An investigational vaccine has significantly extended survival in patients with newly diagnosed as well as recurrent glioblastoma, according to new findings from a phase 3 trial (NCT00045968).
“Immunotherapy is a very promising approach for treating cancer, and the final results of this phase 3 trial, now unblinded and published, offer fresh hope to patients battling with glioblastoma,” commented Keyoumars Ashkan, MB BCh, MD, a professor of neurosurgery at King’s College Hospital, London, UK, and European Chief Investigator of the clinical trial.
This is the first time in nearly 20 years that a phase 3 trial of a systemic treatment has been able to prolong survival to this extent in newly diagnosed disease, and the first time in nearly 30 years that a phase 3 trial of any type of treatment has shown such survival extension in recurrent disease, say the authors.
The product is an autologous tumor lysate-loaded dendritic cell vaccine (DCVax-L) under development by Northwest Biotherapeutics.
The results come from an analysis of 331 patients, with 232 randomly assigned to receive the DCVax-L plus standard of care (temozolomide) and 99 to standard of care and placebo.
Patients with a new glioblastoma diagnosis (nGBM) who received the vaccine survived 19.3 months on average from randomization (22.4 months from surgery), compared with 16.5 months for the control group (hazard ratio (HR), 0.80, P =.002).
Patients with recurrent glioblastoma (rGBM) who were treated with the vaccine survived an average of 13.2 months vs 7.8 months for the control group (HR, 0.58, P < .001).
“The vaccine was shown to prolong life, and interestingly so in patients traditionally considered to have poorer prognosis,” Ashkan commented. “For example, we see clear benefits in the older patient groups as well as in those patients in whom radical surgery was not possible for technical or other reasons,” he added in a statement.
The study was published online November 17 in JAMA Oncology.
Glioblastoma remains a highly lethal brain cancer with a nearly 100% recurrence rate and poor prognosis, the study authors write. The current standard of care for nGBM patients includes surgery, radiotherapy, and chemotherapy, but tumors typically recur in 6-8 months following resection. The median overall survival is about 15-17 months, while 5-year survival is generally less than 5%. There is no standard of care for recurrent disease, they note.
Study Design
The mechanism of action of experimental vaccine centers around the dendritic cell, explained lead author Linda M. Liau, MD, PhD, chair of the Department of Neurosurgery at the University of California, Los Angeles. The concept is taking the patient’s own autologous dendritic cells and pulsing them with antigens, which in this case are taken from the patient’s own tumor tissue, as she explained in a JAMA podcast.
“This is a way to make these non-immunogenic tumors immunogenic,” she said. “This is individualized or personalized immunotherapy as we are using the patient’s own tumor tissue.”
All patients participating in this trial underwent surgical resection, recovery, leukapheresis, and received 6 weeks of postoperative radiochemotherapy prior to enrollment. The median time from surgery to randomization was 3.1 months, and following tumor recurrence, 64 of the 99 patients in the placebo group crossed over to receive DCVax-L. As the crossover depleted the standard of care group, overall survival was assessed by comparison to external control populations (ECPs).
The ECP for the primary endpoint of overall survival included 1366 patients with nGBM who had received standard of care treatment in the control groups of five comparator randomized controlled trials (RCTs). For the secondary endpoint, ECPs comprised 64 patients with rGBM at first recurrence treated with either standard of care or best supportive care or placebo in the control groups of 10 comparator RCTs.
Survival Extended in All Groups
For the primary endpoint of overall survival, there was a 20% relative reduction in risk of death for patients with nGBM who received the DCVax-L, and this benefit increased over time: 15.7% DCVax-L patients vs 9.9% of ECP patients were alive at 48 months and at 60 months, 13% vs 5.7%.
The authors also conducted 6 prespecified subgroup analyses, and those receiving the vaccine had hazard ratios less than 1 in all subgroups, and the difference was statistically significant for 4 of the 6 subgroups.
Among patients with methylated MGMT, median overall survival was 30.2 months for those who received the DCVax-L vs 21.3 months for the ECPs (HR, 0.74; P = .03).
Liau noted that median overall survival in the methylated MGMT group was almost 3 years. “This is very interesting as many immunotherapy trials — such as those with checkpoint inhibitors in glioblastoma — have removed this group from the study,” she said. “It was felt that they were responsive to chemotherapy so we should be testing immunotherapy in the unmethylated group. But our trial showed that the added survival benefit could be quite profound among these patients, although further study is needed.”
For the secondary outcome, patients with rGBM who received DCVax-L after recurrence achieved a 42% relative reduction in risk of death at any point in time. The survival benefit continued over time, similar to nGBM patients: 20.7% vs 9.6% were alive at 24 months after recurrence, and 11.1% vs 5.1% were alive at 30 months.
The DCVax-L was well tolerated, note the authors, with only five serious adverse events reported: three cases of intracranial edema (two at grade 3; one at grade 2), one case of nausea (grade 3), and one case of lymph node infection (grade 3). No evidence of any autoimmune reactions or cytokine storm was observed.
“The results of our trial will allow for further study in the immuno-oncology space,” said Liau. “The reality is that we don’t have enough treatments for our patients, and different groups will respond to different treatments.”
Weighing In
Two experts not involved in the trial were approached by Medscape Medical News for an independent comment.
“The data is compelling and I am a strong advocate for stimulating the body’s own immune system to treat these tumors,” said Joseph C. Landolfi, DO, CPE, Division Chief, Neuro-Oncology and Radiosurgery at Hackensack Meridian Health JFK University Medical Center, Edison, New Jersey. “Any significant improvement in survival for this patient population is a benefit as for some it means being present for significant life events [like] weddings, births, etc.”
Overall, it’s a good study, he said. “This will be another treatment option for those patients who have a newly diagnosed or recurrent glioblastoma should it obtain approval,” he added.
However, Jonathan Lischalk, MD, a radiation oncologist at NYU Langone’s Perlmutter Cancer Center and assistant professor of radiation oncology at NYU Long Island School of Medicine, New York City, was cautious in reacting to the results.
Although the authors utilized a sound primary endpoint, a major criticism of this trial is its externally controlled cohort due to extensive crossover of the control group, he commented. “This certainly makes interpretation of the results more challenging relative to a standard randomized control trial,” he said. “Given that benefits of treatment are measured on the order of months, any biases reflected in the external control group could result in problematic interpretation of the data.”
He also pointed out another issue: this trial was initiated in 2007 and it underwent a 3-year hiatus, and in the meantime there have been a “number of changes in our understanding of glioblastoma multiforme [GBM] and its management.”
“For example, the WHO classification of glioblastoma now reflects prespecified molecular markers including IDH [isocitrate dehydrogenase], though it is unclear from the manuscript how this was handled by the investigators,” said Lischalk.
“In addition, the only landmark GBM trial during this timeframe, published by Stupp et al in 2017, changed standard of care for primary GBM to include tumor-treating fields. This device was only utilized in eight patients within this trial, so it is unclear how these two methods of treatment interact,” he commented.
Despite these concerns, Lischalk emphasized that this trial explores a very novel method of drug therapy for a cancer that continues to pose momentous challenges for patients and oncologists.
“More research is required to explore the resulting immunogenicity from such a vaccine and how it interacts with newer forms of GBM treatment, including tumor-treating fields while stratifying for modern molecular markers,” he said.
“Although the cohort with recurrent GBM in this trial was relatively small, the survival improvement was pronounced, and given the lack of clear standard of care in the recurrent setting, this vaccine may be a good option and should be explored by regulators,” Lischalk added.
However, given the limitations of the trial, and particularly the lack of randomization and internal control, “I do not think a change in standard of care in the upfront setting is warranted at this time,” he said.
This study was supported by Northwest Biotherapeutics, Inc.
Liau reported serving on the board of directors of ClearPoint Neuro outside the submitted work and having a patent pending for combinations of inhibitors with dendric cell vaccines to treat cancer; other co-authors report relationships with industry. The full list can be found with the original article.
JAMA Oncol. Published online November 17, 2022. Full text
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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