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Phase II randomised discontinuation trial of brivanib in patients with advanced solid tumours
Robin L Jones1, Mark J Ratain2, Peter J O'Dwyer3
1Royal Marsden Hospital, Institute of Cancer Research, London, United Kingdom.
Background:
Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).
Patients And Methods:
During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours.
Results:
A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11).
Conclusion:
Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.
Insights
Brivanib showed activity in soft-tissue sarcomas and ovarian cancer, but FGF2 status did not predict its efficacy. Further research is needed to understand brivanib
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Brivanib is a targeted therapy inhibiting vascular endothelial growth factor and fibroblast growth factor (FGF) signaling pathways.
- A Phase II randomized discontinuation trial evaluated brivanib across seven cancer types, including soft-tissue sarcomas (STS) and ovarian cancer.
Purpose of the Study:
- To assess the efficacy of brivanib compared to placebo in patients with FGF2-positive tumors.
- To determine if FGF2 expression is a predictive biomarker for brivanib treatment response.
Main Methods:
- Patients received brivanib during an open-label lead-in, with FGF2 status assessed by immunohistochemistry.
- Patients with stable disease were randomized to brivanib or placebo, with progression-free survival (PFS) as the primary endpoint.
Main Results:
- Brivanib demonstrated activity in STS and ovarian cancer, with trends towards improved PFS compared to placebo (STS: HR 0.64, P=0.09; Ovarian: HR 0.54, P=0.11).
- The study was closed for breast, pancreatic, NSCLC, gastric, and TCC due to lack of efficacy.
- FGF2 expression was not found to be a predictive biomarker for brivanib efficacy.
Conclusions:
- Brivanib exhibited activity in soft-tissue sarcomas and ovarian cancer with an acceptable safety profile.
- FGF2 expression, as assessed, did not reliably predict patient response to brivanib.
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