The results of several clinical studies of Cetuximab ( Erbitux ) have been presented at the American Society of Clinical Oncology ( ASCO ) 41st Annual Meeting.
Irinotecan-refractory metastatic colorectal cancer
Findings were presented of a randomized Phase II trial conducted by the National Cancer Institute to evaluate the efficacy and safety of the use of Erbitux and Avastin ( Bevacizumab ) with or without Irinotecan ( Campto ) in 81 patients with Irinotecan-refractory metastatic colorectal cancer.
Of 41 patients who received Erbitux / Avastin / Irinotecan, 37 percent had a partial response, and the median time to progression was 7.9 months.
Of 40 patients who received Erbitux / Avastin alone, 20 percent of patients had a partial response, and the median time to progression was 5.6 months.
The most commonly reported adverse events in the Erbitux / Avastin / Irinotecan arm were skin rash ( grade 2, 60%; grade 3, 17% ), diarrhea ( grade 2, 29%; grade 3/4, 24% ), fatigue ( grade 2, 32%; grade 3, 10% ) and neutropenia ( grade 3/4, 22% ).
The most commonly reported adverse event in the Erbitux / Avastin arm was skin rash ( grade 2, 65%; grade 3, 20% ).
Non-resectable, EGFR+, metastatic colorectal cancer
An international Phase II study ( EMR-018 ) evaluated the safety and efficacy of Erbitux in combination with FOLFOX-4 ( Oxaliplatin / 5-FluoroUracil / Folinic acid ) as first-line treatment in patients with non-resectable, EGFR-expressing metastatic colorectal cancer.
In a preliminary efficacy analysis of 42 patients, 10 percent had a complete response, 71 percent had a partial response, and 17 percent had stable disease.
Median progression-free survival was 12.3 months.
Nine patients subsequently underwent surgery of their metastases.
The major grade 3/4 toxicities in 43 patients evaluable for safety were acne-like rash ( 30% ), neurotoxicity ( 30% ), diarrhea ( 26% ), neutropenia ( 21% ) and stomatitis/mucositis ( 16% ).
Hypopharyngeal and laryngeal carcinoma
A retrospective subgroup analysis evaluated 171 patients with hypopharyngeal and laryngeal carcinoma who were enrolled in an international Phase III randomized trial ( IMC-9815 ) of 424 patients with locoregionally advanced squamous-cell carcinoma of the head and neck.
The randomized study evaluated the addition of Erbitux to high-dose radiation versus radiation alone, to evaluate the primary endpoint of locoregional control and secondary endpoint of overall survival.
The subgroup analysis was undertaken to assess the rates of organ preservation in patients who had hypopharyngeal and laryngeal carcinoma.
Of the 93 patients receiving Erbitux plus radiation, larynx preservation rates were 90 percent at two years and 87 percent at three years.
Of the 78 patients receiving radiation therapy alone, larynx preservation rates were 80 percent at two years and 77 percent at three years ( hazard ratio 0.51 ).
Because the study was not powered to assess organ preservation, these results were not statistically significant.
EGFR+, advanced ovarian, primary peritoneal and fallopian tube cancer
A Phase II study ( CA225009 ) examining the addition of Erbitux to standard chemotherapy with Paclitaxel and Carboplatin as first-line treatment of EGFR-expressing advanced ovarian, primary peritoneal and fallopian tube cancer.
The primary endpoint is progression-free survival.
Preliminary data were reported for the first 27 patients to complete six cycles of initial treatment.
Of the 12 patients with stage III cancer whose tumor was completely removed by surgery, 91.7 percent achieved a clinical complete response.
Of the nine patients with stage III disease whose tumors could not be completely removed, 44.4 percent achieved a clinical complete response.
Of the six patients with stage IV disease, four were evaluable for efficacy. Of these four, 50.0 percent achieved a clinical complete response.
Commonly occurring grade 3 adverse events in all 27 patients receiving initial therapy were febrile neutropenia ( 18.5% ), hypokalaemia ( 14.8% ) and dyspnea ( 11.1% ).
Three hypersensitivity reactions were reported ( grade 3, 7.4%; grade 4, 3.7% ).
Eighteen patients experienced a rash ( grade 1, 48.1%; grade 2, 18.5% ).
On February 12, 2004, the FDA approved Erbitux ( Cetuximab ) for use in the United States in combination with Irinotecan in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are refractory to Irinotecan-based chemotherapy and for use as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to Irinotecan-based chemotherapy.
The effectiveness of Erbitux is based on objective response rates.
Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux.
Severe infusion reactions, rarely fatal and characterized by rapid onset of airway obstruction ( bronchospasm, stridor, hoarseness ), urticaria, and hypotension, have occurred in approximately 3% ( 20/774 ) of patients with the administration of Erbitux.
Most reactions ( 90%) are associated with the first infusion of Erbitux despite the use of prophylactic antihistamines.
Caution must be exercised with every Erbitux infusion as there were patients who experienced their first severe infusion reaction during later infusions.
Severe infusion reactions require immediate and permanent discontinuation of Erbitux therapy.
Severe cases of interstitial lung disease ( ILD ), which was fatal in one case, occurred in less than 0.5% of 774 patients receiving Erbitux.
Dermatologic toxicities, including acneform rash ( 11% of 774 patients, grade ¾ ), skin drying and fissuring, inflammatory or infectious sequelae ( e.g. blepharitis, cheilitis, cellulitis, cyst ) and paronychial inflammation ( 0.4% of 774 patients, grade 3 ) were reported. Sun exposure may exacerbate any skin reactions.
Hypomagnesemia has been reported with Erbitux when administered as a single agent and in combination with multiple different chemotherapeutic regimens.
The incidence of hypomagnesemia, both overall and severe, is increased in patients receiving chemotherapy and Erbitux as compared to those receiving chemotherapy alone based on controlled clinical trials. Patients receiving Erbitux therapy should be monitored for hypomagnesemia. Magnesium repletion may be necessary based on clinical judgment.
Other serious adverse events associated with Erbitux in clinical trials ( n=774 ) were fever ( 5% ), sepsis ( 3% ), kidney failure ( 2% ), pulmonary embolus ( 1% ), dehydration ( 5% in patients receiving Erbitux plus Irinotecan, 2% receiving Erbitux as a single agent ) and diarrhea ( 6% in patients receiving Erbitux plus Irinotecan, 0.2% with Erbitux as a single agent ).
Additional common adverse events seen in patients receiving Erbitux plus Irinotecan ( n=354 ) or Erbitux as a single agent ( n=420 ) were acneform rash ( 88%, 90% ), asthenia/malaise ( 73%, 48%), diarrhea (72%, 25%), nausea (55%, 29%), abdominal pain (45%, 26%), vomiting (41%, 25%), fever (34%, 27%), constipation (30%, 26%) and headache (14%, 26%).
Source: BMS, 2005