ImClone Systems Incorporated and Bristol-Myers Squibb Company jointly announced that the US Food and Drug Administration (FDA) has approved an update to the Erbitux (cetuximab) product labelling to include overall survival data as a single agent in epidermal growth factor inhibitor (EGFR)-expressing metastatic colorectal cancer (mCRC) patients after failure of both irinotecan- and oxaliplatin-based regimens.
According to a company press release, the approval of the supplemental biologics license application (sBLA) is based on prolonged overall survival from a large, randomized, multicenter, phase III trial comparing Erbitux plus best supportive care (BSC) to BSC alone in 572 EGFR-expressing mCRC patients after failure of irinotecan- and oxaliplatin-based regimens. BSC was considered to be all approved palliative therapies designed to alleviate pain and treat other effects caused by mCRC in this patient population.
"We are very pleased that the FDA has recognized these data as the second disease setting where Erbitux has improved overall survival, which is the ultimate goal of all cancer therapies. This approval for Erbitux as a monotherapy offers an additional treatment option for an expanded patient population, specifically, patients who have failed both irinotecan- and oxaliplatin-based chemotherapy regimens," said Eric K. Rowinsky, M.D., chief medical officer and senior vice president, ImClone Systems.
"Erbitux is now the only approved biologic therapy to demonstrate improved overall survival as a single agent in patients with metastatic colorectal cancer. We continue to be encouraged by the benefits of Erbitux in metastatic colorectal cancer, and are actively exploring its potential in other tumour types," said, Martin Birkhofer, M.D., vice president, Oncology Global Medical Affairs, Bristol-Myers Squibb.
In the US, approximately 154,000 people will be diagnosed with cancer of the colon or rectum this year. More than half of these patients have metastatic disease, or cancer that has spread to other organs, at the time of diagnosis. EGFR is expressed in 60-80 per cent of colorectal cancer tumours. Colorectal cancer is the third most common cancer in both men and women, excluding skin cancer.
Erbitux is a monoclonal antibody (IgG1 Mab) designed to inhibit the function of a molecular structure expressed on the surface of normal and tumour 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 inhibition of cell growth, induction of apoptosis, and decreased matrix metalloproteinase and vascular endothelial growth factor production, the company said.
In vitro, Erbitux can mediate antibody-dependent cellular cytotoxicity (ADCC) against certain human tumour types. While the mechanism of Erbitux's anti-tumour effect(s) in vivo is unknown, all of these processes may contribute to the overall therapeutic effect of Erbitux. EGFR is part of a signalling pathway that is linked to the growth and development of many human cancers, including those of the head and neck, colon and rectum.
Erbitux, as a single agent, is indicated for the treatment of EGFR-expressing, metastatic colorectal carcinoma (mCRC) after failure of both irinotecan-and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing mCRC in patients who are intolerant to irinotecan-based regimens.
Grade 3/4 infusion reactions occurred in approximately 3 per cent of patients receiving Erbitux (Cetuximab) in clinical trials with fatal outcome reported in less than 1 in 1000. Reactions characterized by rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), urticaria, hypotension, loss of consciousness, and/or cardiac arrest. Severe infusion reactions require immediate and permanent discontinuation of Erbitux therapy, according to the company.
Most reactions (90 per cent) were associated with the first infusion of Erbitux despite premedication with antihistamines. Caution must be exercised with every Erbitux infusion, as there were patients who experienced their first severe infusion reaction during later infusions. Monitor patients for 1-hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (e.g., epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions.
In clinical studies of Erbitux, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76-88 per cent of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1-17 per cent of patients. Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Sun exposure may exacerbate these effects
In women of childbearing potential, appropriate contraceptive measures must be used during treatment with Erbitux and for 6 months following the last dose of Erbitux. If Erbitux is used during pregnancy or if patients become pregnant while receiving Erbitux, patients should be apprised of the potential risk for loss of pregnancy or potential hazard to the foetus
Hypomagnesaemia occurred in 55 per cent (199/365) of patients receiving Erbitux and was severe (NCI CTC grades 3 & 4) in 6-17 per cent. The onset of hypomagnesaemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Monitor patients periodically for hypomagnesaemia, hypocalcaemia and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary, the company said.
The most serious adverse reactions associated with Erbitux in mCRC patients are infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus. The most common adverse reactions with Erbitux were fatigue, rash/desquamation, abdominal pain, pain, dry skin, dyspnea, constipation, pruritus, diarrhoea, vomiting, infection without neutropenia, headache, fever, insomnia, cough, dermatology-other, and stomatitis.