Mutation-Targeted Vaccine Fails To Improve Glioblastoma Survival

Use of the epidermal growth factor receptor variant III mutation-directed vaccine rindopepimut is not supported in patients with newly diagnosed glioblastoma

medwireNews: The addition of rindopepimut, a vaccine targeting the epidermal growth factor receptor variant III mutation (EGFRvIII), to temozolomide does not confer a survival benefit in patients with newly diagnosed EGFRvIII-positive glioblastoma, phase III trial results show.

Lead author Michael Weller, from the University Hospital and University of Zurich in Switzerland, and colleagues explain that the potential immunogenicity of the EGFRvIII mutation, which is expressed in 20–30% of glioblastomas, led to the development of rindopepimut, a conjugate of an EGFRvIII-specific peptide and the immunogenic protein keyhole limpet haemocyanin.

Rindopepimut showed encouraging results in previous phase II trials, they comment in The Lancet Oncology, but these findings were not confirmed in the current double-blind, phase III study, which enrolled 745 patients who completed standard chemoradiation after undergoing maximal surgical resection.

Study participants were randomly assigned to receive rindopepimut 500 μg admixed with 150 μg of granulocyte-macrophage colony-stimulating factor (n=371) or a control injection of keyhole limpet haemocyanin 100 μg (n=374) alongside the standard maintenance regimen of temozolomide 150–200 mg/m2 given on the first five days of each 28-day cycle, for six or more cycles.

The primary endpoint of overall survival (OS) in the subset of participants considered to have achieved minimal residual disease (MRD; <2 cm2 of residual enhancing tumour on post-chemoradiation imaging) did not differ significantly between the 195 patients who received rindopepimut and the 210 who received the control, with median OS times of 20.1 and 20.0 months, respectively.

Median OS durations were also comparable for rindopepimut and the control in the overall study population and among patients who had significant residual disease (SRD; ≥2 cm2 of residual enhancing tumour on post-chemoradiation imaging).

However, the ACT IV researchers did note a significant difference in long-term survival favouring rindopepimut among patients with SRD, such that the 2-year OS rates were 30% and 19% for the rindopepimut and control groups, respectively.

“Although further study is needed, this exploratory finding might challenge the view that minimal tumour burden is required for immunotherapy to be most effective”, they remark.

Describing the results as “disappointing”, Michael Weller et al question “the utility of immunotherapy targeting a single tumour antigen with heterogeneous tumour expression”, adding that “multipeptide vaccines against several targets and nonpeptides with higher immunogenicity might turn out to be superior.”

And they conclude: “Combination approaches potentially including rindopepimut might be required to show efficacy of immunotherapy in glioblastoma.”

Reference

Weller M, Butowski N, Tran DD, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol; Advance online publication 22 August 2017. doi: http://dx.doi.org/10.1016/S1470-2045(17)30517-X 

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