Cetuximab/Radiation Improves DFS in Locally Advanced SCCHN

"It is appropriate to offer this regimen to patients with HPV-negative cancer. However, clinicians should weigh this DFS advantage against other factors including acute toxicity and cost," according to the study authors.

Although combining cetuximab (Erbitux) with radiotherapy did not improve overall survival (OS) among patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN), the regimen conferred significantly improved disease-free survival (DFS) without an increase in long-term toxicity, according to findings from the phase 3 NRG/RTOG 0920 trial (NCT00956007).¹

After a median follow-up of 7.2 years (IQR, 5.1-9.2), data showed no significant OS improvement with cetuximab/radiotherapy compared with radiotherapy alone among all randomly assigned and eligible patients (HR, 0.81; 95% CI, 0.60-1.08; P = .0747). In the cetuximab/radiotherapy and radiotherapy alone arms, respectively, the OS rates were 83.4% (95% CI, 79.0%-87.9%) vs 76.4% (95% CI, 71.4%-81.4%) at 3 years and 76.5% (95% CI, 71.4%-81.6%) vs 68.7% (95% CI, 63.1%-74.3%) at 5 years. Analysis showed no significant relationship between human papillomavirus (HPV) status and treatment (P = .8571).

DFS outcomes significantly appeared with the addition of cetuximab to radiotherapy among all randomly assigned and eligible patients (HR, 0.75; 95% CI, 0.57-0.98; P = .0168). The 3-year DFS rates were 78.3% (95% CI, 73.4%-83.2%) in the cetuximab arm vs 71.5% (95% CI, 66.1%-76.8%) in the radiotherapy alone arm, and the 5-year DFS rates were 71.7% (95% CI, 66.3%-77.1%) and 63.6% (95% CI, 57.8%-69.3%) in each respective arm.

A more pronounced DFS benefit with cetuximab/radiotherapy occurred in patients with HPV-negative disease (HR, 0.75; 95% CI, 0.57-0.98; P = .0184) than those with HPV-positive disease (HR, 0.91; 95% CI, 0.23-3.64). However, investigators noted that the interaction between treatment arms and HPV status was not statistically significant (P = .7809).

The 3-year rate of loco-regional failure (LRF) was 14.7% (95% CI, 10.8%-19.2%) with cetuximab plus radiotherapy and 20.2% (95% CI, 15.7%-25.1%) with radiotherapy alone (stratified HR, 0.78; 95% CI, 0.63-0.97; P = .0746). Data showed a stratified HR of 0.67 (95% CI, 0.49-0.92) for competing events.

“[W]e conclude that for intermediate-risk, resectable SCCHN, [radiotherapy plus cetuximab] did not improve OS, but did improve DFS over [radiotherapy] alone, without increasing late toxicity. This is the first significant DFS advance in this setting in over 40 years,” Mitchell Machtay, MD, an associate dean for Clinical Cancer Research, a professor and endowed chair in Cancer Clinical Research in the Department of Radiation Oncology, and a professor in the Department of Medicine at Penn State College of Medicine, wrote with coauthors.¹ “It is appropriate to offer this regimen to patients with HPV-negative cancer. However, clinicians should weigh this DFS advantage against other factors including acute toxicity and cost.”

In this open-label, multicenter trial, a total of 577 patients were randomly assigned to receive cetuximab plus post-operative radiotherapy (n = 290) or radiation alone (n = 287). Protocol treatment consisted of radiotherapy at 2 Gy once daily for 30 doses over 6 weeks with an optional sequential boost of 6 Gy in 3 fractions directed towards regions of close resection margins. Those assigned to the cetuximab arm received the agent at a loading dose of 400 mg/m² at 7 to 10 days prior to beginning radiotherapy followed by 250 mg/m² once weekly throughout radiotherapy and 4 weeks following the end of radiation.

The trial’s primary end point was OS. Investigators also assessed DFS as a key secondary end point and LRF as a tertiary end point.

Patients 18 years and older with pathologically confirmed SCCHN and clinical stage T1, N1-2 or T2-4a, N0-2, M0 disease were eligible for enrollment on the trial.² Other requirements for study entry included having completion of gross total resection of the primary tumor within 7 weeks of registration and a Zubrod performance status of 0 or 1 within 2 weeks of registration.

The median age was 57 years (IQR, 50-64), and most patients had oral cavity cancer (63.6%) and pathologic stage IVA disease (61.2%). Additionally, most patients were male (70.0%), White (86.3%), and non-Hispanic (90.8%). Most of the study population had HPV-negative disease (80.2%), 2 intermediate-risk factors per site reports (36.9%), and no perineural invasion per site reports (60.7%).

Receipt of radiation at 60 to 66 Gy was reported in 90.0% of the cetuximab arm compared with 93.4% of the radiotherapy alone arm. Quality assurance review highlighted that 85.9% and 89.2% of patients in each respective arm received radiotherapy per protocol or at acceptable variations.

Grade 3/4 toxicities affected 70.3% of patients in the cetuximab/radiotherapy arm vs 39.7% of those in the radiotherapy alone arm (P <.0001), with the most common adverse effect (AE) consisting of oral mucositis (38.0% vs 21.6%). Data showed no statistically significant differences in grade 3/4 late toxicities between the respective arms (33.2% vs 29.0%; P = .3101).

References

1. Machtay M, Torres-Saavedra PA, Thorstad W, et al. Postoperative radiotherapy ± cetuximab for intermediate-risk head and neck cancer. J Clin Oncol. Published online January 22, 2025. doi:10.1200/JCO-24-01829
2. RT with or without cetuximab in treating patients who have undergone surgery for locally advanced head and neck cancer. ClinicalTrials.gov. Updated May 28, 2024. Accessed January 28, 2025. https://tinyurl.com/27aktt7s