Reardon on Promising Results With Rindopepimut in Brain Cancer

David Reardon, MD

Rindopepimut is the first immunotherapy to have shown a survival benefit in brain cancers, specifically glioblastoma, explains David Reardon, MD.

Data showcasing the agent's clinical activity were reported from the phase II randomized ReACT study, which examined the efficacy of rindopepimut plus bevacizumab for the treatment of patients with relapsed glioblastoma. At the 2015 ASCO Annual Meeting, 6-month data showed that patients who received rindopepimut plus bevacizumab had a median progression-free survival (PFS) of 27%, compared with 11% in the bevacizumab plus placebo arm. The 73 patients enrolled in the study had newly diagnosed, resected, epidermal growth factor receptor variant III (EGFRvIII) glioblastoma.

Overall survival (OS) in the study was 24% in the rindopepimut/bevacizumab arm, while the bevacizumab/placebo arm had an OS rate of 17%. Median OS was 1 year in the rindopepimut/bevacizumab arm and 8.8 months in the bevacizumab/placebo arm.

In the 6 months since ASCO, the ReACT data have matured and shown that patients who continued to stay on the combination of rindopepimut and bevacizumab had a 25% survival rate at 2 years, compared with a 0% survival rate of those in the bevacizumab and placebo arm.

OncLive: What details can you share regarding the ReACT study?

In an interview with OncLive, Reardon, clinical director at the Center for Neuro-Oncology, Dana-Farber Cancer Institute, discusses the ReACT study's findings and the potential of rindopepimut and other immunotherapy agents for the treatment of patients with brain cancers, specifically glioblastoma.Reardon: The ReACT study is looking at an immunotherapy intervention with recurrent glioblastoma. Glioblastoma is the most common primary cancer that arises in the brain, and it’s tumor type that we do not have good, effective therapies for. Our best standard-of-care can control the disease for about 7 to 8 months, and the average patients are, unfortunately, passing away within 1 year to 1.5 years. We have not been able to define better therapies, despite research and efforts that can improve outcome.

A subset of these glioblastoma tumors has been discovered to express a mutated protein on the surface of the cells called EGFRvIII. We understand EGFRvIII biologically to be a growth factor present on about 30% of glioblastoma tumors that is always activated. When active, it is driving the cellular proliferation and survival pathways. We know that this is a particularly challenging subset of glioblastoma tumors because of the over-activity of this mutated growth factor receptor.

Rindopepimut is a peptide vaccine that targets the specific mutation associated with the EGFRvIII mutated growth factor receptor. A number of studies have shown it to demonstrate promising activity in newly diagnosed patients. Therefore, we reasoned to see if it helps when the tumor recurred after standard therapy.

The ReACT study was designed to see if rindopepimut could improve outcome in glioblastoma patients. The patients were randomized to receive either a placebo vaccine plus bevacizumab, the anti-angiogenic agent, which is approved for glioblastoma, or rindopepimut plus bevacizumab. The study enrolled 73 patients who were randomized 1:1 to the two treatment arms.

The study demonstrated that the patients who received the rindopepimut vaccine had a consistent improvement across all parameters of efficacy that were evaluated. Specifically, PFS was prolonged with rindopepimut versus placebo. The radiographic response rate and, importantly, the durability of those responses, was longer in the patients who received rindopepimut.

Patients in the rindopepimut arm also had a reduced corticosteroid requirement, which is a surrogate of quality of life because steroids can have a detrimental effect on the function and capabilities of patients. Most importantly, rindopepimut recipients had a statistically significant improvement in overall survival.

What information have you gathered from the data in the follow-up to the ReACT study?

This is very important. This is the first randomized study ever in glioblastoma that has shown a benefit with any immunotherapy. As a bigger picture, this provides a proof of concept that immunotherapies can impact brain cancer, specifically here with glioblastoma. Our hope is that it will have an impact like it has had on melanoma, lung cancer, and other types of cancer.We presented this data initially at the 2015 ASCO Annual Meeting and, at that time, the data were not fully mature. Now, we have a mature follow-up and final data associated with this study. Data presented at ASCO were a survival benefit associated with the vaccine.

What can community oncologists take away from this?

What we see now, in the additional 6-month follow-up, is that the survival benefit has actually increased. People who have received the investigational vaccine, who stayed on study and continued to receive treatment, have a 25% survival rate at 2 years compared to 0% of the patients who were on the control arm of the study.One of the critical messages is that we need to identify this subset of glioblastoma patients who have the EGFRvIII mutation in their tumor. It is only 30% of the patients, but we now have a promising therapy that does improve survival. The other aspect of this, particularly relevant for patients with brain cancer, is the side effect profile and the toxicities associated with rindopepimut.

In the next 5 years, what role do you envision immunotherapies having in brain cancer, and where does rindopepimut fit in?

In all of the studies it has been assessed in, rindopepimut has been found to have minimal toxicities. This is a treatment that we want the community oncologists to know about, in that it can improve survival, is safe, and is very well tolerated for this patient population. They have to help us identify who these patients are. The only way to do that is to test the tumor for the expression of this marker, EGFRvIII. That is routinely done by a reverse transcription polymerase chain reaction (RT-PCR) assay. Academic centers can easily, and routinely, do that, but unless that testing is done, these patients will never be identified and they will not have access to this effective therapy.The ReACT study, which was done in recurrent patients, is a very important first step, specifically for rindopepimut. The registration study, a randomized phase III study that was placebo-controlled and double-blinded in newly diagnosed patients with glioblastoma, has completed accrual and will have data reported in 6 to 12 months.

More importantly, providing proof of concept that immunotherapy can help brain cancer patients is a very important step. Most of us were taught, in medical school, that the brain is immuno-privileged and, therefore, immunotherapy may not have as much of an impact for patients with brain cancer. From research, we now know that that is not the case; the relative privilege of the central nervous system is not definitive by any means. There is a dynamic interaction between the systemic immune system and what is reactive in the brain.

Do you think immunotherapies will be used in combinations?

Therefore, immunotherapies can integrate into the brain, pass through the blood-brain barrier, and can have a meaningful impact. Now, we have proof-of-concept that specific immunotherapy treatment can improve survival for this disease. My hope and vision for the next 5 years is that this is the first step, and that many more will come forward looking at a variety of immunotherapy approaches—other vaccine strategies, adoptive T-cell approaches, and, very importantly, what is currently being evaluated, such as the immune checkpoint inhibitors.The benefit we have seen with rindopepimut underscores the critical need we are going to have to develop effective combination therapies. This benefit is real and it is improving survival for patients, but there are many factors that can impact the ultimate, definitive benefit. The tumor can return and could no longer express the EGFRvIII protein.

If we had vaccines that combined and effectively attacked multiple different targets, then the immune editing and immune escape that can ultimately develop could be less likely of an issue.

In addition, we know that tumors have a number of immunosurpressive factors associated with them. Therefore, combining a treatment that has a very potent immunogenic effect, such as a tumor-specific vaccine like rindopepimut, with treatments that can decrease some of the immunosurpressive factors in the tumor microenvironment, like the immune checkpoint inhibitors, is a logical and exciting potential to build on this.

I believe that the next steps are going to be looking at combination therapies, if we are going to fully achieve the potential of these therapies for our patients.