Background
Phase III open-label RCT, N=424 locoregionally advanced unresectable squamous cell carcinoma of oropharynx, hypopharynx, or larynx. Randomized to RT alone vs cetuximab + RT. RT: once-daily (70 Gy/35 fx), twice-daily (72 Gy/60 fx), or concomitant boost (72 Gy/42 fx). HPV status not prospectively assessed. 73 North American institutions, 1999–2002.
Interventions and follow up
Arm A: Cetuximab (400 mg/m² loading, then 250 mg/m²/wk × 7 wk) + RT (once-daily, twice-daily, or concomitant boost)
Arm B: RT alone (same fractionation choices)
Primary endpoint: Duration of locoregional control
mFollow up: 54 mo
Arm B: RT alone (same fractionation choices)
Primary endpoint: Duration of locoregional control
mFollow up: 54 mo
Results
mLocoregional control duration: 24.4 vs 14.9 mo, HR 0.68 (95% CI 0.52–0.89), P=.005
mOS: 49.0 vs 29.3 mo, HR 0.74 (95% CI 0.57–0.97), P=.03
ORR: 74% vs 64%, P=.02
mOS: 49.0 vs 29.3 mo, HR 0.74 (95% CI 0.57–0.97), P=.03
ORR: 74% vs 64%, P=.02
Adverse events
Grade 3+ AEs: 56% (cetuximab+RT) vs 52% (RT)
Cetuximab-specific: grade 3 acneiform rash 17%, grade 3–4 infusion reactions 3%
Radiation dermatitis and mucositis: comparable between arms; no cardiac toxicity excess
Cetuximab-specific: grade 3 acneiform rash 17%, grade 3–4 infusion reactions 3%
Radiation dermatitis and mucositis: comparable between arms; no cardiac toxicity excess
Conclusions
Adding cetuximab to RT significantly prolonged locoregional control (HR 0.68) and OS (HR 0.74, mOS 49 vs 29 mo) without increasing radiation-related toxicity in unresectable LA-HNSCC. First EGFR-targeted agent to demonstrate survival benefit in HNSCC; led to FDA approval of cetuximab + RT.
Key Limitations
HPV status not assessed — critical confound given HPV+ oropharyngeal cancer has far better prognosis; retrospective analyses suggest the OS benefit was likely driven by HPV+ tumors. Comparison was to RT alone, not cisplatin-based CRT (the standard) — no evidence of superiority or equivalence to cisplatin+RT. Only 3 fractionation schemes (not contemporary IMRT). Subsequent trials (RTOG 1016, De-ESCALaTE, JAVELIN HN) showed cetuximab inferior to cisplatin in HPV+ oropharyngeal cancer.
Clinical Context
FDA approved cetuximab + RT for LA-HNSCC in March 2006 based on this trial. Despite approval, cisplatin-based CRT remains the standard of care for fit patients; cetuximab + RT is reserved for cisplatin-ineligible patients. The Bonner regimen has been de-emphasized following negative comparisons against cisplatin in HPV+ disease. ASCO/ESMO retain cetuximab + RT as an option only for cisplatin-ineligible LA-HNSCC.