In the phase II NRG/RTOG 1122 trial, published in Cancer, the combination of bevacizumab (Avastin) and trebananib was found to be well tolerated; however, it did not significantly improve 6-month progression-free survival (PFS), PFS, or overall survival (OS) for patients with recurrent glioblastoma over bevacizumab alone.
Additionally, the shorter PFS observed in the experimental arm with a hazard ratio of 1.51 (P = 0.04) suggested that the addition of trebananib to bevacizumab is detrimental.
“Careful consideration should be given to future trials of [angiopoiein; Ang] inhibitors in combination with bevacizumab given the possible detrimental effects of Ang1 in this study,” the authors wrote. “Dual inhibitors of Ang2 and [vascular endothelial growth factor receptor; VEGFR] are in development and may have therapeutic potential for glioblastoma.”
In this study, patients ≥18 years of age with a Karnofsky performance status ≥70 and glioblastoma or variants in first or second relapse were randomized to 10 mg/kg of bevacizumab every 2 weeks plus 15 mg/kg of trebananib every week or bevacizumab plus placebo. The primary endpoint was 6-month progression-free survival (PFS).
After an initial 6-patient lead-in cohort confirmed the safety of the combination, a cohort of 115 eligible patients were randomized to the control (n = 58) or experimental treatment (n = 57). For patients in the control arm, 6-month PFS was 41.1%, median survival time was 11.5 months (95% CI, 8.4-14.2), median PFS was 4.8 months (95% CI, 3.8-7.1), and radiographic response (RR) was 5.9%. For those in the experimental arm, 6-month PFS was 22.6%, median survival time was 7.5 months (95% CI, 6.8-10.1), median PFS was 4.2 months (95% CI, 3.7-5.6), and RR was 4.2%. The rate of severe toxicities was not shown to be significantly different between the 2 arms.
In a crossover study, 25 patients crossed over from the control arm to receive the open label trebananib and bevacizumab after disease progression. Overall, 22 (88.0%) of these patients were evaluable for 6-month PFS, and only 1 (4.5%) patient was progression-free at 6 months after initial disease progression on bevacizumab. Moreover, 9 (36.0%) patients were evaluable for the best RR, and all had progressive disease based on the RANO criteria. The median survival time from the date of initial progression was 4.9 months (95% CI, 3.8-8.4 months), and the median PFS was 2.3 months (95% CI, 2.1- 3.2 months). No grade 5 adverse events were observed in the crossover cohort, and only 1 (4.0%) patient reported grade 4 sepsis.
“Compared with other randomized studies comparing bevacizumab alone in combination with another systemic agent (such as carboplatin [Paraplatin], dasatinib [Sprycel], or onartuzumab) in recurrent [glioblastoma], our study similarly fails to demonstrate a survival advantage to combination therapy,” the authors wrote.
Bevacizumab is often used to treat patients with recurrent glioblastoma and has already received FDA approval for this designation. Though phase III trials have suggested an improvement in progression-free survival, the addition of bevacizumab to standard therapy has not been associated with improvements in overall survival compared with standard therapy alone.
Lee EQ, Zhang P, Wen PY, et al. NRG/RTOG 1122: A Phase 2, Double-Blinded, Placebo-Controlled Study of Bevacizumab With and Without Trebananib in Patients With Recurrent Glioblastoma or Gliosarcoma. Cancer. doi:10.1002/cncr.32811.