A phase II evaluation of brivanib in the treatment of persistent or recurrent carcinoma of the cervix: An NRG Oncology/Gynecologic Oncology Group study

Abstract

Background Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients. Methods Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800 mg was administered orally every day (1 cycle = 28 days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6 months and objective tumor response. Results Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2 cycles of brivanib with 4 (14%) receiving >10 cycles (range: 1–20). Seven (25%) patients had PFS >6 months (90% CI: 7.3%–33.9%). Two (7%) (90% CI: 1.3%–20.8%) patients had partial tumor response with duration of 8 and 22 months and 12 (43%) had stable disease. The median PFS was 3.2 months (90% CI: 2.1–4.4). The median overall survival was 7.9 months (90% CI: 6.1–11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension. Conclusions Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.

<p>A retrospective six-patient series of apatinib for the treatment of persistent or recurrent carcinoma of the cervix</p>

“…However, further investigation is still needed 24. In contrast to the manageable side effects in the current report, the toxicity happens in some drugs, for example, the usage of sunitinib and brivanib is hampered by the severe toxicity 15. This may attribute to the unspecific inhibition against VEGFRs the central events in angiogenesis 3.…”

“…These data are summarized in Table 4 12–16Table 4Clinic reports of anti-VEFGR in cervical cancerStudyAgentMainly targetTrial designNCohortResponse rateAdverse EffectsReferencePresentApatinibVEGFR-2Retrospective6Advanced/recurrent67% (4/6)Manageable2010PazopanibVEGFR-1, 2, 3Phase II226Persistent IVb, recurrentPFS49.7 weeksManageable[12]2014SunitinibVEGFR-1, 2, 3Phase II19Local advance, resistant–Fistula 26%[13]2015CediranibVEGFR-1, 2, 3Phase II69Advanced/recurrentImproved PFS, but not OS–[14]2016BrivanibVEGFR, FGFRPhase II–Advanced/recurrentSuspendedSevere toxicity[15]2018ApatinibVEGFR-2Phase II–Advanced/recurrentOngoingUnknown[16] …”

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence

“… 93 Two phase II trials demonstrated that brivanib was well-tolerated and worthy of further investigation in persistent or recurrent EC/CC with an ORR of 7% and 8%, respectively. 94 , 95 …”

“…93 Two phase II trials demonstrated that brivanib was well-tolerated and worthy of further investigation in persistent or recurrent EC/CC with an ORR of 7% and 8%, respectively. 94,95 For the development of antiangiogenic agents and other targeted therapies, the addition of bevacizumab to conventional chemotherapy in OC is a very important step. However, most of the analysis reported so far showed that antiangiogenic agents led to no significant improvement in OS for patients with gynecological cancers.…”

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

“…Apart from the above mentioned prominent non-selective TKIs other compounds, like brivanib (BMS582664) a dual FGFR/VEGFR inhibitor, ENMD-2076, lenvatinib (E7080), orantinib (TSU-68), etc., though have shown anti-FGFR properties. However, their effects against VEGFR or other kinases are more relevant [227][228][229][230].…”