NEW YORK & INDIANAPOLIS--(BUSINESS WIRE)--(Eli Lilly and Company (NYSE: LLY) and Bristol-Myers Squibb Company (NYSE: BMY) today announced that the U.S. Food and Drug Administration (FDA) has approved ERBITUX® (cetuximab), in combination with platinum-based chemotherapy with 5-fluorouracil (CT), for the first-line treatment of recurrent locoregional or metastatic squamous cell carcinoma of the head and neck (SCCHN). The approval, which is based on data from the landmark EXTREME (ErbituX in first-line Treatment of REcurrent or MEtastatic head & neck cancer) trial, makes ERBITUX plus CT the first treatment regimen approved in 30 years with extended overall survival in patients with recurrent locoregional or metastatic SCCHN.
EXTREME, which was previously published in the New England Journal of Medicine, was a Phase 3 open label, randomized, multicenter, controlled trial. This study was conducted outside the U.S. by Merck KGaA, Darmstadt, Germany, and used European Union (EU)-approved cetuximab. ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab used in the EXTREME trial; these pharmacokinetic data, together with the results of the EXTREME trial and other clinical trial data establish the efficacy of ERBITUX at the recommended dose. EXTREME showed that cetuximab plus CT in the first-line treatment of recurrent locoregional or metastatic SCCHN resulted in superior efficacy across clinically meaningful endpoints, including overall survival, progression-free survival, and objective response rate compared to CT. Cetuximab plus CT significantly extended patients’ median overall survival by 36% compared to patients who received CT alone (10.1 months vs. 7.4 months, respectively) [HR: 0.80; 95% CI: 0.64-0.98; p=0.034]. Cetuximab plus CT also significantly increased median progression-free survival by 67% (5.5 vs. 3.3 months, respectively) [HR: 0.57; 95% CI: 0.46-0.72; p<0.0001] compared to CT alone. A significant improvement in objective response rate was also demonstrated (36% vs. 20%, odds ratio, 2.33 [95% CI: 1.50-3.60]; p=0.0001).
The full Prescribing Information for ERBITUX includes a boxed warning regarding infusion reactions and cardiopulmonary arrest. Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Healthcare providers should immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions. Cardiopulmonary arrest and/or sudden death occurred in 2% of patients with squamous cell carcinoma of the head and neck treated in a clinical trial with ERBITUX and radiation therapy and in 3% of patients with squamous cell carcinoma of the head and neck treated with EU-approved cetuximab in combination with platinum-based therapy with 5-fluorouracil (5-FU) in the EXTREME trial. Healthcare providers should closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX administration.
Selected adverse events of any grade occurring in at least 10% of patients receiving EU-approved cetuximab in combination with platinum-based therapy with 5-FU or platinum-based therapy with 5-FU alone were: acneiform rash (70% vs 2%, respectively), nausea (54% vs 47%), infection (44% vs 27%), rash (28% vs 2%), diarrhea (26% vs 16%), anorexia (25% vs 14%), pyrexia (22% vs 13%), acne (22% vs 0), dermatitis acneiform (15% vs 0), dry skin (14% vs <1%), alopecia (12% vs 7%), hypokalemia (12% vs 7%), hypocalcemia (12% vs 5%), hypomagnesemia (11% vs 5%), infusion reaction (10% vs <1%), and conjunctivitis (10% vs 0). Since U.S.-licensed ERBITUX provides approximately 22% higher exposure relative to the EU-approved cetuximab, the data provided above may underestimate the incidence and severity of adverse reactions anticipated with ERBITUX for this indication. However, the tolerability of the recommended dose is supported by safety data from additional studies of ERBITUX.
Please see Important Safety Information including Boxed WARNINGS on pages 6-9.
“With the improvements seen across objective response rates, progression free survival, and overall survival, this trial establishes ERBITUX plus CT as a important advancement in the treatment of first-line recurrent or metastatic SCCHN,” said Jan Vermorken, MD, PhD., Professor Emeritus at the University of Antwerp and primary investigator on the EXTREME trial. “Today’s approval is important for patients with SCCHN because ERBITUX is the only biologic agent with a proven overall survival benefit in combination with CT in recurrent or metastatic disease.”
The EXTREME regimen is the only Category 11 recommendation for combination therapy in the professional treatment guidelines for Head and Neck Cancer from the National Comprehensive Cancer Network® (NCCN®) for the indication of recurrent, unresectable, or metastatic disease (non-nasopharyngeal) that is incurable. **
This is the fifth indication approved for ERBITUX and the third indication demonstrating overall survival. ERBITUX was previously approved for the initial treatment of locally or regionally advanced SCCHN in combination with radiation therapy. This approval was based on data from a randomized clinical trial (N=424) where ERBITUX administered at the recommended dose in combination with radiation therapy increased median locoregional control (24.4 vs 14.9 months with radiation alone; P=0.005; HR: 0.68 [95% CI: 0.52-0.89]) and median overall survival (49.0 vs 29.3 months with radiation alone; P=0.03; HR: 0.74 [95% CI: 0.57-0.97]). ERBITUX, as a single agent, is indicated for the treatment of patients with recurrent or metastatic SCCHN for whom prior platinum-based therapy has failed. At that time, the FDA noted that ERBITUX was the first drug approved for head and neck cancer since the 1950’s. ERBITUX remains the first and only monoclonal antibody to be approved by the FDA for this type of cancer.
ERBITUX is FDA approved in colorectal cancer (CRC) as a single agent for the treatment of EGFR-expressing metastatic CRC after failure of both irinotecan- and oxaliplatin-based regimens. This approval was based upon data from a randomized clinical trial (N=572) where ERBITUX administered at the recommended dose in combination with best supportive care (BSC) resulted in median overall survival of 6.14 months vs. 4.57 months with BSC alone (hazard ratio, 0.77; 95% confidence interval, 0.64-0.92; p=0.0046). ERBITUX as a single agent is also indicated for the treatment of EGFR-expressing metastatic CRC in patients who are intolerant to irinotecan-based regimens. ERBITUX, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic CRC in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of ERBITUX in combination with irinotecan is based on objective response rates. The U.S. Prescribing Information further states that no data are available that demonstrate an improvement in disease-related symptoms or increased survival with ERBITUX in combination with irinotecan for the treatment of EGFR-expressing metastatic colorectal carcinoma. Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations.
Since its first approval in 2004, ERBITUX has more than seven years of experience in medical practice. Additionally, approximately 127,000 patients received ERBITUX therapy over that time period in the U.S. alone.
The approval is based on a Phase 3, open-label, multicenter, randomized study of 442 patients with recurrent or metastatic SCCHN who did not receive prior CT. This study was conducted outside the U.S. by Merck KGaA, Darmstadt, Germany, and used EU-approved cetuximab. Erbitux provides approximately 22% higher exposure relative to the EU-approved cetuximab used in the EXTREME study; these pharmacokinetic data, together with the results of the EXTREME study and other clinical trial data establish the efficacy of Erbitux at the recommended dosePatients in this trial, patients were randomized to receive either cetuximab along with a CT (cisplatin or carboplatin and 5-fluorouracil; n=222), or chemotherapy alone (n=220). CT was administered every three weeks for up to 6 cycles, while cetuximab was continued until disease progression or unacceptable toxicity.
The primary endpoint of the pivotal Phase 3 study was overall survival. Secondary efficacy endpoints included progression-free survival and objective response rate.
About Head and Neck Cancer
In 2011, it is estimated that more than 50,000 Americans will develop cancer of the head and neck, including cancers of the tongue, the rest of the mouth, the salivary glands and inside the throat, the voice box and the lymph nodes in the upper neck. Head and neck cancer most often affects people over the age of 50, and men are more than twice as likely to be diagnosed as women. The most common risk factors are tobacco, excessive alcohol use, and HPV infection of the oral cavity.
ERBITUX (cetuximab) is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular structure expressed on the surface of normal and tumor cells called the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1). In vitro assays and in vivo animal studies have shown that binding of ERBITUX to the EGFR blocks phosphorylation and activation of receptor-associated kinases, resulting in induction of apoptosis (cell death), inhibition of cell growth, and decreased matrix metalloproteinase and vascular endothelial growth factor production. In vitro, ERBITUX can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumor types. In vitro assays and in vivo animal studies have shown that ERBITUX inhibits the growth and survival of tumor cells that express the EGFR. No anti-tumor effects of ERBITUX were observed in human tumor xenografts lacking EGFR expression.
Head and Neck Cancer
IMPORTANT SAFETY INFORMATION INCLUDING BOXED WARNINGS
ERBITUX Plus Radiation Therapy and Cisplatin
Late Radiation Toxicities
Pregnancy and Nursing
Please see Important Safety Information and U.S. Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest.
About ERBITUX Patient Programs
Bristol-Myers Squibb and Lilly are committed to supporting patient access to ERBITUX and have put in place a number of programs to help patients and providers. Destination Access™, which is a Reimbursement Support Program, helps patient access by providing benefits investigation support, prior authorization assistance, appeals assistance and patient assistance. More information about our patient assistance program can be obtained by calling 1-800-861-0048.
In addition to Destination Access, The ERBITUX PATIENT SUPPORT PROGRAM has been developed to provide patients and healthcare providers with information and helpful resources on dermatological toxicities associated with ERBITUX and guidance on how to manage them. For additional information, visit www.erbitux.com.
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