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FDA Grants Rindopepimut Breakthrough Designation for EGFRvIII-Positive Glioblastoma

Peter J. Sciavolino, PhD
Published: Monday, Feb 23, 2015

David A. Reardon, MD

David A. Reardon, MD

Rindopepimut (Rintega) has gained a Breakthrough Therapy Designation from the FDA to treat adult patients with glioblastoma multiforme (GBM) that test positive for the epidermal growth factor receptor (EGFR) variant (EGFRvIII).

The application was based on data from the phase II ReACT study in recurrent GBM, the phase II ACT III study in newly diagnosed GBM, and additional phase II studies. ACTIVATE, ACT II, and ACT III—have been completed in newly diagnosed EGFRvIII-positive GBM and have shown efficacy in both overall survival (OS) and median progression-free survival (PFS), according to a press release from Celldex Therapeutics, Inc, the company developing the drug.

A constitutively activated EGFRvIII is expressed in up to 30% of glioblastomas and is associated with poor outcomes.1-4 Rindopepimut (CDX-110) is a vaccine designed to elicit an immune response against the highly immunogenic EGFRvIII epitope expressed on glioblastoma cells.1,5

Findings from ACT III, a multicenter, phase II study examining rindopepimut in combination with standard adjuvant temozolomide chemotherapy for patients with newly diagnosed glioblastoma, were recently published in Neuro-Oncology.1

EGFRvIII as an Exploitable Tumor Marker

In patients with GBM and EGFR amplification, expression of the EGFRvIII variant has been associated with poor survival,3 and tumors of patients with GBM not expressing the EGFRvIII marker seem to show less clinically aggressive behavior.2 In the subgroup of patients with GBM surviving for 1 year or more, expression of EGFRvIII has been shown to be a significant independent negative prognostic indicator.4

Because the EGFRvIII variant is specifically expressed on tumor cells and not present in normal tissues, it has been recognized as an ideal candidate for tumor-directed immunotherapy in the brain.5 Rindopepimut is a peptide vaccine corresponding to the 13-amino acid mutant vIII epitope conjugated to the immunostimulatory carrier protein keyhole limpet hemocyanin (KLH).5 Vaccination with rindopepimut inhibits the growth of EGFRvIII-expressing tumors in experimental mouse models.5 The ACT III study was implemented based on favorable phase II findings in patients with EGFRvIII-positive glioblastoma.6,7

Efficacy in a Difficult-to-Treat Tumor

In ACT III, following an initial priming stage (days 0, 14, and 28) rindopepimut was administered monthly in combination with the current standard of treatment, temozolomide, until intolerance or disease progression in patients with newly diagnosed glioblastoma that was EGFRvIII positive by immunohistochemistry (n = 65).1 The results showed a median PFS of 9.2 months and a median OS of 21.8 months from study entry. The results compared favorably with a historical control cohort of patients, matched for ACT III entry criteria, in whom the median OS from study randomization was 16.0 months for patients with EGFRvIII-positive tumors.1

Notably, the efficacy results of ACT III have demonstrated that the brain, once thought to be an immunologically privileged space, can be effectively targeted using immunotherapy.

“The bottom line is that patients survive longer,” said David A. Reardon, MD, a coauthor of the study, and clinical director of the center for neuro-oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts.

“I was taught 25 years ago in medical school that the immune system doesn’t react in the brain effectively, but there’s been a lot of research done over the last 15 years to show that there is a very dynamic interaction of the immune system in the brain, and systemically, in the rest of the body… this is the first vaccine that has actually shown a survival benefit for patients,” Reardon said.

Reardon noted the 6-month improvement with the vaccine (21.8 months) compared with the historical controls (16 months) in ACT III, which he sees as highly significant.

“Six months may not sound like a big improvement, but for people who are familiar with this type of cancer, people who’ve been doing research and trying to come up with a better treatment, 6 months is a huge improvement. The standard of care, temozolomide, was FDA approved based on a 2.4-month improvement in survival when it was tested in a randomized study,” Reardon stated.


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TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
Community Practice Connections™: Precision Medicine for Community Oncologists: Assessing the Role of Tumor-Testing Technologies in Cancer CareNov 30, 20181.0
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