Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial

Abstract

Background Patients with HPV-positive oropharyngeal squamous cell carcinoma (OPC) have high survival rates when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab, an antibody against the epidermal growth factor receptor, can preserve high survival rates and reduce treatment toxicity is unknown. Methods In a randomized, non-inferiority, multicenter trial, patients with locoregionally-advanced p16-positive OPC were stratified by American Joint Committee on Cancer T (T1-T2 vs. T3-T4) and N (N0-N2a vs. N2b-N3), Zubrod Performance Status (0 vs. 1), and tobacco smoking history (≤ vs. >10 pack-years) and randomized 1:1 to radiotherapy plus cetuximab 400 milligrams per square meter of body surface area (mg/m2), followed by 250 mgs/m2 for seven weekly doses or cisplatin 100 mgs/m2 for two doses, 21 days apart. The sample size was 800 eligible patients. The primary endpoint was overall survival (OS) with non-inferiority margin 1.45 (hazard ratio). Findings From June 2011 through July 2014, 849 patients (805 eligible; 399 cetuximab; 406 cisplatin) were randomized at 182 centers in the United States and Canada. With median follow-up 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criterion for OS. Estimated 5-year OS was 77·9% (95% confidence interval [CI] 73·4-82·5) in cetuximab group versus 84·6% (95%CI=80·6-88·6) in cisplatin group (hazard ratio [HR], 1·45, 1-sided 95% upper CI, 1·94; non-inferiority p=0·5056; 1-sided log-rank p=0.0163). PFS was significantly lower in cetuximab group than in cisplatin group (HR 1·72, 95%CI=1·29-2·29; 5-year rates, 67·3% vs. 78·4%), and LRF was significantly higher (HR 2·05, 95%CI=1·35-3·10; 5-year rates, 17·3% vs. 9·9%). The rate of moderate-to-severe toxicity that was acute (77·4% vs. 81·7%, p=0·1586) and late (16·5 vs. 20·4%, p=0·1904) was similar in the cetuximab and cisplatin groups, respectively. Interpretation For patients with HPV-positive OPC, radiotherapy plus cetuximab demonstrated inferior OS and PFS compared to radiotherapy plus cisplatin; toxicity rates were similar (NCT01302834). Funding National Cancer Institute USA, Eli Lilly and The Oral Cancer Foundation

Validation of NRG oncology/RTOG‐0129 risk groups for HPV‐positive and HPV‐negative oropharyngeal squamous cell cancer: Implications for risk‐based therapeutic intensity trials

“…Of the 20 patients in RTOG‐0522 with LRF, approximately 65% received cetuximab. In RTOG‐1016, the risk of LRF was found to be 2‐fold higher in the patients treated with cetuximab versus those receiving cisplatin, but the risk of distant metastases was similar . It is possible that cetuximab may be responsible for the increase in LRF noted in the current study.…”

“…Although only 8% of the low‐risk group in RTOG‐0129 experienced LRF, 14% in RTOG‐0522 experienced LRF; nevertheless, the rate of distant metastases remained similar (8% vs 6%). It is possible that the addition of cetuximab, which has been established as being inferior to cisplatin in 2 randomized prospective studies, to a treatment arm in RTOG‐0522 accounted for the observed differences in LRF (see Supporting Table 3). Of the 20 patients in RTOG‐0522 with LRF, approximately 65% received cetuximab.…”

Practice patterns and outcomes following radiation dose de‐escalation for oropharyngeal cancer

“…Although the NCDB codes for biologic agents, the specific use of cetuximab cannot be confirmed; there are few other recognized biologic options for nonmetastatic OPSCC. Nevertheless, it is now being appreciated that a replacement strategy may not be optimal based on results of the Radiation Therapy Oncology Group 1016 study as well as a published randomized trial from Europe …”

Immune checkpoint inhibitors for head and neck squamous cell carcinoma: Current landscape and future directions

“…Further, in a multinational, randomized trial, cetuximab‐RT showed a significant improvement in survival compared with RT alone . However, two large prospective trials in patients with HPV+ HNSCC patients have shown cetuximab‐RT to be inferior to cisplatin‐RT . Many prospective HNSCC trials have evaluated different combination strategies with RT, but no doublet‐RT regimen has demonstrated superiority over cisplatin‐RT .…”