A quarter of patients with relapsed glioblastoma multiforme (GBM)-treated with the vaccine rindopepimut (Rintega) plus bevacizumab remained alive at 2 years.
David A. Reardon, MD
A quarter of patients with relapsed glioblastoma multiforme (GBM) treated with the vaccine rindopepimut (Rintega) plus bevacizumab remained alive at 2 years, compared with none in the control arm, according to an updated analysis of the phase II ReACT trial presented at the 2015 Society for Neuro-Oncology Annual Meeting.
The median overall survival (OS) with rindopepimut was 11.3 months compared with 9.3 months in the control arm, representing a 47% reduction in the risk of death (HR, 0.53; CI, 0.32-0.88;P= .0137). Moreover, the vaccine therapy was found to be well tolerated, with very mild adverse events (AEs).
“The long-term survival benefit observed in this study is unprecedented as it is exceedingly rare for patients with highly aggressive, EGFRvIII-positive glioblastomaeven in the newly diagnosed setting—to live beyond two years," said lead investigator David A. Reardon, MD, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute. "Most striking perhaps is that not only are patients living considerably longer, they are also living better, with minimal side effects and a reduced need for steroids.”
Rindopepimut is an immunotherapeutic targeted againstEGFRmutation variant III (EGFRvIII), which is a tumor-specific oncogene expressed in approximately 30% of GBMs that is associated with a poor prognosis. Rindopepimut consist of an EGFRvIII peptide conjugated to keyhole limpet hemocyanin (KLH) and works by generating a specific immune response against EGFRvIII-expressing GBM.
The vaccine represents a ready-to-use formulation and is injected intradermally along with GM-CSF. Bevacizumab is thought to optimize EGFRvIII-specific immune response via inhibition of VEGF, which is thought to mediate immunosuppression, warranting the combination of the two therapies.
In the phase II study, 73 bevacizumab-naïve patients in their first or second relapse with EGFRvIII-expressing GBM were randomized in a 1:1 ratio to either the bevacizumab plus rindopepimut (n = 36) arm or the control (KLH; n = 37) arm. The primary endpoint of the study was progression-free survival (PFS), with objective response rate (ORR), OS, safety, and other measures as secondary endpoints.
In an earlier assessment of the data, the 12-month OS rate was 44% with rindopepimut versus 32% in the control arm. At 18 months, the OS rate was 32% and 13%, for rindopepimut and the control, respectively.
The 6-month PFS rate with rindopepimut was 28% versus 16% with the control (one sidedP= .1163), which met the primary endpoint for the study. The boundary for one side significant was 0.2.
"These resultswere we see modest improvements in PFS but a more substantial improvement in overall survival—are not infrequent with immunotherapy," said Reardon. "In data that led to the approval for ipilimumab in melanoma, PFS was more modest but there was a more substantial improvement in overall survival."
The ORR with rindopepimut was 30% compared with 18% in the control arm, by expert review. At baseline, approximately 50% of patients in both arms were on corticosteroids (≤4 mg). At 2-months, 50% of patients in the rindopepimut arm were able to stop taking corticosteroids versus 26% in the control. By ≥6 months, 33% of patients had reduced steroid use versus none with the control.
"Corticosteroid use and requirement is a very relevant endpoint for our patients," said Reardon. "A higher number in the rindopepimut arm were able to come off and stay off steroids at 2 months and 6 months. Quite significant improvement relative to the control arm."
Overall, there were no serious adverse events (AEs) or treatment discontinuations associated with rindopepimut. The most frequent AEs were grade 1/2 injection site reactions, primarily erythema and pruritus. There was one grade 2 hypersensitivity reaction. There was no evidence of increase cerebral edema with rindopepimut.
“The results of the ReACT study change the way we think about glioblastomaoffering patients and their families new hope in the face of one of the most difficult to treat cancers and upending the notion that the brain, masked behind the blood brain barrier, is beyond the reach of the promise of immunotherapy,” said Reardon. "The ReACT data also build considerable anticipation for the ACT IV study in newly-diagnosed glioblastoma as these patients typically present with much stronger immune systems and stand to derive an even greater benefit.”
In February 2015, rindopepimut was granted a breakthrough therapy designation by the FDA for adult patients with GBM who tested positive for EGFRvIII. This indication was based on data from the phase II ReACT study along with data from the phase II ACT III study for patients with newly diagnosed GBM.
The phase III ACT IV study is currently exploring rindopepimut in newly diagnosed patients EGFRvIII-positive GBM. Following the first interim analysis of this study in June 2015, a data safety and monitoring board recommended the continuation of the study. The second-interim is schedule to occur in early 2016.