Q & A With David Reardon: Immunotherapy in Glioblastoma

David Reardon, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute

One of the most promising findings in glioblastoma to come out recently was an update on the overall survival (OS) benefit from the ReACT trial, a phase 2 study of Rintega (rindopepimut) plus Avastin (bevacizumab) in relapsed glioblastoma. These data were presented in late May at the 2015 annual meeting of the American Society of Clinical Oncology (ASCO), a gathering of nearly 30,000 oncology professionals in Chicago.

Three phase 2 studies of Rintega in newly diagnosed, resected, epidermal growth factor receptor variant III (EGFRvIII) glioblastoma previously demonstrated encouraging progression-free survival (PFS), OS, and safety. Prior compassionate use experiences also demonstrated that similar results might be possible in relapsed patients.

The ReACT trial, presented at ASCO, showed this to be true.

After six months, PFS was 27 percent in the Rintega plus Avastin arm versus 11 percent in the Avastin plus placebo arm in patients who had relapsed and were Avastin naïve.

Overall survival was 24 percent in the Rintega/Avastin arm compared with 17 percent in the Avastin/placebo arm. Median OS was 12 and 8.8 months in the Rintega/Avastin arm and Avastin/placebo arm, respectively.

CURE spoke with David Reardon, clinical director, Center for Neuro-Oncology, Dana-Farber Cancer Institute, president of the Society for Neuro-Oncology, and lead author on the ReACT trial to better understand the significance of these results. In the interview, Reardon also discussed with us another ongoing trial with potential, which looks at MEDI4736 for newly diagnosed patients with glioblastoma.

CURE: What are the most significant findings from the ReACT trial?

Reardon: This [trial] is looking at a novel vaccine therapy for patients with recurrent glioblastoma called Rintega. It is a peptide-based vaccine targeting the EGFRvIII. This is a mutant growth factor that is found in approximately 30 percent of glioblastoma tumors. It is a tumor-specific antigen, meaning it’s not expressed on any normal cells in the body; it’s only present in a glioblastoma tumor. The vaccine targets that unique tumor-specific expression profile. The study that we presented at ASCO looks at Rintega plus Avastin versus Avastin plus placebo. This is a randomized placebo-controlled phase 2 study. The results that we’ve seen with this vaccine are somewhat surprising. We did not expect much activity in the patients with recurrent disease, because they are heavily pretreated and their immune system is weakened. We were surprised to see that the vaccine showed impressive therapeutic benefit, even in patients with recurrence. Patients who had received the vaccine compared with placebo had a statistically significant survival benefit. This is the first immunotherapy of any kind that has been tested in a randomized clinical trial for glioblastoma to show a survival benefit. Patients who received the vaccine also had an improved progression-free survival as well as an improved radiographic response rate. We saw efficacy with the vaccine across the spectrum of different outcomes parameters, but most importantly, there was a demonstration of a survival benefit.

Surprisingly, the patients also had a very robust antibody response to the vaccine. That immune response correlated with and predicted survival benefit. So we may also have a biomarker to go along with the development of this therapeutic that can help guide us in understanding which patients are achieving the most benefit.

Was there any significant toxicity associated with the vaccine?

The vaccine is very well tolerated. There were no major side effects other than grade 1 or 2 skin irritation at the point of injection. This is typically no longer an issue a few days after the injection. So in addition to being something that has a therapeutic benefit, the vaccine is also very well tolerated without any significant side effects. There are not many cancer therapies that can offer that for our patients.

What is the current standard of care for this patient population, and does this study have the potential to change that?

There really is no effective therapy that has been shown to improve survival in patients with recurrence. Based on its radiographic response, the FDA approved Avastin. Unfortunately the benefit of Avastin in terms of survival is pretty limited. There are salvage chemotherapies that have also shown a very limited benefit. But we really don’t have any effective therapies to offer these patients. So this vaccine is a very exciting advancement, both in terms of providing proof of concept in immunotherapy and also because it provides a treatment option for a population where there is really nothing available.

What other studies are you excited about in glioblastoma?

There is an ongoing clinical trial that is looking at a novel therapeutic MEDI4736 that is blocking PD-L1 for newly diagnosed patients with glioblastoma. This is one of the first clinical trials launched to look at immune checkpoint blockade focusing on PD-1 and PD-L1 signaling for this indication. This is a very innovative trial design with three noncomparative cohorts of patients.

In one cohort of patients, their tumors lack MGMT methylation, and we know that these patients have a very poor response to chemotherapy. For these patients we are dropping the chemotherapy and adding a novel immune checkpoint inhibitor MEDI4736 with the standard radiotherapy, which we hope will improve their outcome.

The second cohort of patients has recurrent disease. These patients have progressed after standard of care therapy. These are patients that were naïve to single-agent Avastin, which is the standard of care for recurrent patients in the U.S. They will receive MEDI4736 as a single-agent therapy.

The third cohort consists of patients who are the most refractory and heavily pretreated. Patients in this cohort have progressed on Avastin and radiation. They will receive MEDI4736 and Avastin.

All three arms of this study are currently enrolling patients. There are six centers participating in this study. We look forward to results in the next 6 to 12 months.

What are the expected results?

Immunosuppression is a key factor associated with this cancer. We hope by blocking one of the key mediators of P1 and PDL-1 signaling with MEDI4736, we can provide a therapeutic benefit for these patients. We know that PDL-1 is almost ubiquitously expressed in these tumors, so the target is certainty present.