radiotherapy) or intravenous cetuximab(400 mg/m 2 loading dosefollowed by seven weekly infusions of 250 mg/m 2 ). The primary outcome was overall severe (grade 3–5) toxicity events at 24 months from the end of treatment. The primary outcome was assessed by intention-to-treat and per-protocol analyses. This trial is registered with the ISRCTN registry, number ISRCTN33522080. Findings Between Nov 12, 2012, and Oct 1, 2016, 334 patients were recruited (166 in the cisplatingroup and 168 in the cetuximabgroup). Overall (acute and late) severe (grade 3–5) toxicity did not differ significantly between treatment groups at 24 months (mean number of events per patient 4·8 [95% CI 4·2–5·4] with cisplatinvs 4·8 [4·2–5·4] with cetuximab; p=0·98). At 24 months, overall all-grade toxicity did not differ significantly either (mean number of events per patient 29·2 [95% CI 27·3–31·0] with cisplatinvs 30·1 [28·3–31·9] with cetuximab; p=0·49). However, there was a significant difference between cisplatinand cetuximabin 2-year overall survival (97·5% vs 89·4%, hazard ratio 5·0 [95% CI 1·7–14·7]; p=0·001) and 2-year recurrence (6·0% vs 16·1%, 3·4 [1·6–7·2]; p=0·0007). Interpretation Compared with the standard cisplatinregimen, cetuximabshowed no benefit in terms of reduced toxicity, but instead showed significant detriment in terms of tumour control. Cisplatinand radiotherapy should be used as the standard of care for HPV-positive low-risk patients who are able to tolerate cisplatin. Funding Cancer Research UK.