Antiangiogenic Gene Therapy Added to Bevacizumab Leads to Better Overall Survival in Recurrent GBM

Andrew J. Brenner, MD

Andrew J. Brenner, MD

A novel antiangiogenic gene therapy, added to bevacizumab, led to significantly better overall survival in recurrent glioblastoma multiforme (GBM) compared with historical patients treated with bevacizumab alone, a small phase II trial showed.¹

Patients who received continuous ofranergene obadenovec (VB-111), plus bevacizumab at progression, had a median overall survival (OS) of 59 weeks, which was significantly prolonged compared with a historical median of 32 weeks for bevacizumab monotherapy. Continuous treatment also proved superior to initial treatment with VB-111 followed by bevacizumab monotherapy at disease progression. The combination of VB-111 and bevacizumab was well tolerated and did not produce any unexpected toxicities, as reported at the 2016 ASCO Annual Meeting.

“These results are as good as any that have been reported with this type of agent,” said Andrew J. Brenner, MD, medical director of the Cancer Therapy & Research Center at the University of Texas Health Sciences Center in San Antonio. “The survival essentially doubled in comparison to the historical data with bevacizumab monotherapy.

“The safety and tolerability were manageable and consistent with our expectations. The results supported moving forward with a phase III study in patients with recurrent glioblastoma, which has already begun. We have enrolled more than 50 patients and expect to complete patient accrual by the end of the year.”²

VB-111 is a first-in-class targeted antiangiogenic gene therapy that has applicability to multiple solid tumors. The agent consists of a nonreplicating adenovirus, a modified murine pre-proendothelin promoter, and a fas-Chimera transgene. VB-111 homes in on the endothelium of tumor vasculature, and interaction with tumor blood vessels leads to activation of the gene and apoptosis.

Administered intravenously every 2 months, the agent has broad antiangiogenic activity that leads to tumor starvation and induction of an antitumor immune response. Studies have demonstrated effectiveness in combination therapy, and 3, tumor-specific, phase II trials yielded evidence of an efficacy signal. Safety and tolerability have been documented in more than 170 patients with cancer.

Brenner reported findings from an international multicenter phase II study involving 62 patients with recurrent GBM. Results were compared against historical patients treated with bevacizumab monotherapy.

Bevacizumab has FDA approval and is standard of care for recurrent GBM in the United States. Reports from prospective and retrospective studies have included survival data for bevacizumab monotherapy in recurrent GBM, which could serve as a benchmark for novel agents evaluated in single-arm clinical trials, Brenner and colleagues noted in a poster presentation.

Of the 62 patients enrolled, 46 were included in the efficacy analyses. The first 22 patients discontinued VB-111 at disease progression and initiated bevacizumab monotherapy (limited therapy). Following a protocol amendment, the remaining 24 patients started treatment with VB-111. At progression, bevacizumab was added to treatment, and both drugs were continued until further disease progression (continuous therapy).

For the efficacy analysis, investigators performed a literature search and identified 8 clinical trials involving a total of 694 patients with recurrent GBM treated with bevacizumab monotherapy. They pooled data from the 8 trials to create a historical comparator group. The primary outcome was overall survival (OS). Patients received as many as 13 doses of VB-111. The results showed that continuous treatment with VB-111 plus bevacizumab led to a 38% reduction in the survival hazard, as compared with the historical patients treated with bevacizumab monotherapy (P = .0295). Continuous treatment with VB-111 and bevacizumab added at progression also improved survival compared with VB-111 limited-exposure group (median OS: 59 weeks vs 33 weeks; P =.048).

Subgroup analysis showed that a fever spike following administration of VB-111 was associated with improved survival. Among 25 patients who had at least 1 post—VB-111 fever spike, the median OS was 64 weeks versus 34 weeks for patients without a fever spike (P = .03). “The fever typically appeared within 6 hours of infusion and then resolved within 24 hours,” said Brenner. “The febrile reaction was not consistent. Some patients developed fever after the initial infusion of VB-111 but not after the next infusion. Some did not have a fever spike with the first infusion but did with subsequent infusions. We will continue to study this to understand the association between the fever spike and outcome.”

The fever was the most frequently observed toxicity in patients treated with VB-111. Overall, 34 grade ≥3 adverse events occurred, 7 of which were considered to be possibly related to VB-111: 1 case each of asthenia, pyrexia, brain edema, depressed consciousness, pulmonary embolism (PE) in a patient with a history of PE, thrombocytopenia, and altered mental state.

References

1. Brenner AJ, Coheri YC, Vredenburgh JJ, et al. Ofranogene obadenovec (VB-111), an anti-cancer gene therapy in combination with bevacizumab to improve overall survival compared to bevacizumab monotherapy in patients with rGBM: A phase 2 historically controlled trial.J Clin Oncol. 2016;34 (suppl; abstr 2074).
2. Clinicaltrials.gov. A phase III, pivotal trial of VB-111 plus bevacizumab versus bevacizumab in patients with recurrent glioblastoma (GLOBE). NCT02511405