As has been our custom, we like to provide a recap of the some of the most intriguing news every year that comes out of the Annual Scientific Meeting of the Society for Neuro-Oncology (SNO), the preeminent scientific conference dedicated specifically to brain tumors and brain cancer, which was convened this year on November 20th- 22nd in San Antonio, Texas.
During the multi-day conference, hundreds of presentations and discussions are given, highlighting the latest news and views of the global neuro-oncology field. With so much important information coming out of SNO, NBTS (who also sponsors the conference) sends a number of our staff – including both of our on-staff scientists, CEO, and Chief Research Officer – to take in the news, and help compile a list of some of the most noteworthy developments. Below we share those with you:
Celebrating its 20th year, the Annual Scientific Meeting of the Society for Neuro-Oncology set a record for attendance with more than 2,200 participants from across the field and across the globe. According to SNO, this means the 2015 conference was one of the largest-ever international neuro-oncology meeting.
Standing in stark contrast – and to show how far the field has come – SNO provided a history booklet to attendees with a list of participants at the first-ever SNO organizational meeting (a precursor to the inaugural Annual Scientific Meeting in 1996) in 1995, featuring a total of just 18 attendees! Two of which were NBTS’ founding members Bonnie and Sid Feldman!
Avastin & The Future of Angiogenesis Inhibitors
This year’s “late-breaking abstract” was from a randomized phase III European clinical trial called EORTC 26101, which compared the safety and effectiveness of treating recurrent glioblastoma (GBM) patients with the chemotherapy Lomustine (CCNU) alone against the combination of Avastin (bevacizumab) and Lomustine. We shared a short new release about this study immediately after it was announced.
As per the release, this study failed to show that adding Avastin to Lomustine increases survival for recurrent GBM patients. As Avastin is one of the three current drugs approved to treat GBM patients – yet only conditionally – these results are disappointing, particularly given findings from two other large phase III trials involving Avastin back in 2013.
However, this does not necessarily mean the end of the road for Avastin as a treatment option for GBM patients. The FDA still has to review data that Avastin’s developer – Genentech – submits to the agency for review of its approval status.
Additionally, Avastin is currently being investigated in combination with various other anti-cancer medications as part of a number of ongoing clinical trials. These include a phase II trial called ReACT (which we’ll cover in more detail in the next section), which is using Avastin in combination with an immunotherapy called Rintega (rindopepimut) and is showing some auspicious results.
Finally, a company developing a therapy in the same class of anti-cancer medicines that Avastin falls into – called anti-angiogenic therapies – reported, still very preliminary, but positive results at SNO. VBL Therapeutics presented data showing their lead oncology product VB-111, a first-in-class, targeted, anti-angiogenic gene-therapy agent, demonstrated improved overall survival at 12 months over historical data. These results will need to be confirmed in a randomized, prospectively controlled setting.
Angiogenesis is the process by which a tumor creates its own network of blood vessels to provide an adequate supply of nutrients and oxygen to support its growth. Anti-angiogenic drugs, like Avastin, target specific proteins that researchers have found play a role in angiogenesis and prevent tumors from creating their own blood vessels.
NBTS is closely monitoring the status of Avastin and other anti-angiogenic agents, and will inform the community as we learn more about their future role in treating brain cancer.
ReACT Data Gets Better With Time; Larger Trials Still Needed
If there was one presentation that could be described as the “show-stopper” at this year’s SNO, it was ReACT. As mentioned in the previous section, the data presented from the phase II ReACT immunotherapy study – which compared treating recurrent EGFRvIII-positive GBM patients with Avastin plus placebo control or Avastin plus the experimental immunotherapy Rintega (rindopepimut) – showed encouraging results. Encouraging enough in fact, to receive feature coverage in the Wall Street Journal, Bloomberg, and Forbes.
Data previously presented on Rintega showed a modest survival benefit for patients in the study who received Rintega along with Avastin, versus those who received Avastin alone plus placebo control. However, the newly presented data – which has had more time to mature – also shows that Rintega appears to increase long-term survival significantly (despite still modest overall results).
For example, while median overall survival benefit so far is only a two-month increase (11.3 months vs. 9.3 months), two-year survival rates for the Rintega and Avastin group were 25%, versus 0% for the Avastin-only control group. Dr. David Reardon of Dana-Farber Cancer Institute (and a member of NBTS’ Clinical Trial Endpoints Steering Committee) presented the data and commented that over time the survival curves between the two arms continues to separate and become “even more pronounced.”
Researchers were impressed with the long-term survival rates to date, and the fact that the treatment appeared to be tolerated very well, and even improve other endpoints including a reduction in the need for steroids. The study, however, was small, consisting of only 70 patients. Because of its small size, the FDA has already indicated that a larger randomized study will need to be completed before approval.
Rintega is being developed by Celldex Therapuetics and falls into the ‘vaccine’ category of immunotherapies. Rintega targets the mutant protein called EGFRvIII that is present in about 25% to 30% of glioblastoma cases. The mutation is associated with poor prognosis even compared to other glioblastoma patients.
ReACT is one of two current clinical trials Celldex is running to evaluate Rintega in GBM. The other clinical trial, called ACT IV, is for newly diagnosed EGFRvIII-positive GBM patients.
Note: NBTS provided funding for an early clinical study of Rintega in GBM patients, which provided data supportive of advancing its further clinical evaluation.
Notable Finding Leads to Quick Phase III Trial Launch
At this year’s SNO conference, Dr. John S. Yu (founder of ImmunoCellular Therapeutics) presented data from ImmunoCellular Therapeutics phase II study of ICT-107, an immunotherapeutic agent. While results from the study as a whole were modest, researchers identified one subgroup of patients that appear to respond exceptionally well to the treatment.
Patients with HLA-A2-positive GBMs had “substantial improvements in overall survival,” compared to other patients, according to Dr. Yu. Median overall survival in the HLA-A2-positive group of responders, was 23.1 months compared to 13.7 months in non-responders. Additionally, 60% of HLA-A2–positive patients receiving ICT-107 experienced a significantly increased immune response, compared with 36% of patients in the control group.
Based on these results researchers and ImmunoCellular decided to quickly move to a larger, definitive phase III study on ICT-107 in newly diagnosed HLA-A2-positive GBM patients. The phase III registration trial will enroll more than 400 HLA-A2-positive patients across approximately 120 sites in the US, Canada, and Europe. Patients will be randomized to receive either temozolomide (the current standard of care chemotherapy for newly diagnosed GBM patients) with a control treatment, or temozolomide with ICT-107. The trial hopes to begin enrolling soon.
Like Rintega, ICT-107 falls into the overall “vaccine” category of immunotherapy, but differs in that it is cell-based and uses special dendritic cells prepared from patients’ own blood which are then treated to express antigenic proteins present on glioblastoma tumor cells. The vaccine has been shown to be well tolerated in patients in early studies.
New Immunotherapy Approaches Taking Shape
To date in neuro-oncology, a majority of the immunotherapy candidates that are advancing in clinical study fall into the “vaccine” (like ICT-107 and Rintega) or “oncolytic virus” (like the poliovirus and CMV treatments) categories. At this year’s SNO conference, however, a number of additional and emerging immunotherapeutic approaches for brain tumors were presented. This is critical because, as Dr. Reardon noted during one session, “no single immunotherapeutic agent is going to [be a cure-all] and we need to consider combination approaches.”
“…We Need to Consider Combination Approaches.” – Dr. David Reardon, Dana-Farber Cancer Institute
Immune Checkpoint Inhibitors – In many cancers, tumors protect themselves from the immune system (which would normally destroy invaders and abnormalities in the body) by using molecules known as “immune checkpoints” to block the immune system from recognizing and destroying tumor cells. As such, the class of so-called “immune checkpoint inhibitors” has become an intriguing area of study for cancer immunotherapy experts and researchers, and has seen some progress in other cancers such as lung cancer, kidney cancer, and melanoma. While still very early in their development, a number of companies presented data on their checkpoint inhibitor candidates for treating GBM, demonstrating, thus far, the feasibility of evaluating these further in future clinical trials.
Adoptive Cell Transfer (ACT)/CAR T-Cell Therapy – T-cells are a main component of the human immune system, helping our bodies effectively fight disease. However, many tumors find ways to make themselves ‘invisible’ to T-cells, thus rendering them ineffective at fighting cancer. In recent years, researchers have experimented with a technique called “Adoptive Cell Transfer,” in which a patient’s own T-cells are extracted from their blood and then trained to recognize and kill tumor cells by genetically engineering them to produce special receptors on their surface, called chimeric antigen receptors (CARs). CARs are proteins that allow the T-cells to recognize other specific, corresponding proteins (antigens) on tumor cells. The engineered cells are then infused back into the patient where they multiply, and with guidance from their engineered receptors, recognize and kill cancer cells that harbor the antigen on their surfaces. This is another area that has seen some really positive results in other cancers, particularly blood cancers like leukemia, and is now being explored in early stages for brain tumors. Dr. Carl June, one of the pioneers of this treatment, along with his colleague from Abramson Cancer Center at the University of Pennsylvania, Dr. Donald O’Rourke, presented at this year’s SNO on a pilot study to determine the possible effectiveness of CAR T-cell therapy in patients with EGFRvIII-positive GBM. Dr. O’Rourke, who directs the Human Brain Tumor Tissue Bank at Penn Medicine, showed that in very early findings (the treatment has been applied to only eight patients, and the presentation focused on only five of the eight) the treatment appears to be well-tolerated and shows early signs of therapeutic activity in the patients, making larger studies feasible to move forward with.
Clinical Trials* for Other Gliomas
Most of research above is focused specifically, at this time, on GBM – a grade IV, or high-grade glioma. The reason for the acute focus on GBM is largely attributable to the fact these tumors are the most common and most lethal of malignant brain tumors. In fact, GBMs are so complex and aggressive that many researchers believe that if we can solve GBM, “we can solve any tumor.” In other words, what is learned in GBM studies could also help benefit research on other brain tumor types.
Yet, there were a number of clinical studies presented at this year’s SNO that also looked specifically at other types of high grade gliomas as well as lower-grade gliomas; those that are designated either as grade II or III, such as oligodendrogliomas, astrocytomas, anaplastic astrocytomas, and mixed gliomas.
RTOG 9813 – Dr. Susan Chang (a member of NBTS’ Clinical Trial Endpoints Steering Committee) of the University of California, San Francisco (UCSF) presented results from a phase III study of 196 patients diagnosed with anaplastic astrocytoma, which showed that there is no difference in survival outcomes between a group of patients treated with radiation and temozolomide, and a group treated with radiation and the chemotherapy, nitrosourea. The study also showed that patients better tolerated the radiation and temozolomide combination than radiation and nitrosourea.
CODEL – Dr. Kurt Jaeckle of the Mayo Clinic presented results from a phase III trial of newly diagnosed anaplastic glioma patients with 1p/19q co-deletions, which compared the survival of patients in three different groups: one receiving only radiation, another receiving radiation and temozolomide, and a third receiving temozolomide alone. Patients in the study who received temozolomide only, fared worse than the patients in the other two groups, leading an independent medical committee to recommend closing that arm of the study. Moving forward, 488 newly diagnosed grade III anaplastic glioma patients with a 1p/19q co-deletion will be randomized into one arm receiving radiation and the chemotherapy regimen procarbazine, CCNU, and vincristine (PCV), versus another arm of radiation and temozolomide. The adjusted study is expected to be completed by December 2018.
RTOG 9802 – Dr. Jan Buckner of the Mayo Clinic (and a member of NBTS’ Clinical Trial Endpoints Steering Committee) presented results from a phase III trial of radiation alone versus radiation combined with the chemotherapy regimen of PCV in low-grade gliomas. The results showed that a subgroup of patients – those with IDH1-R132H mutations, which are typically associated with more favorable prognosis – saw marked survival benefits from adding PCV to radiation therapy. Among IDH1 R132H–positive patients, overall survival was superior in patients receiving radiotherapy and PCV (median survival not yet reached at 11.3-plus years), compared to patients receiving radiation alone (10.1 years).
Additionally, Dr. Mitch Berger of UCSF (and a member of NBTS’ Strategic Scientific Advisory Council) gave a presentation providing a strong rationale for aggressive resection policy for low-grade gliomas. This was followed by a discussion led by Dr. Buckner regarding medical management of low-grade glioma patients, including when to begin treatment. Dr. John Costello, also of UCSF (and NBTS’ Scientific Advisory Council), presented on the origins and evolution of low-grade gliomas.
Et cetera, Et cetera, Et cetera
Additional trials, studies, and research that made news from news include the following:
In keeping with the trend of the past couple of years, the two obvious themes of this year’s conference were precision medicine and immunotherapy. While often looked at as two separate therapeutic categories and strategies, it is interesting to note the convergence of the two areas. These overlaps include the use of targeted anti-cancer drugs (i.e. Avastin), typical of precision medicine, which may increase the effectiveness of immunotherapies (Rintega), as well as the need in immune-oncology to still identify tumor-specific markers and the patients expressing the corresponding antigens.
It is also important to note that beyond presentations on results of clinical trials, there was much discussion – playing a big role, in fact, in both keynote speeches from Drs. Don Berry of MD Anderson Cancer Centers and Mark Gilbert of the National Cancer Institute’s Neuro-Oncology Branch (and a member of NBTS’ Endpoints Steering Committee and Medical Advisory Board) – about the need to better conceive, design, and collaborate on clinical trials in the precision medicine era. Dr. Berry spoke in detail about the GBM AGILE trial that NBTS just helped announce, while Dr. Gilbert discussed the need for more collaboration in clinical research to realize precision medicine, including to help recruit for clinical trials which currently enroll only 5% of malignant brain tumor patients, according to Dr. Gilbert. Dr. Gilbert’s remarks were buttressed by observations by Dr. John Sampson of Duke University (a member of NBTS’ Scientific Advisory Council), who reported that 53% of current brain tumor clinical trials are taking place at only one institution, and only 16% of trials are enrolling more than 100 patients, leading to lengthy start-up times for trials and studies that are likely under-powered from a statistical standpoint. Others noted that almost all of the positive trials presented at this year’s conference required multi-institutional involvement to reach the necessary number of patients.
Collaboration is of course a hallmark of NBTS’ approach to funding advances in brain tumor research, including our signature program the Defeat GBM Research Collaborative and our efforts co-leading the Jumpstarting Brain Tumor Drug Development Coalition (whose work on improving imaging in brain tumor research was a theme that cut across SNO this year). And the message from researchers themselves at this year was clear: we have to maintain the focus. We promise we will. To get involved please visit here.
To see a list of award winners at SNO, please visit here.
* If you are a loved one are interested in clinical trials, but sure to ask your doctor about all the options available.