David Reardon, MD
Treatment with the immunotherapy rindopepimut (Rintega) plus bevacizumab resulted in a 47% reduction in the risk of death compared with bevacizumab and a control for patients with relapsed glioblastoma multiforme (GBM), according to an updated analysis of the phase II ReACT trial presented at the 2015 Society for Neuro-Oncology Annual Meeting.
In the updated findings for overall survival (OS), 25% of patients treated with rindopepimut remained alive at 2-years compared with none in the control arm. The median OS with rindopepimut was 11.3 versus 9.3 months in the control arm (HR, 0.53; CI, 0.32-0.88; P
“The mature data from the ReACT study indicates that rindopepimut continues to show a marked benefit with a reduction in hazard ratio and long-term survival associated with the rindopepimut vaccine,” said lead investigator David A. Reardon, MD, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute. “Importantly, the advantage for the rindopepimut arm was observed consistently across all measures of efficacy.”
Rindopepimut consists of an EGFRvIII peptide conjugated to keyhole limpet hemocyanin (KLH). The vaccine works by generating a specific immune response against tumors that express EGFRvIII, which is a tumor-specific oncogene expressed in approximately 30% of GBMs.
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 bevacizumab plus rindopepimut (n = 36) or control (KLH; n = 37). The primary endpoint of the study was progression-free survival (PFS), with objective response rate (ORR), OS, safety, and other measures as secondary endpoints.
Rindopepimut was administered at 500 micrograms along with 150 micrograms of GM-CSF. The KLH control was given at 100 micrograms. Bevacizumab was administered intravenously at 10 mg/kg every 2 weeks in both arms. Patients in each arm had received prior treatment with conventional radiation therapy and temozolomide.
The median age of patients in the investigational arm was 59 versus 55 years in the control. A majority of patients in the rindopepimut arm had experienced one relapse (92%). In the control arm, 76% of patients were in their first relapse and 24% had experienced two prior relapses. Approximately 50% of patients in both arms were on corticosteroids (≤4 mg).
"It does not appear that any of these factors, which were modestly favoring the rindopepimut arm, really correlated with outcomes, which has been demonstrated for EGFRvIII populations in other studies," explained Reardon.
In earlier assessments of the data from the ReACT trial, 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. Five patients in the rindopepimut arm continue to receive treatment.
"What we've seen over time is that the curves continue to separate, and more strongly favor rindopepimut," said Reardon. "At each subsequent interim analysis, a significantly higher percent of patients in the rindopepimut arm were alive."
The 6-month PFS rate with rindopepimut was 28% versus 16% with the control (one sided P
= .1163), which met the primary endpoint for the study. The boundary for one side significant was 0.2.
By longrank testing, the hazard ratio for PFS was 0.72 and the P
value was .2187. By investigator assessment, the PFS rate at 6 months was 28% in the rindopepimut arm compared with 14% in the control arm (HR, 0.62; CI, 0.38-1.03; longrank P
“These results—were 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.”
By expert review, the ORR with rindopepimut was 30% compared with 18% in the control arm. According to investigator assessment, ORR was 23% and 9%, for rindopepimut and the control, respectively.
The duration of response was 7.8 months with rindopepimut by expert review and 9 months by investigator assessment. In the control arm, the response duration was 5.6 and 7.4 months, by expert and investigator assessment, respectively.
“The radiographic response rate both by expert review and investigator consistently favored the rindopepimut arm,” said Reardon. “More importantly—because we know with bevacizumab we can see improvements in MRI scans—there's a consistent extension in the duration of response in the rindopepimut arm.”
In the rindopepimut arm at 2 months, 50% of patients were able to stop taking corticosteroids versus 26% in the control arm. By ≥6 months, 33% of patients had reduced or stopped 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.”
The most frequently reported all-grade adverse events (AEs) experienced by patients in the rindopepimut arm versus the control were arthralgia (23% vs 5%, respectively), nausea (23% vs 11%), back pain (17% vs 8%), vomiting (17% vs 5%), diarrhea (17% vs 5%), and falls (17% vs 5%). In some incidences, AEs were lower in the rindopepimut arm versus the control, specifically for hemiparesis (6% vs 16%, respectively), hyperglycemia (9% vs 11%), and headaches (23% vs 24%).
The most frequently reported grade ≥3 AEs in the rindopepimut arm were convulsion (11%) and back pain (6%). For the control arm, grade ≥3 AEs consisted of hyperglycemia (8%), hypertension (8%), hemiparesis (5%), headache (5%), and fatigue (5%).
“We confirmed that this vaccine is quite safe and extremely well tolerated, here in the recurrent disease setting,” explained Reardon. “There were no unexpected toxicities, outside of what we would expect with bevacizumab. No serious AEs or discontinuation of treatment-related to AEs. Basically patients experienced a mild erythema at the injection site as the only consistent adverse event."
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.
Reardon DA, Desjardins A, Schuster J, et al. ReACT: Long-term survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Presented at: 2015 Annual Meeting of the Society for Neuro-Oncology; November 19-22, 2015; San Antonio, TX. Abstract IMCT-08.
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