On November 7, 2011, the U.S. Food and Drug Administration approved cetuximab (Erbitux, ImClone LLC, a wholly-owned subsidiary of Eli-Lilly and Company) in combination with platinum-based therapy plus 5-florouracil (5-FU) for the first-line treatment of patients with recurrent locoregional disease and/or metastatic squamous cell carcinoma of the head and neck (SCCHN).
The approval was based primarily on the results of a multi-center clinical study conducted outside the U.S. in 442 patients with metastatic or locally recurrent head and neck cancer who were not suitable for potentially curative treatment with surgery or radiation. The study used a European Union (EU) approved cetuximab rather than the US-approved cetuximab (Erbitux). Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab; these pharmacokinetic data, together with the results of the study conducted in Europe and other clinical trial data using Erbitux establish the safety and efficacy of Erbitux at the recommended dose.
The trial enrolled 442 patients; 222 patients received cetuximab plus cisplatin (or carboplatin) with 5FU and 220 patients received cisplatin (or carboplatin) with 5-FU. The selection of cisplatin or carboplatin was at the discretion of the treating health care provider.
Either cisplatin (100 mg/m2 intravenously day 1) or carboplatin (AUC 5 intravenously day 1) with 5-FU (1000 mg/m2/day continuous intravenous infusion days 1–4) were administered every 3 weeks (1 cycle). A maximum of 6 cycles was administered in the absence of disease progression or unacceptable toxicity. Cetuximab, 400 mg/m2 intravenously, was administered as an initial dose followed by cetuximab, 250 mg/m2 intravenously weekly, in combination with chemotherapy. After completion of 6 planned courses, patients demonstrating at least stable disease on cetuximab in combination with chemotherapy continued cetuximab monotherapy (250 mg/m2 weekly) in the absence of disease progression or unacceptable toxicity.
Of the 442 randomized patients, the median age was 57 years, 90% were male, 98% were Caucasian, and 88% had baseline Karnofsky Performance Status ≥80. Thirty-four percent had oropharyngeal, 25% laryngeal, 20% oral cavity, and 14% hypopharyngeal primary tumors. Fifty-three percent had recurrent disease without metatases; the remaining 47% had metastatic disease including recurrence.
Sixty-four percent received cisplatin while 34% received carboplatin as initial therapy. Approximately 15% of patients changed from cisplatin to carboplatin during the treatment period.
The major efficacy outcome measure of the trial was overall survival (OS). Other outcome measures included progression-free survival (PFS) and objective response rate (ORR).
The median follow-up at the time of the OS analysis was 19.1 and 18.2 months for the cetuximab plus chemotherapy arm and the chemotherapy alone arm, respectively. Overall survival was significantly improved in patients receiving cetuximab plus chemotherapy compared to those receiving chemotherapy alone (HR=0.80; 95% CI: 0.64, 0.98; p = 0.034, stratified log-rank test). The median survival for patients receiving cetuximab plus chemotherapy was 10.1 months compared to 7.4 months for those receiving chemotherapy alone.
Progression-free survival was also significantly improved in patients receiving cetuximab plus chemotherapy (HR=0.57; 95% CI: 0.46, 0.72; p<0.0001, stratified log-rank test). The median PFS times were 5.5 and 3.3 months in the cetuximab plus chemotherapy and the chemotherapy alone arms, respectively. The objective response rates were 35.6% and 19.5% [Odds Ratio (OR) 2.33; 95% CI: 1.50, 3.60; p-value 0.0001, Cochran-Mantel-Haenszel test] in the cetuximab plus chemotherapy and the chemotherapy alone arms, respectively.
Exploratory subgroup analyses were conducted in subgroups by initial platinum therapy (cisplatin or carboplatin). For patients (N=284) receiving the EU-approved cetuximab plus cisplatin with 5-FU compared to cisplatin with 5‑FU alone, the difference in median overall survival times was 3.3 months, with median OS times of 10.6 and 7.3 months respectively [HR 0.71 (95% CI: 0.54, 0.93)]. The difference in median progression-free survival was 2.1 months, with median PFS times of 5.6 and 3.5 months respectively [HR 0.55 (95% CI: 0.41, 0.73)]. The objective response rates were 39% and 23% respectively [OR 2.18 (95% CI: 1.29, 3.69)]. For patients (N=149) receiving cetuximab plus carboplatin with 5-FU compared to carboplatin with 5-FU alone, the difference in median overall survival was 1.4 months, with median survival of 9.7 and 8.3 months, respectively [HR 0.99 (95% CI: 0.69, 1.43)]. The difference in median progression-free survival was 1.7 months with median PFS times of 4.8 and 3.1 months, respectively [HR 0.61 (95% CI: 0.42, 0.89)]. The objective response rates were 30% and 15%, respectively [OR 2.45 (95% CI: 1.10, 5.46)].
The most common adverse reactions (≥25%) in patients treated with cetuximab plus chemotherapy were nausea, anemia, vomiting, neutropenia, rash, asthenia, diarrhea, and anorexia. Conjunctivitis occurred in 10% of the patients receiving cetuximab plus chemotherapy. Other adverse reactions, sometimes severe, caused by cetuximab included infusion reactions, hypomagnesemia, hypocalcemia and hypokalemia. Death attributed to cardiovascular event or sudden death was reported in 3.2% of the patients in the cetuximab plus chemotherapy arm and in 1.9% in the chemotherapy alone arm.
Health care providers should closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after cetuximab administration.
The approved dose of Erbitux is 400 mg/m2 intravenously as an initial dose, followed by 250 mg/m2 intravenously weekly in combination with cisplatin or carboplatin plus continuous infusion 5-FU.
Full prescribing information, including clinical trial information, safety, dosing, drug-drug interactions and contraindications is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125084s153lbl.pdf1
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm2, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
About the Center for Drug Evaluation and Research > Cetuximab (Erbitux)
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