| General information |
| Database: | DB00991 |
| Objective: | The antiepidermal growth factor receptor monoclonal antibody cetuximab has improved survival in patients with metastatic, chemotherapyrefractory, wildtype KRAS colorectal cancer. The addition of brivanib, a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor and fibroblast growth factor receptor, to cetuximab has shown encouraging early clinical activity. |
| Authors: | Siu LL, et al |
| Title: | Phase III randomized, placebocontrolled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapyrefractory, wildtype KRAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. |
| Journal: | J Clin Oncol. |
| Year: | 2013 |
| PMID: | 23690424 |
| Trial Design |
| Clinical Trial Id: | NCT00640471 |
| Agent: | cetuximab
|
| Target: | Epidermal growth factor receptor
|
| Cancer Type: | colorectal cancer |
| Cancer Subtype: | KRAS wildtype metastatic colorectal cancer |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | cetuximab + brivanib alaninate |
| Study Type: | Phase III randomized, placebocontrolled study |
| Key Patients Feature: | patients with metastatic, chemotherapyrefractory, wildtype KRAS colorectal carcinoma |
| Biomarker: | wildtype KRAS |
| Biomark Analysis: | cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapyrefractory, wildtype KRAS colorectal cancer. |
| Control Group Info: | cetuximab plus brivanib alaninate versus cetuximab plus placebo |
| Treatment Info: | patients were randomly assigned 1:1 to receive cetuximab 400 mg/m(2) intravenous loading dose followed by weekly maintenance of 250 mg/m(2) plus either brivanib 800 mg orally daily (arm A) or placebo (arm B). |
| Primary End Point: | overall survival (OS). |
| Secondary End Point: | NA |
| Patients Number: | 750 |
| Trial Results |
| DLT_MTD: | NA |
| Objective Response Rate: | arm A vs arm B: 13.6% v 7.2% |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 5.0 months in arm A and 3.4 months in arm B (HR, 0.72; 95% CI, 0.62 to 0.84; P < .001). |
| Median OS A vs. C: | in the intenttotreat population was 8.8 months in arm A and 8.1 months in arm B (hazard ratio [HR], 0.88; 95% CI, 0.74 to 1.03; P = .12). |
| Adverse Event(agent arm): | Lotheyrgrade and allgrade ontreatment adverse events are provided in Appendix Table A1 (online only). These ontreatment adverse events were consistent with those reported for each drug given as monotherapy. The addition of brivanib to cetuximab in arm A led to a statistically significantly higher incidence of grade 3 or worse nonhematologic adverse events (78% in arm A v 53% in arm B), especially in fatigue, hypertension, rash, and gastrointestinal toxicity, including abdominal pain, diarrhea, dehydration, and anorexia (P < .05). Hematologic adverse events were uncommon in both arms. Grade 3 or higher biochemical changes, including hyponatremia, increases of liver aminotransferases and increased thyroid stimulating hormone, occurred more frequently in arm A (P < .05), but these changes rarely led to clinical sequelae. Only one patient in the entire study (arm A) died as a result of possible complications from protocol treatment and underlying CRC. |
| Conclusions: | Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapyrefractory, wildtype KRAS colorectal cancer. |