Rindopepimut Shows Unprecedented Promise in Brain Cancer: Q&A With David Reardon

Rindopepimut in Glioblastoma

David Reardon, MD

Rindopepimut is the first immunotherapy to have ever shown a survival benefit in brain cancers, specifically glioblastoma, said David Reardon, MD, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, in an exclusive interview withTargeted Oncologyat the 20^thAnnual SNO Meeting.

After 6 months, data presented at the ASCO 2015 meeting stated that the phase II ReACT showcased a progression-free survival (PFS) of 27% in patients enrolled in its rindopepimut plus bevacizumab arm. This is in contrast to the PFS of 11% in its 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 has an OS rate of 17. Median OS was 1 year in the rindopepimut/bevacizumab and 8.8 months in the bevacizumab/placebo arm.

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

TARGETED ONCOLOGY:

What is the ReACT study?

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 a type of tumor that we don’t 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 a year to a year and a half. We have not been able to define better therapies despite research and effort 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 have promising activity in newly diagnosed patients. We therefore reasoned we should see if it helps when the tumor had 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.

What was demonstrated with the study was the patients who received the rindopepimut vaccine had a consistent improvement across all of the parameters of efficacy that were evaluated. Specifically, the patients’ progression-free survival was prolonged with rindopepimut versus a 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.

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 and lung cancer and other types of cancer.

TARGETED ONCOLOGY:

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

REARDON:

We presented this data initially at ASCO 2015 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 we see now in the additional 6 months’ worth of follow-up in the patients is that the survival benefit has actually increased. For people who have received the investigational vaccine, who stayed on study and continued to receive treatment, we have a 25% survival rate at 2 years compared to 0% of the patients that were on the control arm of the study.

TARGETED ONCOLOGY:

What can community oncologists take away from this?

REARDON:

One of the critical messages is 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 brain cancer patients, is the side effect profile and the toxicities of rindopepimut.

Rindopepimut, in all the studies it has been assessed in, had minimal toxicities. This is a treatment that we want the community oncologists to know about, in that it can improve survival and it is safe and 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.

TARGETED ONCOLOGY:

Five years from now, where do you see immunotherapies in brain cancer, and where does rindopepimut fit in?

REARDON:

The ReACT study done in recurrent patients is a very important first step, specifically for rindopepimut. The registration study, a randomized phase III study placebo-controlled double blind in newly diagnosed glioblastoma patients, has complete accrual and will be reporting within 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 brain cancer patients. We now know from research that is not the case and that 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.

So 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. So my hope, my 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, the immune checkpoint inhibitors.

TARGETED ONCOLOGY:

Do you think immunotherapies will be used in combinations?

REARDON:

The benefit we’ve seen with rindopepimut underscores the critical need we are going to have to develop effective combination therapies. This benefit is real, it is improving survival for patients, but there are many factors that can impact the ultimate, definitive benefit. The tumor can reoccur and can 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, so combining a treatment that has a very potent immunogenic effect, like 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 very strongly that the next steps are going to be to have to look at combination therapies if we are going to fully achieve the potential of these therapies for our patients.