Radiotherapy Plus Cetuximab or Cisplatin in HPV-Positive Oropharyngeal Carcinoma


Key Points

  • Cetuximab plus radiotherapy was associated with poorer overall and progression-free survival vs cisplatin plus radiotherapy.
  • The overall incidence of acute grade 3 or 4 toxicity and late grade 3 or 4 toxicity did not significantly differ between groups.

In a noninferiority phase III trial (NRG Oncology RTOG 1016) reported in The Lancet, Gillison et al found that radiotherapy plus cetuximab (Erbitux) was associated with poorer overall survival vs radiotherapy plus cisplatin in patients with human papillomavirus (HPV)-positive oropharyngeal carcinoma. It was hypothesized that cetuximab might maintain a high proportion of patient survival and reduce acute and late toxicity.

Study Details

In the trial, 849 patients with histologically confirmed disease (American Joint Committee on Cancer 7th edition clinical categories T1–T2, N2a–N3 M0 or T3–T4, N0–N3 M0) from 182 sites in the United States and Canada were randomly assigned between June 2011 and July 2014 to receive radiotherapy plus cetuximab (n = 425) or radiotherapy plus cisplatin (n = 424); of these, 399 patients assigned to cetuximab and 406 assigned to cisplatin were subsequently considered to be eligible. Treatment consisted of cetuximab at a loading dose of 400 mg/m2 5 to 7 days before radiotherapy, followed by 250 mg/m2 weekly for seven doses (total = 2,150 mg/m2) or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total =200 mg/m2). All patients received accelerated intensity-modulated radiotherapy at 70 Gy in 35 fractions over 6 weeks at 6 fractions per week, with 2 fractions given on 1 day at least 6 hours apart.

The primary endpoint was overall survival in the modified intent-to-treat population (all eligible patients), with a noninferiority margin of 1.45 for the 95% upper confidence interval (CI) of the hazard ratio.

Survival Outcomes

Median follow-up was 4.5 years. Radiotherapy plus cetuximab did not meet the noninferiority margin in overall survival analysis (hazard ratio [HR] = 1.45, one-sided 95% upper CI = 1.94; P = .5056 for noninferiority); overall survival was significantly worse with cetuximab (2-sided 95% CI = 1.03–2.05, P = .0163) vs cisplatin. Estimated 5-year overall survival was 77.9% in the cetuximab group vs 84.6% in the cisplatin group. Progression-free survival was also significantly poorer in the cetuximab group (HR = 1.72, P = .0002), with estimated 5-year rates of 67.3% vs 78.4%. Locoregional failure was significantly more likely in the cetuximab group (HR = 2.05, 95% CI = 1.35–3.10), with 5-year rates of 17.3% vs 9.9%.  


Acute grade 3 or 4 toxicity occurred in 77.4% of the cetuximab group vs 81.7% of the cisplatin group (P = .1586). Acneiform rash was significantly more common in the cetuximab group; myelosuppression, anemia, nausea, vomiting, anorexia, dehydration, hyponatremia, kidney injury, and hearing impairment were significantly more common in the cisplatin group. Late grade 3 or 4 toxicity occurred in 16.5% vs 20.4% (P = .1904). Hearing impairment was significantly more common in the cisplatin group. There was no significant difference between groups in treatment-related grade 3 or 4 adverse events over time; at 1 year, the rates were 8.5% vs 10.0%.

The investigators concluded, “For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma.”

Maura L. Gillison, MD, of the Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, and Andy M. Trotti, MD, of the Department of Radiation Oncology, Moffitt Cancer Center, are the corresponding authors for The Lancet article.

Disclosure: The study was funded by the National Cancer Institute, Eli Lilly, and The Oral Cancer Foundation.The study authors’ full disclosures can be found at

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