Glioblastoma Multiforme: Advancements in the Treatment Paradigm of the Malignant Condition

Over the past decades, there has been an eruption in understanding treatment strategies of gliomas with the development of clinical immunotherapy, providing exceptional success in employing checkpoint inhibitors and cancer vaccines as treatment options that have given significant momentum to the growth of the GBM market. The pre-existing treatment includes complete resection followed by radiotherapy and pharmacological treatment with chemotherapeutic agents, such as temozolomide – a major type of high-grade glioma.

Avastin (bevacizumab) is approved in the GBM market in adult patients whose cancer has progressed after prior treatment (recurrent or rGBM). In September 2009, the US Food and Drug Administration (FDA) granted accelerated approval of Avastin for people with rGBM, followed by its full approval in December 2017; since then, Avastin remains the standard of care in refractory GBM. Although Mvasi (bevacizumab-awwb, Amgen) was the first Avastin biosimilar to get FDA approval in 2017, Zirabev proved to be a better biosimilar for GBM patients when launched in 2019. 

GBM Failure Stories: Missing Clinical Trial Endpoints

The development of new drugs for this hard-to-treat disease is a slow and incremental process. Most of the investigational medications for GBM hit a snag before even entering the GBM therapeutics market as the rate of successfully achieving their primary endpoints remains extremely low. Bristol Myers Squibb (BMS) witnessed one such failure in 2019 as the company had to shelve its approval plans for Opdivo (nivolumab) due to its inability to meet the primary endpoint in Phase III CheckMate-498 trial.

Additionally, Tocagen’s Toca 5 trial evaluating gene therapy and prodrug combination of Toca 511 and Toca FC (Phase II/III) in recurrent GBM failed to improve overall survival (OS). As it happened, the patients in the study group did worse than those in the control group. Such failures are not new to GBM drug development. Adopting a conservative approach, we are sceptical about the future of several investigational therapies; however, we still count on these therapies to accomplish the needful.

In August 2022, Kazia Therapeutics faced a significant setback when its lead glioblastoma candidate, paxalisib, failed to meet the predefined criteria necessary to advance in the pivotal GBM AGILE trial, a global umbrella study assessing various therapies for this aggressive brain cancer. The Global Coalition for Adaptive Research, the study’s sponsor, informed Kazia that paxalisib had not met specific endpoints essential for progression to the trial’s second phase. This disappointment cast a shadow over the drug’s future, with implications suggesting it might be removed from the ongoing trial framework.

Fast forward to July 2024, and Kazia Therapeutics is attempting to turn this narrative around. By re-evaluating the trial data and strategically adjusting the study parameters—specifically by removing part of the control arm—the biotech company has uncovered survival data that could potentially pave the way for accelerated approval from the FDA. This innovative approach stems from the same platform study, which compares various treatments, including those developed by Bayer and Biohaven, against a standard-of-care control in a flexible, adaptive trial design. Kazia’s determination to find a silver lining from its initial failure has ignited hope within the research community.

Despite the challenges, the data revealed a nuanced picture. In the subgroup analysis of patients with recurrent glioblastoma, paxalisib’s performance, while falling short of the control treatment lomustine, still provided crucial insights. The median overall survival for those treated with paxalisib was 8.05 months, compared to 9.69 months for lomustine, based on a cohort of 213 patients evenly divided between the two treatments. Kazia now believes there’s a positive narrative to share, highlighting its commitment to advancing research in the tough landscape of glioblastoma treatment.

Pharma companies’ Showing Glimmers of Promise in GBM Market

The key pharma players engaged in developing novel therapeutic modalities for GBM include Bayer, Chimerix, Aivita Biomedical, Denovo Biopharma, Northwest Therapeutics, VBL Therapeutics, Laminar Pharmaceuticals, MedImmune, DNAtrix, Immunomic Therapeutics, Imvax, MimiVax, CNS Pharmaceuticals, Epitopoietic Research Corporation (ERC), Istari Oncology, SonALAsense, and several others.

The glioblastoma market is expected to grow significantly during the study period from 2020 to 2034. In the United States, the market is projected to increase at a CAGR of 13.1% during the study period (2020-2034) This growth highlights the rising demand for effective treatments and ongoing research efforts in this challenging field.

The target pool for most of these medications is a mix of newly diagnosed and recurrent GBM patients. Most of these are targeted therapies inhibiting specific molecular targets, including EGFR (epidermal growth factor receptor), mTOR (mammalian target of rapamycin), PI3K (phosphatidylinositol 3-kinase), VEGF (vascular endothelial growth factor), and XPO1 Inhibitor (Exportin 1).

A few of the prospective emerging therapies are as follows:

In July 2024, Kazia Therapeutics is pursuing an FDA accelerated approval pathway for its investigational glioblastoma drug paxalisib, following the release of secondary overall survival data from the Phase II/III GBM-AGILE trial. This global study is designed to evaluate multiple investigational glioblastoma treatments against standard care. While paxalisib showed no efficacy in patients with recurrent disease, achieving a median overall survival (OS) of 8.05 months compared to 9.69 months for lomustine, it demonstrated promise among newly diagnosed patients, where it yielded a median OS of 14.77 months—slightly better than the 13.84 months seen with temozolomide.

In contrast, Kintara Therapeutics has faced challenges with its drug VAL-083. After presenting compelling patient case studies at the 2023 European Association for Neuro-Oncology Annual Meeting in September, Kintara announced on October 31, 2023, that VAL-083 did not outperform current standards of care in the GBM AGILE study, leading the company to suspend its development and redirect focus towards its second program, REM-001. With Kazia’s paxalisib demonstrating potential in newly diagnosed glioblastoma patients, expectations lean more favorably towards this drug as a promising therapeutic option in the ongoing battle against this challenging cancer.

In August 2023, an international team of researchers, led by the University of Michigan Health Rogel Cancer Center and the Chad Carr Pediatric Brain Tumor Center, made a groundbreaking discovery regarding the drug candidate ONC201. This compound has shown promise in improving survival rates for patients with diffuse midline gliomas (DMG), including the aggressive diffuse intrinsic pontine glioma (DIPG), for which there are currently no effective treatments. The findings, published in the journal Cancer Discovery, revealed that ONC201 nearly doubled survival compared to previous patients, marking a significant advancement in the fight against this challenging brain tumor.

Diffuse midline gliomas, particularly those harboring the H3K27M mutation, have a dismal overall survival rate of only 11–15 months, primarily due to the tumors’ location within critical brain regions. In the trials involving 71 patients with H3K27M-mutated diffuse midline gliomas, those with non-recurrent tumors at enrollment achieved a median overall survival of nearly 22 months, with nearly one-third of participants living beyond two years. “It’s an incredibly difficult tumor to treat,” stated senior author Carl Koschmann, M.D. This study represents a significant breakthrough, as previous efforts have failed to improve outcomes in over 250 clinical trials.

The encouraging results of ONC201’s efficacy highlight the need for further validation through larger studies, such as the Phase III ACTION trial, which is currently recruiting 450 patients across 11 countries. Patients will receive ONC201 following front-line radiation therapy, the standard of care, to assess its effectiveness as a monotherapy. According to Chimerix CEO Mike Andriole, these findings offer strong confidence in ONC201’s potential to provide a much-needed therapeutic option for this vulnerable patient population, who have limited treatment alternatives.

Additionally, Ziopharm also presented positive results in Phase II, evaluating IL-12 along with a PD-1 inhibitor for GBM.

What are the prevailing unmet needs?

Given the tremendous unmet need in the GBM market, therapies able to extend OS, including immunotherapies, novel vaccines, and immune checkpoint inhibitors, could provide a valuable treatment option for GBM patients who do not respond to or experience a recurrence of their disease following conventional therapy. Unfortunately, limited therapeutic access to a brain tumor and peritumoral tissue caused by the blood-brain barrier (BBB) still offers a challenge to optimize glioma treatment, despite such efforts.

Sadly, there are issues with the standard clinical trial model, enabling them to deliver new and improved treatments to patients facing a GBM diagnosis. Most GBM patients are usually not expected to remain alive while a single drug is getting tested.  Efforts to bring any one particular new product to the GBM market may last more than 8 years, cost hundreds of millions of dollars per treatment tested, require an enormous amount of devotion and leave us no closer to a cure than when the process had all started.

The Era of Personalized Cancer Vaccines

Vaccines engender a beacon of hope amidst the washout of various drug prospects in achieving clinical endpoints in this tough-to-treat indication. Few companies have established data to prove that vaccines targeted against tumor-specific mutations might be a successful way to leverage the immune system against cancer and that even tumors in the brain might be treatable. It is interesting to note that the emerging market of glioblastoma includes innovative gene therapy. This is accompanied by several promising vaccine and immunotherapy candidates, including VBI-1901, AV-GBM-1, and ITI-1000 (pp65 DC Vaccine), as well as Tasadenoturev (DNX-2401) developed by VBI Vaccines, Aivita Biomedical, Immunomic Therapeutics, and DNAtrix, respectively.

During the recent American Association for Cancer Research (AACR) in April 2021, Immunomic Therapeutics announced its worldwide license and development collaboration agreement with Lineage Cell Therapeutics on the clinical development of a novel VAC product candidate for GBM. Previously the company had published Phase II results of ITI-1000 (pp65 DC vaccine) and remains quite optimistic about its CMV-Specific Dendritic Cell Vaccines. Its optimism is based on its approach of harnessing the body’s immune system to recognize, attack and destroy tumor cells that express CMV, over-expressed in GBM.

Recently, another dendritic cell personalized cancer vaccine, AV-GBM-1, also demonstrated an improvement in PFS in patients with newly diagnosed GBM in its Phase II trial. Aivita Biomedical considers its PFS of 10 months as a significant victory against GBM. However, the company is expected to submit more data from late-phase trials to establish complete efficacy in the future.

Although cancer vaccines are expected to boost the oncology sector and, as a consequence GBM market as well in the coming years, when it comes to GBM, we still need to wait for robust efficacy data in high stage trials improving survival. Also, the difficulty of producing and harvesting enough vaccine cannot be ignored, which will diminish its ultimate availability for clinical usage.

Value Addition by Devices

In addition to these pharmacological interventions, oncologists have started relying on the FDA approved wearable and portable device Optune, which has marked a significant advancement in GBM treatment by adding months and sometimes years to these patients’ lives since its initial approval in 2011. Initially, Optune was approved for patients whose GBM had recurred or progressed after chemotherapy. However, later in 2015, the FDA broadened the approval to newly diagnosed patients too.

Considering that the prognosis of GBM remains poor, with a median survival of about 15 months, there are few patients whose possibility of living beyond 5 years is doubled or tripled with the usage of this device, which is good news for cancer that is difficult to tame. Although GBM’s clinical development has witnessed many stumbling blocks, it has still managed to come a long way.