Neuro-oncologists seek balance between optimism, realism amid promising immunotherapy data
A brain cancer diagnosis historically has been tantamount to an almost-immediate death sentence.
Only one-third of those diagnosed with brain and other central nervous system cancers survive 5 years, and a review published in June in Annals of Translational Medicine showed survival rates for glioblastoma — the most common and most aggressive malignant brain tumor — essentially remained unchanged in the past 40 years.
Results of several studies released this year, however, suggest reasons for optimism.
Checkpoint inhibitors, novel treatments developed using vaccines and oncolytic viruses, and tumor treating fields — an antimitotic treatment modality delivered by a portable, home-use medical device — have demonstrated considerable efficacy against brain tumors.
In March, the CBS program 60 Minutes featured researchers from Preston Robert Tisch Brain Tumor Center at Duke University Medical Center who showed in a phase 1 trial that a re-engineered poliovirus could attack recurrent glioblastoma.
“This past year, we’ve had more press for primary brain tumors than ever,” Ashley L. Sumrall, MD, medical oncologist at Levine Cancer Institute at Carolinas HealthCare System and a HemOnc Today Editorial Board member, said in an interview. “If nothing else, we’ve had a nice public discussion about brain tumors.”
Still, experts warn celebration may be premature. In the field of neuro-oncology — in which clinically meaningful progress has been limited — there can be a tendency to become overly optimistic about early data.
“As a community, we are used to getting our hopes up, and often, the results of later-phase trials are unfortunately not as promising as we might come to expect,” Sumrall said. “The [poliovirus] trial was portrayed as revolutionary, but we can’t jump to conclusions with phase 1 data. As a result, many patients felt misled by the information presented, which is an issue we are addressing so that we can help ensure that our patients are exposed to the best, most appropriate care that’s out there.”
Although advances in immunotherapies and precision medicine in other oncology subspecialties have prompted researchers to discuss the possibility of cures, neuro-oncologists — although optimistic — must remain cautious.
“We can’t put the cart before the horse,” Sumrall said. “I, along with the entire neuro-oncology community, want the field to move forward and to give patients multiple options, but we’re obligated to be realistic with our patients and to consider how each treatment impacts an individual patient’s journey.”
HemOnc Today spoke with neuro-oncologists about the momentum in their field; whether excitement needs to be tempered; the potential advantages and disadvantages of oncolytic viruses under investigation in the Duke study and others; and the role vaccines and other immunotherapies may play in the treatment of brain cancers.
The potential of immunotherapy for the treatment of many cancer types has triggered tremendous excitement. Even in the field of neuro-oncology — in which survival is still measured in months for tumors like glioblastoma multiforme (GBM) — researchers are hopeful immunotherapy will lead to research breakthroughs.
“There has been mounting interest in immunotherapies as a treatment for glioblastoma,” Clark Chen, MD, PhD, chief of stereotactic and radiosurgery, director of medical education and assistant professor in the division of neurosurgery at University of California, San Diego, told HemOnc Today. “This interest is largely driven by published results demonstrating startling efficacies against melanoma, as well as promising preliminary results. We are seeing long-term survivorship in those who had melanoma spread throughout their body — patients for whom we would have expected death within 3 months prior to the availability of immunotherapy.”
Immunotherapies may benefit patients with brain tumors because these tumors have dense concentrations of tumor-infiltrating lymphocytes, which create an immuno-active environment. Further, GBM and other brain cancers frequently have high PD-L1 expression, a target of immunotherapies to help activate the immune system.
Novel treatments for GBM — arguably the most difficult target in cancer — often demonstrate great early promise that is unsustained in later-stage studies, experts said. Still, finding an agent that extends survival even by a few months is considered a breakthrough in this setting, and researchers hope immunotherapies will further extend the survival benefit.
“For glioblastoma patients, median survival of 2 years has been noted for select patients who underwent immunotherapy,” Chen said. “If median survival surpasses 2 years and these results are recapitulated in a randomized control study setting, the landscape of glioblastoma therapy will forever be changed.”
Much of this excitement has stemmed from the efficacy of nivolumab (Opdivo, Bristol-Myers Squibb) and other checkpoint inhibitors that provoke an anticancer immune system response beyond that achieved by traditional chemotherapeutic or radiotherapeutic methods.
Researchers of a currently recruiting NCI-sponsored trial (NCT02311920) seek to evaluate the combination of temozolomide (Temodar, Merck) with nivolumab and/or ipilimumab (Yervoy, Bristol-Myers Squibb) in patients with newly diagnosed GBM or gliosarcoma. The first set of results are expected in May.
Further, Bristol-Myers Squibb is sponsoring the CheckMate 143 trial (NCT02017717) to evaluate the safety and efficacy of nivolumab vs. bevacizumab (Avastin, Genentech) in patients with recurrent GBM, as well as nivolumab with or without ipilimumab in patients at various stages of treatment. However, final data collection is not expected until June 2017.
Additional trials are planned or ongoing involving pembrolizumab (Keytruda, Merck) and other checkpoint inhibitors.
Still, the results thus far have not been comparable to those seen in other tumor types, Roger Stupp, MD, professor and chairman of the department of oncology and director of University Hospital Cancer Center at University of Zurich in Switzerland, told HemOnc Today.
“Nivolumab and other checkpoint inhibitors are promising agents in some solid tumors like melanoma and lung cancer, but it is quite disappointing in others,” Stupp said. “For primary brain tumors, the preliminary experience of nivolumab does not appear overwhelming; however, the formal results of the initial studies have not yet been presented.”
An investigational combination of nivolumab, ipilimumab and radiation also is attracting attention, Stupp said.
“Lower-than-usual doses may provide a sufficient antitumor effect without substantial toxicity,” he said. “Nevertheless, this combination is also potentially toxic and dangerous, and should not be applied outside clinical trials.”
Many clinicians with whom HemOnc Today spoke agreed identifying the ideal doses to yield the greatest benefit with least harm is a critical step to unlocking the potential of immunotherapy for neuro-oncology.
“There are definitely challenges in treating brain tumors with immune checkpoint inhibitors, but there is tremendous potential for combination therapies — it is so obvious that it is almost embarrassing to state — and we are pursuing them,” Matthias Gromeier, MD, associate professor of surgery, medicine, and molecular genetics and microbiology in the department of neurosurgery at the Preston Robert Tisch Brain Tumor Center at Duke University, told HemOnc Today. “Any type of cancer immunotherapy that elicits effective responses may benefit from those combinations, so I see a lot of potential there.”
Polio to fight cancer
Gromeier is the principal investigator of the Duke trial evaluating the poliovirus for GBM that was featured on 60 Minutes in March. With the release of their data, Gromeier and colleagues sparked optimism within the neuro-oncology community, as well as the general public.
Duke researchers evaluated a genetically engineered poliovirus (PVS-RIPO) in which the disease-causing ability of the polio was removed by splicing a rhinovirus into its genome. PVS-RIPO is then infused directly into the GBM tumor, where it infects and kills tumor cells while also activating the immune system.
Although 11 of the 22 patients enrolled in the trial had died by the time the show aired, a few patients experienced never-before-seen outcomes. Survival appeared well beyond that of any previous dataset.
“Those patients portrayed continue to do exceptionally well and have complete clinical and radiographic responses, which is remarkable because these patients are now at 40 months,” Gromeier said. “We have learned a great deal about how to institute this therapy and how to manage toxicity, and we have arrived at what is probably an optimal use of this agent as far as we can understand it. We are very optimistic.”
Further studies to evaluate PVS-RIPO for adults and children with GBM are in development, Gromeier said.
Still, others caution the current results were part of a phase 1 trial, and it may be too early to make definitive assessments of the novel therapy.
“In my opinion, the 60 Minutes depiction was a little too rosy,” Sumrall said. “There were some messages that were portrayed in a very unclear way. The problem is, every patient with glioblastoma now wants to discuss that treatment.”
When the data were first presented at the Society for Neuro-Oncology Meeting in 2014 in Miami, “there wasn’t a sense of overwhelming enthusiasm because it looked very much like other phase 1 trials that we’ve seen before and we, as a community, are used to getting our hopes up,” Sumrall added. “Then, when it moves to a later-phase trial, our hopes are dashed.”
Stupp expressed a similar opinion.
“It is possibly a great idea, and [the researchers] have shown great persistence to pursue this approach all the way to clinical trials,” Stupp said. “But the news is not yet ready for prime time. This is an ongoing phase 1 study, and one does not normally report on ongoing, phase 1 studies.”
Despite these criticisms, Gromeier stands behind his team’s research and approach and believes they have followed an appropriate protocol.
“We are pursuing this very cautiously and in a very measured and responsible way,” Gromeier said. “We are considering extending this to other indications, but only after a very substantial preclinical effort to provide a substantial empirical rationale.”
The current approach in GBM is the product of 20 years’ worth of effort, Gromeier added.
“We are maintaining a very careful strategy going forward,” he said. “It is very legitimate to present these kinds of responses that were shown in the piece because they are unusual in the type of disease we are targeting, and it was made perfectly clear where we stood in our clinical investigations, including where the problems were. I don’t think we were irresponsible in any way.”
An alternate virus approach
Poliovirus, however, is not the only genetically engineered virus under evaluation for the treatment of cancer, and specifically GBM. In fact, studying viruses in this manner dates back nearly 100 years.
Toca 511 & Toca FC (Tocagen Inc.) — an investigational combination treatment that received FDA orphan drug designation in August — is being tested in the treatment of GBM. Toca 511 is a retroviral replicating vector that selectively delivers a gene for cytosine deaminase to the tumor. Toca FC is a novel formulation of the antifungal drug flucytosine, which is converted into anticancer drug 5-FU within infected cancer cells.
“The premise of this approach is that you are selectively targeting the tumor cells and sparing the normal cells,” Manmeet Ahluwalia, MD, FACP, director of the brain metastasis research program and associate director of clinical trials and operations of the Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center of the Neurological Institute at Cleveland Clinic, as well as a HemOnc Today Editorial Board member, said in an interview.
Toca 511 is given to patients as a one-time injection directly into the tumor or in the wall of the resection cavity during surgery.
This novel therapy provides a reminder that there may be many strategies to treat brain tumors with immunotherapeutic approaches, Chen said.
“Toca-511, a virus used for gene-therapy against glioblastoma, has been shown to induce an immune response against glioblastoma cells,” Chen said. “Similar effects have been reported for standard chemotherapy, such as temozolomide, the standard-of-care therapy for glioblastoma.”
Potential synergistic combinations of those treatments and immunotherapies may warrant investigation, Chen said.
“It is important to note that there are many ways that we can capitalize on the innate immune system of our patient population,” Chen said. “Although drugs that modulate the immune response have demonstrated tremendous potential, we, as a research community, should not lose sight of other means of modulating the immune system.”
Vaccines and other treatment options
The armamentarium for neuro-oncologists is expanding to include a variety of treatment approaches.
Stupp — principal investigator for Novocure’s tumor treating fields trials — believes the concept of loco-regional treatment in which patients use insulated transducer arrays placed directly on the skin in the region surrounding the tumor offers tremendous promise. The therapy creates an alternating electric field within the tumor that attracts and repels charged components of the cells during mitosis, thus disrupting cell division.
Stupp said the premise is often mocked by peers in the field, but phase 3 data show the addition of tumor treating fields to temozolomide significantly prolonged PFS and OS in patients with newly diagnosed glioblastoma.
Data presented at this year’s ASCO Annual Meeting showed patients who received the combination achieved a median PFS of 7.1 months — calculated from time of randomization — whereas patients who received temozolomide alone achieved a median PFS of 4.2 months (HR = 0.69; 95% CI 0.55-0.86). The addition of tumor treating fields also conferred improvements in the 2-year survival rate (43% vs. 29%) and median OS (19.4 months vs 16.6 months; HR = 0.75; 0.59-0.95).
Gromeier called the treatment “scientifically dubious,” whereas Sumrall, who acknowledged she initially was skeptical, said she “had to eat crow” after seeing the data.
Vaccines — another immunotherapy approach under investigation in neuro-oncology — also have their share of supporters and detractors.
Dendritic cell vaccines present foreign antigens to the immune system, which generates an immune response. However, these vaccines require patients undergo surgery, and their manufacture is a high-cost, labor-intensive procedure.
The ICT-107 (ImmunoCellular Therapeutics) vaccine — which targets six antigens associated with glioblastoma — was the first dendritic cell immunotherapeutic vaccine to yield a positive effect on clinical outcome. Results of a phase 2 trial — presented by Patrick Y. Wen, MD, director of the center for neuro-oncology at Dana-Farber Cancer Institute and professor of neurology at Harvard Medical School, and colleagues at the 2014 ASCO Annual Meeting — showed ICT-107 significantly improved median PFS by 15.6 months (24.1 vs. 8.5; HR=0.25; P = .005) compared with a matched control vaccine in a subset of per-protocol patients with HLA-A2–positive disease and methylated MGMT. The treatment also improved PFS and OS in HLA-A2–positive patients with unmethylated MGMT, but this association did not reach statistical significance.
“Standard-of-care chemotherapy, temozolomide, has little or no treatment benefit for newly diagnosed GBM patients with unmethylated MGMT, which is the majority of patients,” Wen said in a press release. “ICT-107 has shown the potential to meaningfully extend both OS and PFS without significant side effects in this patient population which has the poorest prognosis for survival. ... As the methylated MGMT group is followed further, I am optimistic that the already very large increase in PFS for treated patients ultimately may translate into a survival benefit.”
SurVaxM (MimiVax) — a synthetic long peptide mimic vaccine — is another vaccine under evaluation for brain tumors. The vaccine targets survivin, a protein for cell survival that is present in many types of cancers.
“Survivin is an intracellular protein that regulates cell division and has also been shown to inhibit apoptosis,” said Ahluwalia, who is leading a trial evaluating SurVaxM plus temozolomide in patients with newly diagnosed GBM. “High-level survivin expression is associated with a poor prognosis, and survivin expression in tumors is also associated with a high rate of disease recurrence and resistance to therapy.”
The research of SurVaxM in newly diagnosed GBM has progressed to a phase 2 trial. A phase 1 study demonstrated safety and preliminary efficacy in patients with recurrent malignant glioma, Ahluwalia said.
However, Stupp questioned whether a vaccine-based approach is viable in this setting based on the design of these clinical trials.
“[The dendritic cell vaccine] has been out for more than a decade; however, for some reason, the promoters were hoping that they could get away without performing an adequate trial,” Stupp said. “Finally, a randomized trial has been initiated that will hopefully answer the question on the value of this approach — [something] that should have been done many years ago.
“[The SurVaxM trial] will be very difficult to draw a conclusion from because it was a phase 2, non-controlled study, so similar to many non-conclusive trials presented at ASCO this year. So, these are likely to be 4 lost years, even if the results are ‘promising,’ because we still need another large and comparative trial.”
It also may be difficult to achieve outcomes with vaccines in the real-world setting that are comparable to those achieved on clinical trials, Gromeier said.
“Dendritic cells have very difficult protocols because they are very expensive, cumbersome and difficult to administer,” he said. “You may see responses in phase 1 trials that later on are not replicable because the technologies are too complicated and too involved. I don’t think we can dismiss [these vaccine approaches] entirely, but I think we have better options that are available and we need to pursue them.”
Still, the research continues. Despite the controversies that surround each treatment modality, the goal is the same — to improve outcomes for patients with brain tumors, Chen said.
“What we learned from studies performed over the past 40 years is that glioblastoma is an extraordinarily complex disease,” he said. “I believe that meaningful impact against this disease will require an integration of multiple types of therapies, targeting distinct aspects of the tumor physiology.
“Although the field of glioblastoma immunotherapy remains in its infancy, there is no doubt in my mind that it will play key roles in our quest to combat this horrendous disease.” – by Anthony SanFilippo
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For more information:
Manmeet Ahluwalia, MD, FACP, can be reached at email@example.com.
Clark Chen, MD, PhD, can be reached at firstname.lastname@example.org.
Matthias Gromeier, MD, can be reached at email@example.com.
Roger Stupp, MD, can be reached at firstname.lastname@example.org.
Ashley L. Sumrall, MD, can be reached at email@example.com.
Disclosure: Gromeier reports ownership in intellectual property related to the poliovirus study. Stupp reports an unpaid consultant/advisory role with, as well as travel expenses and accommodations from Novocure. Ahluwalia, Chen and Sumrall report no relevant financial disclosures.
Are tumor-treating fields a viable treatment option for brain tumors?
Electric fields — utilized in medicine for many decades — can exert varying biological effects depending on the frequency. Frequencies between 100 kHz and 300 kHz have been identified to specifically disrupt the process of mitosis and have been shown to inhibit growth of cancer cell lines in vitro and various solid tumors in vivo. This technology has been applied in the clinical setting in the form of tumor treating fields (TTFs).
TTFs are administered via a system of treatment arrays placed on the patient’s body. The first such system was tested in brain tumors and specifically in glioblastoma (GBM). Studies in both recurrent and newly diagnosed patients with GBM showed that this treatment can improve survival with minimal toxicity.
Since the FDA approved TTF technology for recurrent GBM in 2011, several hundred patients received the treatment by prescription.
Although the treatment is chronic and requires almost continuous use — a minimum of 18 hours a day — to be effective, it does not cause side effects typically seen with chemotherapy or radiotherapy. Patients do not experience hematologic toxicity, nausea, vomiting, loss of appetite or cognitive difficulties.
The initial clinical trial that ultimately led to FDA approval for recurrent GBM showed that this new form of antimitotic therapy provides similar PFS and OS as available chemotherapies typically used in this clinical setting. However, patients treated with TTF experienced less toxicity and had overall better quality of life — despite the chronic nature of TTF therapy and the necessary headgear associated with it.
An analysis of the large database of all TTF prescription-treated patients showed certain factors improved outcomes. Researchers observed longer survival in patients treated earlier (1st progression vs. 2nd and subsequent progressions), patients with high Karnofsky performance status, and those with treatment compliance exceeding 75%.
This treatment modality that could be considered the first “wearable” cancer therapy may not be easily accepted by every patient. Although motivated individuals who have good support system at home usually accept TTF more readily, patients with neurological deficits or without adequate social support might experience difficulties. In either case, the manufacturer of TTF device — recently named Optune — developed excellent patient-support systems.
New data are emerging for combined therapy using TTF with temozolomide chemotherapy for patients with newly diagnosed GBM. Both interim and full dataset analyses from the EF-14 study (n = 700) confirmed a significant 3-month survival benefit with combined therapy. The PFS also appeared superior in TTF-treated patients (7.1 vs. 4.2 months). The side-effect profile was very favorable with no new unexpected adverse effects reported.
Based on these robust phase 3 randomized trial results, the FDA granted approval for the use of Optune in combination with temozolomide for patients with newly diagnosed GBM. This is the second paradigm shift in neuro-oncology in the last 10 years — the first being the addition of temozolomide to radiotherapy as the standard of care in 2005.
TTFs are being tested in other types of primary brain tumors and brain metastases. They are a viable treatment option for many patients with recurrent GBM — especially when other treatment modalities are contraindicated, poorly tolerated or simply ineffective — and will play an important role in treating patients with brain malignancies in the years to come.
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Maciej M. Mrugala, MD, PhD, MPH, is associate professor of neurology, neurological surgery and medicine; the Alexander M. Spence endowed chair in neuro-oncology and chief of the division of neuro-oncology at University of Washington School of Medicine. He can be reached at firstname.lastname@example.org. Disclosure: Mrugala reports consultant/advisory roles with Novocure, Prime Oncology and Sigma-Tau Pharmaceuticals.
Ultimately, tumor treating fields may be counterproductive toward important research against invasive brain cancer.
Although there is, admittedly, some benefit to tumor treating fields (TTFs), the therapy may not work for invasive gliomas. When you evaluate the invasive components of the tumors, the cells are not actively dividing, so devices such as TTFs that inhibit cell proliferation may not work. TTFs may be beneficial by inhibiting cell proliferation, but the question is, by promoting tumor invasion, are we changing the biology of the tumor? This issue needs to be studied further.
The same effect occurred with bevacizumab (Avastin, Genentech). We saw that tumors did shrink and patients did benefit, but then late-stage clinical trials failed because somehow the biology of the tumor changes with treatment and some become even more invasive. With TTFs, we may find out a few years from now that, yes, patients do benefit marginally — after all, it’s not curative — but what happens if the cells do not divide? What are we doing about invasion — are we promoting the tumor cells to become more invasive?
I still have some biases against TTFs. It is OK that we are using it right now because it helps some patients, but I suspect using this treatment may prevent us from finding treatments that are going to be more effective.
We may be dealing with tumors that are even more aggressive, and having this device on the head may complicate the design of upcoming clinical studies. How do we incorporate the fields into other treatments? How do they affect immunotherapies? How do they affect immune response? Do TTFs also kill antitumor immune cells such as T cells or natural killer cells?
There is some benefit to this therapy, but I do not think it is a long-term solution and it will complicate some future developments. In upcoming phase 3 trials that are being developed, we do not know how we can incorporate TTFs into trial design, nor how they will affect other treatment. Further, for something that only has a marginal benefit, it is not viable as a long-term option if it is going to impede the process of developing newer, better treatments for this disease in the future.
Behnam Badie, MD, FACS, is vice chair of and professor in the department of surgery, chief of the division of neurosurgery, and director of the brain tumor program at City of Hope in Duarte, California. He can be reached at City of Hope, 1500 Duarte Road, Duarte, CA 91010. Disclosure: Badie reports no relevant financial disclosures.