Glioma Vaccine Improves Survival and Heads Toward Phase 3

Janis C. Kelly

October 15, 2010

October 15, 2010 — An experimental vaccine targeted at epidermal growth-factor receptor variant III (EGFRvIII) improved progression-free survival and median overall survival in newly diagnosed glioblastoma patients in a small phase 2 study published online October 4 in the Journal of Clinical Oncology.

The vaccine, known as rindopepimut (CDX-110, Celldex Therapeutics), was used in 18 patients who were also treated with gross total resection, external-beam radiation therapy, and concurrent temozolomide. The vaccine group was compared with a matched control group of 17 patients treated with the same basic regimen but without rindopepimut. Patients in the vaccine group received 3 initial intradermal vaccinations every 2 weeks starting 4 weeks after the completion of radiation, and monthly thereafter until radiographic evidence of progression. All patients in both groups had EGFRvIII-expressing primary glioblastoma multiforme.

After adjustment for age and Karnofsky performance status, the overall survival of vaccinated patients was 5-fold better than that in the control group (hazard ratio, 5.3; P = .0013). Overall survival was longest in vaccinated patients who developed specific antibody or delayed-type hypersensitivity responses to EGFRvIII.

The vaccine extended median survival time from the expected 15 months to 26 months. Patients in the vaccine group also experienced a much longer progression-free survival period than those who did not receive the vaccine (14.2 vs 6.3 months).

The researchers found that the peptide vaccine eliminated cancer cells carrying EGFRvIII. At recurrence, EGFRvIII was no longer expressed in 82% of vaccinated patients.

The vaccine did not produce any symptomatic autoimmune reactions.

Lead researchers John Sampson, MD, from Duke University Medical Center in Durham, North Carolina, said: "Our study results demonstrate that vaccinating patients who have newly diagnosed EGFRvIII-positive [glioblastoma multiforme] with a peptide containing an EGFRvIII-specific epitope is safe, induces specific immunity against EGFRvIII, and is associated with the elimination of EGFRvIII-expressing cells at recurrence. This observation that an EGFRvIII-targeted vaccine is capable of potentially eliminating EGFRvIII-expressing tumor cells in the majority of patients is an intriguing finding, and is consistent with what we found in our preclinical studies in mice. It suggests that the immunologic privilege of the brain may not be absolute in this context."

Dr. Sampson also noted that an advantage of this vaccine is that it is available "off the shelf" and does not require labor-intensive cell preparation techniques. A disadvantage is that only one third of glioblastoma multiforme patients have EGFRvIII-expressing tumors.

Rindopepimut is headed for phase 3 trials, and the pace of research is expected to accelerate now that Pfizer has returned worldwide development and commercialization rights to Celldex Therapeutics (Celldex stock dropped 36% in September when the end of the company's deal with Pfizer was announced). A statement from Celldex says that the company expects to report new data from the ACT III study in November at the 2010 Society for Neuro-Oncology annual meeting. Preliminary ACT III data reported at the 2010 American Society of Clinical Oncology annual meeting showed that rindopepimut produced 70% progression-free survival at 5.5 months, but the researchers had to eliminate the control group of this open-label trial because most patients dropped out when they found they would be getting only standard therapy (J Clin Oncol. 2010;28[15 Suppl]:abstract 2014).

Problems Ahead?

In an accompanying editorial, Pedro Lowenstein, MD, says the report by Dr. Sampson and colleagues highlights the difficulties of conducting clinical trials with cancer vaccines. Dr. Lowenstein is from the Gene Therapeutics Institute at Cedars-Sinai Medical Center and the David Geffen School of Medicine at the University of California, both in Los Angeles.

Recruiting enough patients with brain tumors that are immunoreactive for EGFRvIII to conduct large-scale, randomized, double-blind, phase 3 trials is going to be a problem, he predicts.

"Sampson et al report an increased [overall survival] of 9 months, compared with contemporaneous controls. If a comparable difference could be maintained in a larger randomized trial, the use of the EGFRvIII vaccine in suitable patients would be amply justified. The challenge remains how to determine the rational use of EGFRvIII vaccine in the absence of a large, randomized, double-blind, controlled, phase 3 trial," Dr. Lowenstein writes.

The editorial also highlights potential economic problems ahead for cancer vaccines; they come at a high cost. As an example, Dr. Lowenstein cites the recently approved sipuleucel-T (Provenge, Dendreon) for prostate cancer.

"At an estimated total cost of $93,000 (or $23,000 per month of survival advantage with a 4-month median increased survival) compared with conventional standard of care costs of $1800 per month, the treatment is more likely to be used in the United States than in other health systems," Dr. Lowenstein said.

Dr. Sampson reports serving in a consultant or advisory role and receiving honoraria and research funding from Celldex Therapeutics. Dr. Lowenstein has disclosed no relevant financial relationships.

J Clin Oncol. Published online October 4, 2010. Abstract, Abstract


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