Combo Shows No Additional Benefit in Glioblastoma

An increased clinical benefit was not seen when onartuzumab was added to Avastin (bevacizumab) for patients with recurrent glioblastoma multiforme (GBM), according to study results that were published in the Journal of Clinical Oncology.

However, patients with high hepatocyte growth factor (HGF) expression or unmethylated MGMT may derive clinical benefit from this combination regimen, Timothy Cloughesy, M.D., and colleagues noted in the study. Further research is warranted to validate these prognostic markers.

The phase 2 GO27819 trial assessed the safety and efficacy of onartuzumab added to Avastin, which received FDA approval in May 2009 as a single agent in the second-line treatment of patients with glioblastoma.

Exploratory biomarker analyses were also conducted in the study to identify an association between GBM subtype, HGF expression, or MGMT methylation and improved outcomes from the combination.

The phase 2 study randomized 129 patients 1 to 1 to either 15 mg/kg of onartuzumab once every three weeks plus 15 mg/kg of Avastin once every three weeks (64 patient) or Avastin with placebo (65 patients). Patients had recurrent disease after prior chemoradiation and had never received Avastin before.

An additional arm was originally included in the trial studying onartuzumab plus placebo, however, the cohort was placed on hold during a safety assessment.

Baseline patient characteristics were well balanced between the 2 arms of the study. The median age was 57 in the onartuzumab/ Avastin arm and was 55 in the Avastin/placebo arm. More than half of the patients (56.6 percent) had a Karnofsky performance score (PS) of 70 percent or 80 percent, and the rest had a PS of 90 percent or 100 percent.

After a median follow-up of 9.8 months for the onartuzumab arm and 9.9 months for the Avastin plus placebo arm, 92 percent and 85 percent of patients had discontinued treatment, respectively. The median progression-free survival (PFS) in the intention-to-treat population was 3.9 months with onartuzumab/ Avastin and 2.9 months with Avastin/placebo. The six-month PFS rate was 33.9 percent in the onartuzumab and Avastin arm versus 29 percent for the Avastin and placebo arm.

Median overall survival (OS) was 8.8 months versus 12.6 months for onartuzumab/ Avastin and Avastin/placebo, respectively. The objective response rate (ORR) was 22.2 percent in the onartuzumab arm, which included one complete response (CR), and the ORR in the Avastin and placebo arm was 23.7 percent, including three CRs.

General disorders of any grade occurred in 70.8 percent of patients in the onartuzumab/ Avastin arm and 57.8 percent in the Avastin /placebo arm, including peripheral edema (44.6 percent vs 14.1 percent, respectively), asthenia (24.6 percent vs 21.9 percent) and fatigue (15.4 percent vs 20.3 percent). Nervous system disorders were also common, experienced by 49.2 percent of patients in the onartuzumab group and by 75 percent in the Avastin group.

Grade 3 or higher adverse events (AEs) were noted in 25 patients (38.5 percent) in the onartuzumab/ Avastin arm and by 23 patients (35.9 percent) in the Avastin /placebo arm. A greater proportion of peripheral edema and hypoalbuminemia were both noted in the group receiving onartuzumab.

Two deaths occurred in the onartuzumab/ Avastin arm, both due to intestinal perforation, and one death occurred in the Avastin/placebo arm due to intracranial hemorrhage.

More patients had mesenchymal GBM (56 patients) than the proneural (28 patients) or proliferative (20 patients) subtype. No difference in PFS was noted with the mesenchymal subtype over the other subtypes, as had been seen in the AVAglio trial. Retrospective analyses of the AVAglio trial, which explored Avastin plus radiotherapy and temozolomide in GBM, had demonstrated a greater benefit for patients with mesenchymal or proneural GBM when receiving the Avastin combination, although only the proneural subtype showed a benefit in OS.

The AVAglio study also showed an association between the mesenchymal phenotype and expression of MET ligand HGF, which suggested “that this may be a common occurrence in glioblastoma biology,” the study authors noted.

In the GO27819 trial, high expression of HGF (upper 25 percent by polymerase chain reaction) seemed to be predictive of efficacy with the onartuzumab/ Avastin combination in patients with the mesenchymal subtype. Patients with higher HGF levels in the onartuzumab/Avastin arm had longer median PFS than patients in the Avastin/placebo arm of 6.1 months versus 2.8 months, respectively. The opposite was seen in patients with lower HGF expression.

MGMT methylation, a well-known prognostic marker in glioblastoma, was also explored among 47 patients with methylated MGMT and 57 with unmethylated MGMT. Patients with unmethylated MGMT had better outcomes in the onartuzumab/Avastin arm, and multivariate analyses confirmed the potentially predictive effect of treatment with the combination for patients with unmethylated MGMT.

MET status was intended to be a part of the analyses, yet only five patients were MET-positive according to a greater than 50 percent staining cutoff by immunohistochemistry, which did not allow for a large enough population to study.

“Although the biomarker data are compelling and should inform future trials targeting the MET pathway, their exploratory nature and relatively small sample size make it difficult to infer firm conclusions on the clinical utility of HGF expression or MGMT methylation as predictive markers in glioblastoma,” the authors said in the study. “Future prospective studies are necessary to validate these results.”