By Jeffrey Bacha, Chairman, President & CEO of DelMar Pharmaceuticals
Glioblastoma multiforme (GBM), the most common primary brain tumor in adults, afflicts approximately three of every 100,000 people world-wide and accounts for roughly 15,000 new patients every year in the U.S. Currently, the GBM treatment market is in excess of $1 billion in annual sales, which is expected to grow by more than 11 percent between 2014 and 2022  due to rising awareness, research and development in drug delivery technologies, and modern diagnostic techniques. 3
So, what does all of this mean for current GBM patients and the cancer treatment industry going forward? This article will examine the treatments available for GBM patients to date, the challenges associated with developing new potential treatment options, and companies/products to watch in the coming years as advancements continue in the GBM drug discovery space.
GBM Treatments: Drug Discovery Challenges And Current Landscape
There has been a tremendous effort to develop new treatment options for GBM patients over the past few decades in spite of some significant challenges, including:
- Localization of tumors in the brain, wherein most drugs cannot cross the blood brain barrier;
- Inherent resistance to currently available chemotherapy due to resistance mediated by an enzyme called MGMT, which repairs the damage to the tumor caused by the drugs;
- Limited capacity of the brain to repair itself;
- The “infiltrative” nature of the GBM tumor and the migration of malignant cells into adjacent brain tissue;
- The variability of tumor blood supply which inhibits effective drug delivery; and,
- The inherent toxicity and side-effects of many GBM treatments. 
There are currently two classes of chemotherapy that are available to GBM patients today: alkylating agents, such as temozolomide (Temodar/Temodal/Temcad) or nitrosoureas (carmustine/BCNU, lomustine/CCNU) and bevacizumab (Avastin). Temozolomide was approved by the FDA in 2005 and is the standard chemotherapy for newly diagnosed GBM patients. Treatment with temozolomide has shown an increase in survival in some patients, particularly in combination with radiation therapy. Bevacizumab was approved in 2009 for patients whose tumors have recurred following standard radiation and temozolomide; it has not been shown to improve survival.
Upon initial diagnosis, GBM patients are typically treated with a combination of the following
- Surgery – The benefit of this treatment is to “debulk” the tumor, which reduces symptoms and helps prolong life in some patients. However, GBM brain tumors are rarely removed in their entirety because a wide margin of healthy tissue around the tumor would also need to be removed. Therefore, recurrence following surgery alone is nearly 100 percent.
- Chemo and Radiotherapy - Radiation therapy combined with chemotherapy has been shown to prolong GBM patient survival compared to surgery alone. Patients receive radiotherapy and chemotherapy for approximately six weeks and then continue with maintenance chemotherapy. Adjuvant and concomitant temozolomide with radiation was associated with improvements in overall survival (14.6 vs 12.1 months) and the likelihood of being alive in 2 years (26 percent vs 10 percent).
- Maintenance Chemotherapy - The aim of maintenance chemotherapy following radiation is long-term tumor control. But, approximately two thirds of newly diagnosed GBM patients are resistant to chemotherapy due to high levels of a DNA-repair enzyme called MGMT. Clinical trials are underway for a new drug candidate that will be effective independent of MGMT-mediated resistance.
- Bevacizumab – Bevacizumab inhibits blood vessel growth and thereby aims to “starve” the tumor. Positive results were shown in other cancers, but this therapy has not demonstrated a survival improvement in GBM. One benefit is that some GBM patients require reduced doses of steroids when taking bevacizumab, which can have a favorable quality of life impact.
There are also a few investigational therapies that are currently being used by GBM patients, including:
- Immunotherapy & Vaccines – this treatment is designed to boost the body's natural defenses to fight the cancer, which has been a long-standing goal of cancer researchers, and has shown complete responses in some patients for certain types of tumors. This methodology uses materials either made by the body or in a laboratory to improve, target, or restore the patient’s immune system function. Advanced human clinical trials are ongoing with a number of vaccines and immunotherapies and hopes are high that patient benefit will be realized.
In general, immunotherapies and vaccines are used in addition to chemotherapy in the treatment of cancer, not as an alternative. However, in spite of the promises, many challenges remain, such as manufacturing difficulties and costs, the limitations of immunotherapies to autologous cell therapies, and significant side-effects, such as massive uncontrolled inflammatory/immune reactions including death.
- Gene Therapy – This treatment involves the transfer of lethal genes to tumor cells, with early reports indicating the eradication of experimentally implanted brain tumors in rodents. However, the application of this strategy to human gliomas has not resulted in a therapeutic benefit, likely due in part to the low transfection rate of the particular gene within the human tumors.
- Electrotherapy -The FDA recently granted accelerated approval to a device that delivers low-intensity electrical fields to the brain of GBM patients whose tumors recurred following surgery, radiation, and chemotherapy. This device continues to be studied in advanced clinical trials.
The Future Of GBM Treatments: Companies And Drug Candidates To Watch
Recent advances in immunotherapy, gene therapy, and the identification of a novel chemotherapy that is active against GBM independent of MGMT-resistance bears promise in treating GBM. But there are also a number of clinical trials underway that are seeking other means of increasing survival and improving quality of life for GBM patients, including the following:
- Celldex - Rindopepimut vaccine has shown promise in GBM patients with an EGFRv3 mutation. Data presented at ASCO supports a survival benefit in patients with the mutation who have failed standard of care with chemotherapy and radiation when added to Avastin versus Avastin alone. An ongoing clinical trial in newly diagnosed patients is expected to present data in late 2015 or 2016.
- Immunocellular - ICT-107 is an immunotherapy targeting a subset of tumor-related antigens. ICT-107 failed to meet its endpoints in a Phase 3 clinical trial; however, retrospective analysis of the data suggested a survival benefit in patients with low-expression of MGMT in comparison to chemotherapy alone (i.e. where temozolomide works), but no benefit was seen in patients with MGMT-related resistance to chemotherapy. A new Phase 3 clinical trial has been requested by the FDA to further investigate these observations.
- DelMar Pharmaceuticals - VAL-083 is a chemotherapy that targets the tumor’s DNA at a different site compared to temozolomide. In pre-clinical studies VAL-083’s anti-tumor activity has been shown to be independent of MGMT-mediated resistance. In clinical trials, VAL-083 has demonstrated a dose-response trend and clinically meaningful survival benefit in patients who have failed standard of front-line therapy with chemotherapy and radiation and second line therapy with Avastin. Additional data from the Phase 1/2 clinical trial is expected in late 2015. Phase 2/3 clinical trials are expected to commence in 2016.
- Roche - Avastin was approved by the FDA in 2009 for the treatment of GBM patients who have failed standard of front-line therapy with chemotherapy and radiation. The approval was based on an improvement in progression-free survival; however, no survival benefit has been reported. Results of a survival trial in this population are expected in late 2015. Results of two separate Phase 3 clinical trials with Avastin in newly-diagnosed patients result in worsening of symptoms, and Avastin will not be approved for treating newly diagnosed patients.