Outcomes of the ACT III Study: Rindopepimut (CDX-110) Therapy for Glioblastoma.

G lioblastoma multiforme (GBM) is the most common primary brain tumor in adults. Standard therapy, including maximal surgical resection, concomitant chemoradiation therapy, and adjuvant temozolomide, results in a median progression-free survival (PFS) of approximately 8 months and a median overall survival (OS) of 16 to 19 months from diagnosis. Targeted immunotherapy trials are one potential method of improving outcomes for this disease. The most common genetic alteration in GBM is overexpression of epidermal growth factor receptor (EGFR), and the most common EGFR mutation subtype is EGFRvIII. This subtype, which is present in approximately 25% of cases, is associated with poor prognosis in GBM. The mutation results in expression of a unique glioblastoma cell surface receptor that is not expressed in normal brain tissue, making it an excellent immunotherapeutic target. Rindopepimut (CDX-110) is an injectable peptide vaccine that specifically targets this cell surface receptor. A recent multicenter phase II study of this agent has been reported with promising results for GBM (ACT III). The authors enrolled 65 adult patients pooled from 33 study centers with newly diagnosed EGFRvIII1 GBM who had undergone gross total resection and standard radiotherapy and were starting standard temozolomide chemotherapy. EGFRvIII1 status was confirmed with tumor immunohistochemistry and polymerase chain reaction assays. Rindopepimut was administered with intradermal injections, first in an initial priming phase and then at monthly intervals, staggered with temozolomide treatments. Patient clinical status, anti-EGFRvIII antibody titers, PFS, and OS were closely monitored. Radiation Therapy Oncology Group (RTOG) 0525 trial data were queried, and 74 trial participants with EGFRvIII1 GBM and other similar characteristics were selected to act as a historically matched cohort for comparison. For patients treated with rindopepimut, the median PFS was 9.2 months (95% confidence interval, 7.4-11.3) and median OS was 21.8 months (95% confidence interval, 17.9-26.5) from study entry (ie, approximately 3 months after diagnosis; Figure). In comparison, the “matched” RTOG cohort patients showed a median OS of 16.0 months after randomization. The authors found that anti-EGFRvIII antibody titers increased . 4-fold over baseline levels in 85% patients treated with rindopepimut, demonstrating robust, specific, and durable immune responses, despite concurrent temozolomide therapy. In general, rindopepimut was well tolerated: There were no fatal adverse events, no cumulative toxicity over time (median duration of rindopepimut treatment was 7.4 months), and primarily mild to moderate injection site reactions, including erythema and pruritus. Finally, a subanalysis of tumor samples taken from 10 rindopepimut patients with tumor recurrence showed that many of these tumors no longer expressed EGFRvIII. The 3 existing phase II trials of rindopepimut (including this study) demonstrate a pooled median PFS of 12.3 to 15.3 months from diagnosis and a median OS of 24 months from diagnosis. We eagerly await the results of the double-blind, phase III trial (ACT IV), which will randomize patients with resected EGFRvIII1 GBM to receive either rindopepimut or a control injection.