A phase II trial of brivanib in recurrent or persistent endometrial cancer: An NRG Oncology/Gynecologic Oncology Group Study

Abstract

Purpose Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC). Patients and Methods Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed. Results Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1–24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6–31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9–43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and Angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS. Conclusion Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.

FGFR1 Induces Glioblastoma Radioresistance through the PLCγ/Hif1α Pathway

“…Preclinical or clinical trials evaluating the antitumor effect of FGFR inhibitors are under current, most of them concerning tyrosine kinase inhibitors targeting FGFR as single agents or in combination with other drugs (for review, ref. 44) or for some of them with radiotherapy (45). For our part, we recently reported preclinical evidence that targeting FGFR1 in association with radiotherapy could overcome the radioresistance of glioblastoma cells, sustaining the hypothesis that FGFR inhibitors might be not used as single agents but in combination with radiotherapy (13) in high-grade glioma treatment.…”

Tumor genotype and immune microenvironment in POLE-ultramutated and MSI-hypermutated Endometrial Cancers: New candidates for checkpoint blockade immunotherapy?

“…of 12-15% [6,7]. Use of multitargeted VEGF/FGFR inhibitors (brivatinib, lenvatinib) has produced encouraging findings (response rates 14-19%) [3,8]. In a phase II trial, AEZS-108, an LHRH agonist conjugated to doxorubicin, was active and well-tolerated in LHRH receptor positive recurrent EC [9].…”

Second-line dovitinib (TKI258) in patients with FGFR2-mutated or FGFR2-non-mutated advanced or metastatic endometrial cancer: a non-randomised, open-label, two-group, two-stage, phase 2 study

“…Investi gators have previously reported results of a phase 2 study of brivanib, an inhibitor of VEGF receptor and FGF receptor, in patients with recurrent or persistent endometrial cancer after one or two cytotoxic regimens. 26 19% of these patients receiving brivanib achieved an overall response, and they had a progression-free survival rate at 6 months of 30·2% (90% CI 18·9-43·9). 26 However, the eff ect of FGFR2 inhibition in that study is not clear because only three patients had FGFR2 mutations.…”

“…26 19% of these patients receiving brivanib achieved an overall response, and they had a progression-free survival rate at 6 months of 30·2% (90% CI 18·9-43·9). 26 However, the eff ect of FGFR2 inhibition in that study is not clear because only three patients had FGFR2 mutations. 13,27 In another phase 2 study of single-agent nintedanib (an inhibitor of VEGF, platelet-derived growth factor, and FGF receptors that has a similar half maximal inhibitory concentration against FGFR2 as has dovitinib) 28 9·4% of patients with recurrent or persistent, previously treated endometrial cancer achieved an overall response, and the progression-free survival rate at 6 months was 21·9%.…”