Phase IIa Study of SurVaxM Plus Adjuvant Temozolomide for Newly Diagnosed Glioblastoma

Abstract

Purpose: Despite intensive treatment with surgery, radiation therapy, temozolomide (TMZ) chemotherapy, and tumor-treating fields, mortality of newly diagnosed glioblastoma (nGBM) remains very high. SurVaxM is a peptide vaccine conjugate that has been shown to activate the immune system against its target molecule survivin, which is highly expressed by glioblastoma cells. We conducted a phase IIa, open-label, multicenter trial evaluating the safety, immunologic effects, and survival of patients with nGBM receiving SurVaxM plus adjuvant TMZ following surgery and chemoradiation (ClinicalTrials.gov identifier: NCT02455557).

Methods: Sixty-four patients with resected nGBM were enrolled including 38 men and 26 women, in the age range of 20-82 years. Following craniotomy and fractionated radiation therapy with concurrent TMZ, patients received four doses of SurVaxM (500 μg once every 2 weeks) in Montanide ISA-51 plus sargramostim (granulocyte macrophage colony-stimulating factor) subcutaneously. Patients subsequently received adjuvant TMZ and maintenance SurVaxM concurrently until progression. Progression-free survival (PFS) and overall survival (OS) were reported. Immunologic responses to SurVaxM were assessed.

Results: SurVaxM plus TMZ was well tolerated with no serious adverse events attributable to SurVaxM. Of the 63 patients who were evaluable for outcome, 60 (95.2%) remained progression-free 6 months after diagnosis (prespecified primary end point). Median PFS was 11.4 months and median OS was 25.9 months measured from first dose of SurVaxM. SurVaxM produced survivin-specific CD8+ T cells and antibody/immunoglobulin G titers. Apparent clinical benefit of SurVaxM was observed in both methylated and unmethylated patients.

Conclusion: SurVaxM appeared to be safe and well tolerated. The combination represents a promising therapy for nGBM. For patients with nGBM treated in this manner, PFS may be an acceptable surrogate for OS. A large randomized clinical trial of SurVaxM for nGBM is in progress.

FIG 1.

Survival outcomes of treated patients measured from start of SurVaxM treatment. (A) mPFS and mOS in months for patients from the start of treatment (first immunization). PFS or OS as a percentage of all evaluable patients at 6, 12, 24, and 36 months from the start of treatment. (B) Data points represent Cox HRs of OS for each subgroup. Error bars represent 95% CI of HRs. P < .01 for methylated MGMT patients (HR, 0.36; 95% CI, 0.18 to 0.71) and patients younger than 65 years (HR, 0.41; 95% CI, 0.21 to 0.81) Stratification by IDH1, KPS, and survivin expression did not produce significantly different HRs (post hoc analyses). HR, hazard ratio; Exp., expression; IDH, isocitrate dehydrogenase; KPS, Karnofsky performance status; meMGMT, methylated MGMT; MGMT, O-6-methylguanine-DNA methyltransferase; mOS, median overall survival; mPFS, median progression-free survival; NR, no response; OS, overall survival; PFS, progression-free survival; SVN, survivin; unMGMT, unmethylated MGMT; wt, wild-type.

FIG 2.

PFS and OS of patients treated with SurVaxM. (A) Kaplan-Meier curves of PFS and OS for all evaluable patients. (B) Correlation between OS and PFS for all patients (r = 0.79; 95% CI, 0.66 to 0.87). Kaplan-Meier curves of (C) PFS and (D) OS for patients on the basis of MGMT status. Kaplan-Meier curves of (E) PFS and (F) OS for patients by IDH1 status. (G) PFS and (H) OS by age. P values use log-rank (Mantel-Cox). IDH, isocitrate dehydrogenase; meMGMT, methylated MGMT; MGMT, O-6-methylguanine-DNA methyltransferase; OS, overall survival; PFS, progression-free survival; unMGMT, unmethylated MGMT; wt, wild-type.

FIG 3.

CD8+ T-cell responses to SurVaxM. PBMCs were harvested from blood obtained at approximately 17 weeks (V5 time point). Stimulation of patient PBMCs by peptides in vitro was followed by assessment of activation markers and cytokines. (A) CD69-, (B) HLA-DR-, (C) TNFα-, and (D) IFNγ-positive cells (gated on CD3+CD8+) following stimulation with the specified peptides. *P < .05; **P < .005; ***P < .0005. (E-G) Plots showing expression of activation markers and cytokines expressed by CD3+CD8+ PBMCs (> 1% increase) following stimulation with SVN-1/-2, versus OS. Data points represent Cox HRs of OS for each subgroup. Error bars represent 95% CI of HRs. Stratification did not produce significantly different HR for T-cell response correlations with OS (post hoc analyses). CEF, CMV-EBV-influenza peptides; HR, hazard ratio; IFN, interferon; MGMT, O-6-methylguanine-DNA methyltransferase; OS, overall survival; PBMCs, peripheral blood mononuclear cells; SVN, survivin; TNF, tumor necrosis factor.

FIG 4.

Humoral responses in patients treated with SurVaxM. (A) Anti–SurVaxM-specific antibody (IgG) titers in patients over time. (B) Correlation between OS and anti-SurVaxM IgG titers. Data points represent Cox HRs of OS for each subgroup. Error bars represent 95% CI of HRs. P = .0146 for patients with IgG responses > 30,000 in titer (HR, 0.41; 95% CI, 0.20 to 0.84). Additional stratification by IDH1 and MGMT showed trends to better HR with high (> 30,000) IgG (in red; post hoc analyses). (C) Kaplan-Meier analysis of IgG stratification. Titer > 30,000, mOS = 43.1 months; 95% CI, 12.5 to 18.7 (red). Titer < 30,000, mOS = 15.8 months; 95% CI, 33.5 to 52.3 (blue). Hi, high; HR, hazard ratio; IDH, isocitrate dehydrogenase; IgG, immunoglobulin G; Lo, low; meMGMT, methylated MGMT; MGMT, O-6-methylguanine-DNA methyltransferase; mOS, median overall survival; mut, mutation; OS, overall survival; Pre-Imm., pre-immune; unMGMT, unmethylated MGMT; wt, wild-type.

FIG A1.

Clinical trial summary. (A) Treatment schedule overview for patients on trial. (B) Recruitment and inclusion of patients on study. Sixty-four patients were recruited and included in the study. One patient who received only a single priming dose of SurVaxM was excluded from efficacy analysis but was included in the final safety analysis. IDH, isocitrate dehydrogenase; MGMT, O-6-methylguanine-DNA methyltransferase; MRI, magnetic resonance imaging; TMZ, temozolomide.

FIG A2.

Molecular profiling analysis of patient tumors. Thirty-three patient tumors were assessed by RNAseq and assigned to subtypes on the basis of gene expression as described in the study by Wang et al. GBM, glioblastoma; GSVA, gene set variation analysis; IDH, isocitrate dehydrogenase.