Brivanib Plus Cetuximab Delivers Mixed Results in Colorectal Study

Lillian L. Siu, MD

Adding brivanib alaninate to cetuximab had no survival advantage over cetuximab alone in patients with KRAS wild-type (WT) chemorefractory metastatic colorectal cancer, according to results of a randomized, phase III trial reported at the ASCO 2012 Gastrointestinal Cancers Symposium. However, both progression-free survival (PFS) and overall response rate (ORR) were improved with the addition of brivanib.

Biomarker analysis of this trial is ongoing to determine if specific biomarkers can be identified that are associated with preferential benefit from brivanib, explained lead author Lillian L. Siu, MD, a senior staff physician in the Division of Medical Oncology and Hematology at Princess Margaret Hospital, Toronto, Canada.

Brivanib, an investigational drug under development by Bristol-Myers Squibb, is a tyrosine kinase inhibitor that targets vascular endothelial growth factor 2 (VEGF) and fibroblast growth factor receptors. Cetuximab (Erbitux, Bristol-Myers) is an epidermal growth factor receptor inhibitor (EGFR) that has improved survival in patients with metastatic, chemorefractory KRAS WT colorectal cancer.

The NCIC Clinical Trials Group and AGITG CO.20 trial, sponsored through the Canadian Cancer Society and the Australasian Gastro-Intestinal Trials Group, enrolled 750 patients with chemorefractory, KRAS WT, and metastatic colorectal cancer. Participants were randomized 1:1 to receive either brivanib 800 mg/day orally plus a loading dose of intravenous cetuximab 400 mg/m2 on day 1, then 250 mg/m2 per week versus placebo and the same dose of cetuximab.

Both arms were well balanced for prognostic factors, including gender, age, and performance status. More than 90% of patients in both arms received more than three prior lines of therapy (as either neoadjuvant, adjuvant, or metastatic therapy); 40% had one prior anti- VEGF therapy. No prior anti-EGFR therapy was allowed.

The study failed to meet its primary endpoint of overall survival (OS). Median OS was 8.8 months in the brivanib arm versus 8.1 months in the control arm. Looking at both planned and unplanned subgroup analyses, no difference in OS was seen between the two arms for any subgroup.

Median PFS was 5 months in the brivanib arm versus 3.4 months in the control arm (P <.0001), but no difference between the two arms in relative PFS benefit was observed in any subgroup.

According to RECIST criteria, partial response was 13.6% in the experimental arm versus 7.2% in the control arm (P = .004). There were no complete responses in either arm.

Illustration courtesy of the American Society of Clinical Oncology

Fewer patients in the experimental arm received at least 90% of the planned dose intensity of either drug versus the control arm for cetuximab. Study drugs were discontinued more frequently in the experimental arm.

Grade 3 or higher nonhematologic adverse events (fatigue, hypertension, gastrointestinal toxicity, and constitutional symptoms) were more frequent in the brivanib arm (78% vs 53%, respectively).

Siu said that the on-treatment adverse events were consistent with those reported for each drug as monotherapy.

Ninety-seven percent of patients were assessable for quality of life as reflected by time to deterioration on physical function and global subscales; the control arm had better quality of life on these parameters.

Siu LL, Shapiro JD, Jonker DJ, et al. Phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with metastatic (MET) chemotherapy refractory K-RAS wild-type (WT) colorectal carcinoma (CRC): The NCIC Clinical Trials Group and AGITG CO.20 trial. J Clin Oncol. 2012;30 (suppl 4; abstr 386).