First-Line Erbitux Ups H&N Survival

ASCO—Cetuximab (Erbitux) added to standard first-line chemotherapy with cisplatin or carboplatin plus fluorouracil (5-FU) yielded a statistically and clinically significant 35% survival advantage over these regimens without cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN), reported lead investigator Jan Baptist Vermorken, MD, PhD. He presented the results of the multicenter randomized phase III European EXTREME (Erbitux in First-line Treatment of Recurrent or Metastatic Head & Neck Cancer) study at the 2007 meeting of the American Society of Clinical Oncology.

"This is the first systemic treatment in 25 years to show a survival benefit over platinum-based chemotherapy in recurrent or metastatic squamous cell carcinoma of the head and neck," commented Dr. Vermorken, professor of oncology at the University of Antwerp, Belgium.

Novel therapies for head and neck cancer are clearly needed, he said, as median survival typically reported for relapsed SCCHN patients on standard chemotherapy is 6 to 7 months, and median progression-free survival time is about 2 months.

Unlike in the United States, where cetuximab is approved as single-agent therapy of recurrent or metastatic SCCHN, in Europe cetuximab is only approved for the treatment of locally or regionally advanced disease, in combination with radiotherapy.

Cetuximab, an IgG1 monoclonal antibody, specifically targets the epidermal growth factor receptor (EGFR), which is highly expressed in nearly all patients with squamous cell head and neck cancer. EGFR expression is strongly prognostic of local control, disease-free survival, and overall survival in this population.

Included in the trial were patients with stage III/IV recurrent and/or metastatic SCCHN who were not candidates for local therapy. They were required to have at least one bi-dimensionally measurable lesion (by CT or MRI) and a Karnofsky Performance Status (KPS) of at least 70. No prior EGFR testing was required.

A total of 442 patients (399 men) were randomized to receive either cetuximab (250 mg/m² weekly, following a 400 mg/m² initial dose) plus either cisplatin (at 100 mg/m² IV on day 1) or carboplatin (AUC 5, on day 1) plus 5-FU (at 1,000 mg/m²/d continuous infusion on days 1 to 4), every 3 weeks (n = 222), or the same chemotherapy regimen without cetuximab (n = 220), for a maximum of six chemotherapy cycles.

Treatment with cetuximab continued until progression or unacceptable toxicity. Crossover was not allowed. The primary endpoint was overall survival.

The majority of patients (about 60%) had well-differentiated or moderately differentiated tumors. Most (about 80%) had received prior radiotherapy, and about 40% had prior chemotherapy (allowed for locally advanced SCCHN if completed 6 months prior to study entry). Following randomization, about two-thirds of patients received cisplatin (based on individual institution choice).

Study Results

Survival analysis was conducted after 343 events were reached. Median survival was 10.1 months for patients in the cetuximab plus chemotherapy arm vs 7.4 months in the chemotherapy-alone arm (HR 0.797, P = .036). One-year survival was 39% in the experimental arm vs 31% in the control arm.

A subgroup analysis did not reveal any predictors of poor response to cetuximab, including prior radiotherapy or current treatment with cisplatin vs carboplatin, although the evidence for benefit in the patients receiving cisplatin was somewhat greater than for those receiving carboplatin.

Safety Analysis

An interim safety analysis on 429 patients (median number of cycles, four) showed a similar incidence of grade 3-4 adverse events (72% in the experimental arm vs 69% in the control arm), with a slightly higher incidence in the cetuximab arm of grade 3-4 vomiting/diarrhea and, as expected, acne-like rash and infusion reactions, Dr. Vermorken reported.

A total of 9% of cetuximab-treated patients vs 6% of controls discontinued therapy because of adverse events. Deaths were mostly a result of tumor progression, not toxic death, Dr. Vermorken said. Data on clinical response and time to tumor progression will be available at a later date.

"The survival benefit is among the longest ever seen in a large clinical trial among these patients," Dr. Vermorken concluded. "With new targeted agents such as cetuximab, we are on the brink of changing the way we treat patients with head and neck cancers."