Glioblastoma with extreme nuclear enlargement.
Glioblastoma with extreme nuclear enlargement.

Results from a study, published in Clinical Cancer Research, a journal of the American Association for Cancer Research suggest that adding rindopepimut, a cancer vaccine to the standard therapy of bevacizumab (Avastin®; Genentech/Roche) may improve outcomes in patients with EGFRvIII-positive recurrent glioblastoma multiforme.

Rindopepimut, (Rintega®; Celldex Therapeutics; also known as CDX-110, pf-04948568 and ALT-110) , is a vaccine targeting the EGFR deletion mutation EGFRvIII and consists of an EGFRvIII-specific peptide conjugated to keyhole limpet hemocyanin (KLH). [1]

The keyhole limpet hemocyanin is a natural protein isolated from the marine mollusc keyhole limpet. Keyhole limpet hemocyanin is an immunogenic carrier protein that, in vivo, increases antigenic immune responses to haptens and other weak antigens such as idiotype proteins.

The study was funded by Celldex Therapeutics.

Photo 1.0: John H. Sampson, MD, Ph.D., chair of the Department of Neurosurgery at Duke University in Durham, North Carolina.
Photo 1.0: John H. Sampson, M.D., Ph.D., chair of the Department of Neurosurgery at Duke University in Durham, North Carolina.

ReACT study
The results of the Phase II ReACT clinical study confirm that patients with recurrent EGFRvIII-positive glioblastoma treated with standard bevacizumab, and who also received the cancer vaccine rindopepimut, had better clinical outcomes. including improved overall survival.[2]

“There is increasing evidence that vaccines can be efficacious for the treatment of cancer,” noted John H. Sampson, MD, Ph.D., chair of the Department of Neurosurgery at Duke University in Durham, North Carolina.

“Our results indicate that vaccines targeted against tumor-specific mutations might be a successful way to leverage the immune system against cancer and that even tumors in the brain might be able to be treated by immunotherapy.”

Essential component
The epidermal growth factor receptor (EGFR) is an essential component in many signaling pathways that promote cell proliferation and survival.

“The EGFR splice variant EGFRvIII results in a constitutively activated form of the protein, thereby enhancing tumor cell growth,”  Sampson explained.

“Roughly one-third of glioblastomas harbor EGFRvIII and the presence of this splice variant is associated with reduced long-term survival in this patient population, he added.

Being a constitutively activated mutation of EGFR means that the EGFRvIII neoantigen is not expressed in normal, healthy, tissues but only expressed in glioblastoma, providing rindopepimut tumor-specific activity.

EGFRvIII is alsofound in various other cancers including breast, ovarian, metastatic prostate, colorectal, and head and neck cancers. EGFRvIII contains an 83 amino acid deletion in its extracellular domain and has been shown to transform NIH/3T3 mouse embryonic fibroblast cells in vitro.

Progression-free survival
While results from prior phase II clinical trials found that the addition of this cancer vaccine to standard treatment improved progression-free survival and overall survival in patients with newly diagnosed EGFRvIII-positive glioblastoma as compared with historical control datasets, a phase III study conducted in this patient population did not indicate that adding rindopepimut to standard chemotherapy improved overall survival, Sampson explained.

Bevacizumab, a VEGF inhibitor, is the standard treatment for patients with relapsed, EGFRvIII-positive glioblastoma. The ReACT clinical trial was designed to study if the addition of rindopepimut to bevacizumab improved progression-free survival for these patients.

Study design
This double-blind, randomized study enrolled 73 bevacizumab-naïve patients with EGFRvIII-positive glioblastoma across 26 hospitals in the United States. Of these patients, 36 were assigned to receive bevacizumab and rindopepimut, and 37 were assigned to receive bevacizumab and KLH as a control injection.

In the vaccine arm, patients received 500 µg of rindopepimut admixed with 150µg of GM-CSF; in the control arm, patients received 100 µg of KLH. Vaccination occurred on days 1, 15, 29, and then once monthly.

All patients received bevacizumab (10 mg/kg) every two weeks. Treatment continued until intolerance, withdrawal of consent, or disease progression. The primary endpoint was Progression-Free Survival at six months (PFS6).

Study results
Compared with patients in the control arm, patients assigned to receive rindopepimut had increased PFS6 (16% versus 28%, respectively). This difference was, however, not statistically significant.

Furthermore, in this study, the 24-month overall survival rate was significantly improved for patients who were assigned to receive rindopepimut compared with those assigned to receive bevacizumab alone (20% versus 3%, respectively).

Finally, the difference in overall survival between the two arms was significant: compared with patients in the control arm, patients who were assigned to receive the vaccine had a 47% reduced risk of death.

Cerebral edema
Glioblastomas often result in cerebral edema, known as a swelling in the brain, which can be treated with corticosteroids. Among patients treated for cerebral edema at study entry, 33% in the rindopepimut arm were able to discontinue corticosteroids for at least six months, compared with none in the control arm.

“An active tumor generates substantial edema and requires a lot of corticosteroids,” explained Sampson.

“We feel that the reduction in corticosteroid use is a surrogate way of identifying patients that are responding to treatment,” he concluded.

Study limitation
The researchers recognized that the limitations of the study include its small sample size and a lack of central pathology review.

Clinical trial
A Study of Rindopepimut/GM-CSF in Patients With Relapsed EGFRvIII-Positive Glioblastoma (ReACT) – NCT01498328

Reference
[1] Harris JR, Markl J. Keyhole limpet hemocyanin: molecular structure of a potent marine immunoactivator. A review. Eur Urol. 2000;37 Suppl 3:24–33. doi:10.1159/000052389
[2] Elsamadicy AA, Chongsathidkiet P, Desai R, et al. Prospect of rindopepimut in the treatment of glioblastoma. Expert Opin Biol Ther. 2017;17(4):507–513. doi:10.1080/14712598.2017.1299705