The addition of a combination of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors to chemotherapy has not improved outcome in first-line treatment of advanced colorectal cancer. However, in early-phase evaluation, the addition of the investigational VEGF and fibroblast growth factor tyrosine kinase inhibitor brivanib to the EGFR inhibitor cetuximab (Erbitux) produced encouraging antitumor activity in wild-type KRAS metastatic colorectal cancer.

As reported in the Journal of Clinical Oncology by Lillian L. Siu, FRCPC, MD, Senior Staff Physician in the Division of Medical Oncology and Hematology at Princess Margaret Hospital, and Professor of Medicine at the University of Toronto, Canada, and colleagues, the phase III NCIC Clinical Trials Group and AGITG CO.20 trial has shown that the addition of brivanib to cetuximab resulted in no overall survival benefit and increased toxicity in patients with chemotherapy-refractory metastatic wild-type KRAS colorectal cancer, despite prolonged progression-free survival and improved response rate.¹ Both brivanib and cetuximab dose intensities were limited by toxicity in the combination group.

CO.20 Trial

In this trial, 750 patients were randomly assigned to receive cetuximab (400 mg/m² loading dose followed by weekly maintenance of 250 mg/m²) plus either oral brivanib at 800 mg/d (n = 376) or placebo (n = 374). The primary endpoint of the trial was overall survival.

The combination group and the cetuximab-alone group were well matched for baseline characteristics, including age (median, 64 and 63 years), sex (66% and 63% male), Eastern Cooperative Oncology Group (ECOG) performance status (0 or 1 in 89% and 90%), site of primary cancer, sites of metastatic disease (liver in 77% and 76%, lung in 65% and 60%), number of disease sites (three or more in 50% and 48%), prior radiotherapy (32% and 35%), prior adjuvant chemotherapy (38% and 39%), number of prior chemotherapy regimens (>3 in 92% and 91%), prior VEGF inhibitor therapy (40% and 42%), and proportion of patients with normal lactate dehydrogenase (LDH; 29% and 30%). Mutant KRAS was found in 2.4% of patients in the combination group and in 3.2% of the cetuximab-alone group.

Survival Data

Median follow-up was 18.7 months, and 17% of combination patients and 20% of cetuximab-alone patients received other anticancer treatment after disease progression. There was no significant difference between the combination and cetuximab-alone groups in overall survival (median, 8.8 vs 8.1 months, hazard ratio [HR] = 0.88, P = .12). One-year overall survival rates were 35.8% vs 30.9%.

Results were similar after adjustment for potential prognostic factors in a multivariate analysis and in a sensitivity analysis among the 725 patients with confirmed wild-type KRAS status. Planned subgroup analyses showed a borderline significant benefit of combination therapy in patients with ECOG performance status of 0 or 1 (P = .052), but no significant differences according to age or sex. Post hoc analyses according to prior VEGF inhibitor therapy and baseline LDH level showed a trend toward significant benefit of the combination in patients with normal LDH levels.

Progression-free survival was significantly prolonged in the combination group (median 5.0 vs 3.4 months, HR = 0.72, P < .001). A similar degree of benefit was observed among patients with ECOG performance status of 0 or 1 and across all subgroups according to age, sex, prior VEGF inhibitor therapy, and LDH levels. Objective response rates (all partial responses) were 13.6% in the combination group and 7.2% in the cetuximab-alone  group (P = .004), and median durations of response were 5.8 and 5.4 months.

Toxicity Findings

The spectrum of adverse events with combination therapy was consistent with the toxicity profiles of either agent given alone. Grade 3 or higher adverse events occurred in 78% of patients in the brivanib-plus-cetuximab group and in 53% of patents in the cetuximab-alone group (P < .001), with rates being significantly higher in the combination group for fatigue (25% vs 11%), hypertension (11% vs 1%), rash (10% vs 5%), abdominal pain (10% vs 5%), dyspnea (8% vs 5%), dehydration (7% vs 2%), and anorexia (5% vs 1%).

Hematologic adverse events were uncommon in both groups. Rates of grade 3 or higher AST increase (17% vs 6%), ALT increase (21% vs 4%), hyponatremia (13% vs 7%), and increased thyroid-stimulating hormone (24% vs 4%) were significantly higher with combination treatment.

Brivanib/placebo treatment was discontinued due to adverse events in 22% of combination group patients and in 3% of the cetuximab-alone group, with fatigue, increased aminotransferases, and dyspnea being the most common reasons. Cetuximab dose intensity of at least 90% was received by 57% of patients in the combination group compared with 83% of cetuximab-alone patients, and dose intensity of brivanib/placebo was at least 90% in only 48% of patients in the combination group and in 87% of the cetuximab-alone group. As noted by the investigators, reduced dose intensity of cetuximab in the combination arm may have been due to brivanib-related toxicity, which may have contributed to reduced efficacy of the combination.

The investigators concluded, “Despite positive effects on [progression-free survival] and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve [overall survival] in patients with metastatic, chemotherapy-refractory, wild-type KRAS [colorectal cancer].” They noted, “Despite not meeting its primary end point, CO.20, with its large sample size as well as annotated tissue repository, will provide an invaluable clinical and correlative scientific data resource to enhance the biologic understanding of metastatic [colorectal cancer].” ■

Disclosure: For full disclosures of the study authors, visit jco.ascopubs.org.

Reference

1. Siu LL, Shapiro JD, Jonker DJ, et al: Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: The NCIC Clinical Trials Group and AGITG CO.20 trial. J Clin Oncol 31:2477–2484, 2013.