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Brain Cancer Vaccine Prolongs Survival in Mid-Stage Trial

FDA grants ‘breakthrough therapy’ designation

Positive results from a randomized, double-blind, phase II study of rindopepimut (Rintega, Celldex Therapeutics, Inc.) in patients with epidermal growth factor receptor variant III (EGFRvIII)-positive, recurrent glioblastoma (GB) have been reported at the 2015 American Society of Clinical Oncology annual meeting in Chicago.

The study’s primary endpoint –– progression-free survival at 6 months (PFS6) –– was met, and a clear advantage was demonstrated across several clinically important endpoints, including overall survival (OS), long-term PFS, the objective response rate (ORR), and the need for steroids.

Rindopepimut is an investigational EGFRvIII-specific therapeutic vaccine. Patients with GB that express the EGFRvIII mutation typically have a worse prognosis compared with the overall glioblastoma population, including poorer long-term survival.

The ReACT trial was a randomized, controlled, exploratory study designed to determine whether adding rindopepimut to standard-of-care bevacizumab (BV; Avastin, Genentech) would improve outcomes for patients with EGFRvIII-positive, recurrent GB across multiple measures. A total of 140 patients (intent to treat [ITT], n = 73; per protocol [PP], n = 67) were bevacizumab-naïve at study entry. Investigator-reported interim data including study results through October 2014 were announced in late 2014. The new data presented at ASCO included study results through March 2015 for both the ITT and PP populations.

In the ITT group, the PFS6 rates were 36% for rindopepimut plus BV compared with 16% for control plus BV (P = 0.1163). In the PP group, the corresponding rates were 30% and 12% (P = 0.0310).

Nine patients in the rindopepimut ITT arm continue to be followed for survival, including six without disease progression receiving ongoing treatment. Six patients in the control arm continue to be followed for survival, including two without disease progression receiving ongoing treatment. At 12 months, 45% of rindopepimut patients (ITT) were alive compared with 31% of control patients. The corresponding survival rates at 18 months were 30% and 15%.

Nine of 30 evaluable ITT patients (30%) in the rindopepimut arm experienced a confirmed OR compared with six of 34 evaluable patients (18%) in the control arm. Nine of 29 evaluable PP patients (31%) in the rindopepimut arm experienced a confirmed OR compared with five of 32 evaluable patients (16%) in the control arm. Five patients in the rindopepimut arm experienced durable responses exceeding 6 months, and three of these patients experienced durable responses exceeding 12 months. In contrast, only one PP patient in the control arm experienced a durable response exceeding 6 months, and none experienced a response exceeding 12 months.

Rindopepimut is an investigational therapeutic vaccine that targets the tumor-specific oncogene EGFRvIII, a functional and permanently activated variant of EGFR –– a protein that has been well-validated as a target for cancer therapy. The expression of EGFRvIII has been correlated with increased tumorigenicity in mouse models and with poor long-term survival in clinical studies of patients with GB. In addition, EGFRvIII-positive cells are believed to stimulate the proliferation of non-EGFRvIII cells through interleukin-6 cell-to-cell signaling and to release microvesicles containing EGFRvIII, which can merge with neighboring cells and transfer tumor-promoting activity. EGFRvIII expression may also be associated with tumor stem cells that have been identified in GB. These cells contribute to resistance to cytotoxic therapy and tumor recurrence.

EGFRvIII is expressed in tumors in approximately 30% of patients with GB. It has not been detected at a significant level in normal tissues; therefore, targeting of this tumor-specific molecule is not likely to affect healthy tissues.

The most common adverse events associated with rindopepimut include injection-site reactions, fatigue, rash, nausea, and pruritus.

In February 2015, the FDA granted a “breakthrough therapy” designation to rindopepimut for the treatment of adult patients with EGFRvIII-positive GB.

Source: Celldex Therapeutics; May 31, 2015.

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