Andrew S. Chi, MD, PhD
The heterogenic nature of brain tumors has historically made the malignancy a difficult one to treat, with very few therapies panning out in large clinical trials. However, despite the letdown of prior research, the future looks bright for immunotherapies and novel targeted approaches for patients with gliomas, many of which have already been developed for other types of cancer.
“We have so much knowledge about the biology of these tumors and a proliferation of different drugs and therapies that have been developed over the past few years are working in other cancers,” Andrew S. Chi, MD, PhD, head of Neuro-Oncology at NYU Langone’s Laura and Isaac Perlmutter Cancer Center, told OncLive
. “We have to figure out how to get these drugs to work in brain cancers.”
Therapies targeted against IDH1/2
represent a potential treatment paradigm for patients with glioma. Additionally, novel approaches, such as those using alternating electric fields have demonstrated efficacy. In October 2015, Optune, a device using tumor treating fields, became the first FDA-approved therapy in more than a decade to demonstrate a statistically significant extension in overall survival (OS) for patients with newly diagnosed glioblastoma multiforme (GBM).
Immunotherapy has also generated a great deal of excitement. Recently, the PD-1 inhibitor nivolumab (Opdivo) demonstrated early signs of activity as a monotherapy for patients with recurrent GBM. Furthermore, other immune-based therapies targeted against EGFRvIII have shown exceptional signs of activity and tolerability.
Adding to the excitement, preclinical research conducted on tumor samples and mouse models showed that the protein FGL2, which is secreted by GBM, causes the upregulation of immune suppression mechanisms. In early studies, an anti– FGL2 antibody demonstrated therapeutic potential, suggesting the possible role for a novel immunotherapy.
“FGL2 is not just working on immune checkpoints. It’s also working on other cells that are also contributing to the tumormediated immune suppression,” Amy Heimberger, MD, professor in the Department of Neurosurgery, University of Texas MD Anderson Cancer Center, told Targeted Oncology. “We think this is going to impact more patients because it hits more than one mechanism and we think it will have a more profound impact.”
Checkpoint Inhibitors Show Early Promise
The CheckMate-143 study is comparing nivolumab alone (3 mg/kg) versus bevacizumab alone (10 mg/kg) in patients with recurrent GBM. Preliminary results from an earlier phase of the study showed that nivolumab monotherapy had a median OS of 10.5 months, with 40% of patients alive after one year of follow-up.1
Traditionally, bevacizumab has shown a median OS between 7 and 10 months and a 1-year OS rate of around 25%.
The study is now proceeding to a phase III expansion, which is already under way. The estimated completion date for collecting data on the primary outcome measures of safety and OS is June 2017. An estimated 440 patients are expected to enroll (NCT02017717).
“Immunotherapies are really riding a big wave in research and therapeutic development and they are generating a lot of excitement in a lot of cancer types, as well as brain cancer,” said Chi. “When these immunotherapies work in other cancers, they have worked phenomenally well.”
In addition to nivolumab, the PD-1 inhibitor pembrolizumab (Keytruda) and the PD-L1 inhibitor durvalumab are also being explored in phase II studies for patients with glioma. These trials are looking at the agents as monotherapy and in combination with bevacizumab or radiotherapy. The pembrolizumab trial plans to enroll 80 patients (NCT02337491) and the durvalumab trial is looking to enroll 100 patients (NCT02336165).
“The excitement for brain cancers has been high because, when you look at the biology of these tumors, there is significant rationale that these immunotherapies should work,” said Chi. “Whether it be vaccines or immune checkpoint inhibitors, there has been a tremendous amount of research into the immunobiology, gliomas in particular, that suggests that some of these immune therapies should work.”
Chimeric Antigen Receptors in Glioma
Chimeric antigen receptor (CAR) T-cell therapies targeted against CD19 have shown exciting promise for patients with hematologic malignancies, where they have demonstrated impressive efficacy in both chronic lymphocytic leukemia and acute lymphoblastic leukemia. Now, following this proof of principle, these agents are being explored across a variety of solid tumors.