Background
Phase III RCT (EXTREME) of 442 patients with previously untreated recurrent or metastatic squamous-cell carcinoma of the head and neck. Exclusions: surgery or RTx <4wk prior, prior chemotherapy (unless part of multimodal treatment for locally advanced disease >6mo earlier), and nasopharyngeal carcinoma.
Interventions and follow up
Arm A: cisplatin 100 mg/m2 D1 (or carboplatin AUC 5 D1) plus 5-FU 1000 mg/m2/d x4 days q21d for up to 6 cycles
Arm B: cisplatin (or carboplatin) and 5-FU plus cetuximab 400 mg/m2 loading then 250 mg/m2 weekly; cetuximab continued as maintenance after chemotherapy
Primary endpoint: overall survival
Secondary endpoints: PFS, ORR, disease control, safety
Arm B: cisplatin (or carboplatin) and 5-FU plus cetuximab 400 mg/m2 loading then 250 mg/m2 weekly; cetuximab continued as maintenance after chemotherapy
Primary endpoint: overall survival
Secondary endpoints: PFS, ORR, disease control, safety
Results
mOS: 7.4mo vs 10.1mo (arm A vs B); HR 0.80, 95% CI 0.64-0.99; P=.04
mPFS: 3.3mo vs 5.6mo; HR 0.54, 95% CI 0.43-0.67; P<.001
ORR: 20% vs 36%; P<.001
mPFS: 3.3mo vs 5.6mo; HR 0.54, 95% CI 0.43-0.67; P<.001
ORR: 20% vs 36%; P<.001
Adverse events
Infectious/metabolic (arm A vs B): sepsis 1 vs 9 cases, P=.02; hypomagnesemia 3 vs 11 cases, P=.05
Cetuximab-related: grade 3 skin reactions ~9%; infusion reactions grade 3 (n=4) and grade 4 (n=2) in the cetuximab arm; otherwise the incidence of grade 3-4 events was similar between arms
Cetuximab-related: grade 3 skin reactions ~9%; infusion reactions grade 3 (n=4) and grade 4 (n=2) in the cetuximab arm; otherwise the incidence of grade 3-4 events was similar between arms
Conclusions
Adding cetuximab to platinum-fluorouracil chemotherapy improved overall survival, progression-free survival, and response rate in first-line recurrent or metastatic squamous-cell carcinoma of the head and neck, establishing the EXTREME regimen as a standard of care.
Key Limitations
Open-label; absolute OS gain modest (~2.7 months); regimen toxicity and triplet burden; predates PD-1 immunotherapy, which has since supplanted EXTREME as first-line standard for many patients (per KEYNOTE-048).
Clinical Context
EXTREME was the first regimen to demonstrate an OS benefit in first-line R/M HNSCC and gained FDA/EMA support for cetuximab in this setting. It served as the comparator arm in KEYNOTE-048; ESMO guidelines now favor pembrolizumab-based therapy first-line, reserving EXTREME for PD-L1-negative disease or where immunotherapy is contraindicated.