H. C. Engelbrecht
Data cutoff was March 12, Abstract On November 7, , the U.
This is a category about rijksmonument number View all coordinates using: OpenStreetMap - Google Earth. With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, was not significantly different between the two randomized treatment groups. For the refractory disease indication, three phase II studies were performed—one in the U. Two studies evaluated cetuximab combined with other agents and one evaluated cetuximab monotherapy.
The latter multicenter clinical trial included patients with recurrent or metastatic SCCHN who had documented disease progression within 30 days of a platinum-based chemotherapy regimen. Median duration of response was days [ 8 ]. The present cetuximab U. Cetuximab, in combination with platinum-based therapy and 5-fluorouracil 5-FU , is compared with platinum-based therapy and 5-FU alone.
The pivotal study was a phase III randomized trial conducted in 80 European centers [ 6 , 13 , 14 ]. The study period was between December 14, and December 28, Data cutoff was March 12, Secondary objectives were to compare progression-free survival PFS time, disease control, best overall response rate, duration of response, time to treatment failure, safety, and quality of life QoL.
Results were not reviewed by the FDA and are not included in this submission. Control patients received cisplatin, or carboplatin, plus 5-FU in the same doses and schedules without cetuximab.
The choice of chemotherapy cisplatin or carboplatin for individual patients was at the discretion of the investigator. Chemotherapy could be continued for a maximum of six cycles in the absence of progressive disease PD or unacceptable toxicity. Patients randomized to cetuximab treatment who had not progressed or developed unacceptable toxicity continued on weekly cetuximab until the occurrence of progressive disease PD or unacceptable toxicity.
Patients in the chemotherapy-only arm did not receive cetuximab after progression. In the event of chemotherapy intolerance, cetuximab-treated patients could continue receiving cetuximab alone. In the event of cisplatin intolerance, cisplatin could be replaced by carboplatin at the discretion of the investigator.
Effective contraception for both male and female subjects, if risk of conception existed, was also required. Patients were excluded from study entry if they had received prior chemotherapy, except if given as part of a multimodal treatment for locally advanced disease that was completed more than 6 months prior to study entry. Patients could not have received surgery excluding diagnostic biopsy or radiation therapy within 4 weeks of study entry.
Patients receiving other concomitant anticancer therapies were also excluded as were patients with documented brain or leptomeningeal metastasis and those with clinically relevant coronary artery disease, a history of myocardial infarction in the last 12 months, or a high risk of uncontrolled arrhythmia or cardiac insufficiency.
Other exclusion parameters included known drug abuse with the exception of alcohol abuse , previous monoclonal antibody therapy, treatment with other EGFR signal transduction inhibitors, a previous malignancy within the last 5 years, investigational medication within 30 days before study entry, known allergic reaction against any of the components of the study treatment, pregnancy or a medical or psychological condition that would not permit the subject to complete the study or sign informed consent.
Randomization, in a 1: Patients were seen weekly for cetuximab administration. Laboratory studies were repeated every 3 weeks. Radiologic studies of tumor response were performed every 6 weeks.
Tumor response was based on imaging and classified according to modified World Health Organization criteria as assessed by the investigator. The objective response rate was defined as the proportion of subjects having achieved confirmed CR plus PR according to radiologic assessments.
The primary statistical analysis for OS was based on the intent-to-treat population i. The hazard ratio of cetuximab plus chemotherapy over chemotherapy alone was calculated by Cox's proportional hazards model, which included stratification covariates, KPS, and prior chemotherapy, in addition to randomized treatment.
Exploratory efficacy analyses were performed to determine the effect of the initial platinum treatment regimen and to determine the predictive value of EGFR determination by immunohistochemisty or by gene copy number FISH. Primary data were not submitted for the FISH analysis.
An increase of the median OS time from 7 months to 9. A minimum of deaths events were required. Duration of 20 months was needed to observe deaths approximately 34 months after randomization of the first subject. During the follow-up phase, information on subsequent lines of treatment and survival data was collected every 3 months.
Safety information was coded using Medical Dictionary for Regulatory Activities version 8. Demographics, KPS, tumor status, prior therapy, and platinum regimen of the study population are shown in Table 1. Approximately two thirds of the patients in both arms received cisplatin therapy as the initial chemotherapy regimen. Fifteen of No patient who initially received carboplatin switched to cisplatin.
The remaining patients had either completed or discontinued study treatment. The major reason for discontinuation was disease progression Other reasons for study withdrawal included symptom deterioration, withdrawal of consent, noncompliance, and loss to follow-up.
Overall survival is presented in Figure 1. The median overall survival was Kaplan-Meier curve for overall survival in patients with recurrent locoregional disease or metastatic squamous cell carcinoma of the head and neck. The combination of cetuximab and platinum-based chemotherapy also resulted in a statistically significant improvement in PFS time compared with chemotherapy alone. The median PFS was 5.
The complete response rate was 6. The odds ratio for cetuximab plus chemotherapy compared with chemotherapy alone was 2. The median duration of response was 5. An exploratory analysis was performed to compare results in cisplatin- or carboplatin-treated patients. A statistically significant improvement in survival was observed when cetuximab was combined with cisplatin plus 5-FU compared with cisplatin plus 5-FU alone HR: Median OS times were For patients receiving carboplatin, a 1.
Exploratory analyses of PFS and RR by initial platinum therapy showed no apparent difference for these efficacy parameters in the subgroups of patients who initially received cisplatin or carboplatin therapy. No predictive association between EGFR expression by immunohistochemistry and overall survival was detected. FISH results, based on an evaluation of at least 50 cells, were available from These subjects were equally distributed between the two treatment groups in the cetuximab plus chemotherapy group, in the chemotherapy group.
The median number of cetuximab infusions was 17 range: The number of cetuximab infusions, cumulative dose, and relative dose intensity were similar in cisplatin- and carboplatin-treated patients. The median number of cisplatin infusions was approximately four range: The median number of carboplatin infusions was approximately six range: The median number of 5-FU infusions was approximately 5 range: The addition of cetuximab to 5-FU and platinum therapy lead to an overall increase in the incidence of treatment discontinuation Twenty percent of the patients discontinued cetuximab due to an AE.
The most common AEs leading to cetuximab discontinuation were skin and subcutaneous disorders including acne, rash, urticaria, and exfoliative rash 4. The most common AEs leading to cetuximab delay were skin rash 4.
Cetuximab dose reduction was required in 4. Chemotherapy was discontinued in The most common AEs leading to chemotherapy discontinuation were neutropenia 2. The most common AEs leading to chemotherapy delays were neutropenia Common AEs requiring chemotherapy dose reductions were neutropenia 5. The overall incidence of AEs in the current study is shown in Table 2.
Death was attributed, by the investigator, to cetuximab in one patient. Serious AEs were reported slightly more frequently in the cetuximab-containing arm compared with the chemotherapy-alone arm Anemia, neutropenia, and tumor hemorrhage were reported at a higher rate in the chemotherapy-alone arm. Grade 3—4 adverse events including skin, gastrointestinal, and electrolyte disturbances hypocalcemia, hypokalemia, hypomagnesemia occurred in higher frequency in the cetuximab-containing arm, consistent with the known safety profile of cetuximab.
Grade 3—4 anemia and dyspnea were observed at a higher incidence in chemotherapy-alone arm. The addition of cetuximab to platinum therapy, in particular cisplatin, led to a higher incidence of hypomagnesemia.
The incidence of hypomagnesemia was Pulmonary disorder manifesting as interstitial lung disease is a known adverse event associated with cetuximab.
In the current trial, one instance of grade 1 interstitial lung disease was reported in the cetuximab-containing arm.