Immunotherapy Combination Extends Survival for Patients With Relapsed Glioblastoma

Adding the immunotherapeutic vaccine Rintega (rindopepimut) to Avastin (bevacizumab) may help boost survival in patients with a genetic subtype of glioblastoma associated with poor outcomes, according to results from the phase 2 ReACT study.

These results were presented at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

Patients with glioblastoma who have the EGFRvIII mutation have more aggressive tumors that are resistant to chemotherapy, explained Fabio M. Iwamoto, the deputy director of the Division of Neuro-oncology at Columbia University Medical Center. This mutation is present in about 30 percent of glioblastomas and is estimated to contribute to about 4,000 U.S. cases and 800 EU cases of glioblastomas each year. The good news is that the mutation is very tumor specific.

“It’s not expressed in normal tissue, which makes it a good target for immunotherapy,” Iwamoto says.

Rintega targets cells that carry the mutation for destruction by the immune system, and the drug has demonstrated improved progression-free survival (PFS), overall survival (OS), and a good safety profile in three phase 2 trials in patients newly diagnosed with glioblastoma, explained David A. Reardon, clinical director of the Center for Neuro-Oncology at the Dana-Farber Cancer Institute, who presented the ReACT results. The vaccine has also been used on a compassionate basis in patients with relapsed glioblastoma, according to Reardon.

There is also a strong case for combining Rintega with anti-VEGF therapy like Avastin, according to Reardon, who explained that VEGF can promote immunosuppression in the tumor, so blocking immunosuppression while administering Rintega could further boost the immune response to the tumor.

The phase 2 ReACT trial put this theory to the test and demonstrated an OS benefit for patients with relapsed glioblastoma who were treated with Rintega in addition to Avastin. In the trial, 72 patients with glioblastoma who were Avastin naïve and EGFRvIII positive experiencing their first or second relapse were randomized to receive Avastin plus an injection of Rintega or Avastin plus a placebo injection.

Both Reardon and Iwamoto, who gave an independent assessment of the study, agreed that the study confirmed that Rintega has a good safety profile in this patient population. Reardon said that the vaccine was only associated with mild and temporary injection-site reactions. There were no unexpected toxicities associated with Avastin or signs of cerebral edema, he noted.

“[Rintega] has had a well-established, outstanding safety profile in studies in newly diagnosed glioblastoma patients and that experience was maintained in the context of recurring patients,” Reardon says.

In the intent-to-treat analysis at six months, PFS in the Avastin/placebo vaccine control group was 16 percent compared with 28 percent in the Avastin/Rintega group, Reardon reported. The Kaplan Meyer curves of the data showed that for much of the first six months the two groups had very similar PFS, but at the end of the six-month period the Rintega group began to show response. This finding will have important implications for the design of future studies, according to Iwamoto, who noted that the studies should be designed so they can be extended, if necessary, to give patients enough time to respond.

An independent panel of neuroradiologists analyzed images of the patients’ tumors and found an improved response in the Rintega group compared with the control (30 versus 18 percent). Reardon said patients in the Rintega group maintained this response longer than those in the control group, and some continue to maintain this improvement. Iwamoto cautioned that evidence from studies of immunotherapies for solid tumors has demonstrated that, “It’s hard to define progress by imaging.”

There were also more tangible benefits for the patients administered Rintega, with 56 percent of the patients receiving the vaccine able to stop using corticosteroids compared with 42 percent of controls.

“Our patients will be very happy to know that [Rintega] is associated with a reduction in corticosteroid usage,” Reardon says. “A higher percentage were able to come off of corticosteroids and maintain being off for a prolonged period.”

Finally, the intent-to-treat analysis found that OS improved from 9.3 months in the control group arm to 11.6 months in the Rintega arm. These benefits were maintained even within patient subgroups.

“When we looked at outcome across a variety of prognostic factors, the addition of Rintega improved [OS] across groups,” Reardon says. Additionally, Reardon said that he was pleased that the patients developed a robust tumor-specific response despite their history or relapse. He noted that the study documented a four-fold increase in anti-EGFR antibody titers.

"What I've just told you is historic data; this is the first immunotherapeutic that has shown a survival benefit for glioblastoma,” Reardon says. Iwamoto cautioned that the study has a small sample size and wide confidence intervals. But he acknowledged that results of the three trials so far have been consistent. “The overall survival is clearly different,” Iwamoto says.

Data from a phase 3 randomized trial of Rintega in newly diagnosed patients with glioblastoma are expected in the next two months, Reardon noted.

Reardon DA. ReACT: Overall survival from a randomized phase II study of rindopepimut (CDX-110) plus bevacizumab in relapsed glioblastoma. Presented at: 2015 American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, IL. Abstract 2009.