Final efficacy and safety analyses from the phase 3 CheckMate 548 trial of nivolumab
According to final efficacy and safety analyses
of the phase 3 CheckMate 548 study (NCT02667587
) that were presented at the Society for Neuro-Oncology (SNO) 2021 Annual Meeting plenary session in Boston, United States, adding nivolumab to the standard of care radiation and temozolomide does not improve survival among patients with newly diagnosed glioblastoma.
Researchers investigated the safety and efficacy of adding nivolumab – a ‘checkpoint inhibitor’ drug that binds to a protein called PD-1 – to radiotherapy and chemotherapy in patients with newly diagnosed glioblastoma that had methylated or indeterminate MGMT
promoter status. A total of 716 patients were randomized in equal groups to receive either nivolumab or placebo alongside standard care.The primary endpoints were progression-free survival (PFS) and overall survival (OS).
The median progression free survival was 10.6 months in the nivolumab group and 10.3 months in the placebo group. The median overall survival (OS) was 28.9 months in the nivolumab group and 32.1 months in the placebo group. In patients with a >5% PD-L1 expression, the median progression free survival was 8.4 months in the nivolumab group and 9.9 months in the placebo group. Grade 3 to 4 adverse events were noted in 52.4% of treated patients in the nivolumab group compared with 33.6% in the placebo group. Read more (free registration may be required).
Tumor Treating Fields (TTFields) in combination with pembrolizumab and adjuvant temozolomide improves progression free survival in glioblastoma, according to study
In a phase 2 pilot study called “2-THE-TOP
” of 25 patients with newly-diagnosed glioblastoma, researchers found an increase in progression free survival when Tumor Treating Fields (TTFields) were combined with pembrolizumab and adjuvant temozolomide. In those patients with greater than nine months of follow-up, median progression-free survival (which was the primary endpoint), was at least 11.2 months with 24% of the patients having a complete or a partial response. Twelve patients were progression free and 15 were still alive at the time of release of data. The comparison arm was historical data from the EF-14 study in which patients received TTFields and adjuvant temozolomide. The results of the study were presented at the annual Society for Neuro-Oncology (SNO) conference in Boston, USA, this month. Read more
Combination treatment with dabrafenib and trametinib
In a study published in The Lancet Oncology
, investigators found that a combination of two targeted cancer drugs showed “clinically meaningful” activity in patients with glioblastoma that carried a rare genetic mutation. The phase 2 efficacy trial called ROAR (Rare Oncology Agnostic Research) has been open to enrollment since 2014 in 13 countries. The study is a so-called “basket” trial where patients who share a common tumour characteristic (in this case the BRAF v600E mutation) but have different cancers, are enrolled in the same trial.
The researchers combined the two drugs dabrafenib and trametinib, both of which target proteins in the MAPK pathway, a signaling chain of proteins that works by regulating cell growth. The goal of the study is to determine the overall response rate of dabrafenib combined with trametinib in patients with BRAF V600E-mutated cancers. This combination has also been used to treat melanoma, non-small cell lung cancer, and thyroid cancer. The drug combination shrank tumours by >50% in one-third of 45 patients and three patients had complete responses. This study also includes patients with thyroid and biliary tract cancers, gastrointestinal stromal tumours, hairy cell leukemia, multiple myeloma, low- and high-grade glioma brain tumours, amongst others. Read more: here and here.
Major UK study will look at whether cannabis extract-based drug Sativex can extend survival in glioblastoma
A three-year phase 2 trial (“ARISTOCRAT”) will be carried out by researchers at Leeds University in the UK led by professor of clinical oncology and neuro-oncology Dr Susan Short, to determine whether adding Sativex (nabiximols) to standard chemotherapy for recurrent glioblastoma can extend survival.
Sativex is an oral spray containing cannabinoids THC and CBD (which is already licensed and sold by other companies in some markets for neuropathic pain, spasticity, overactive bladder, and other symptoms of multiple sclerosis). Glioblastoma cells have been shown to have receptors to cannabinoids on their cell surface, and lab studies suggest cannabinoid drugs may slow tumour growth.
The Leeds investigators aim to recruit more than 230 patients with glioblastoma at 15 NHS hospitals in the UK from March 2022, who will be treated after evidence of first disease progression following first-line radiotherapy and temozolomide chemotherapy .
The ARISTOCRAT study follows on from the positive results in an earlier trial where Sativex was given in combination with temozolomide in 27 patients. Researchers found that the regimen was well tolerated and showed evidence of improved progression-free survival (PFS) as well as overall survival (OS). Read more.
Researchers at NIH find increased financial toxicity and distress in brain tumour patients during the Covid-19 pandemic
In a study presented at the Annual Meeting of the Society for Neuro-Oncology (SNO) 2021 in Boston, USA, researchers from the Neuro-Oncology Branch (NOB) of National Institutes of Health (NIH) found that during the COVID-19 pandemic, patients with primary brain tumours faced greater ‘financial toxicity’ and distress. It is well known that brain tumour patients have a high symptom burden and functional limitations. The NIH researchers assessed financial toxicity and patient reported outcomes (PROs) from 112 participants in the NOB’s Natural History Study during the period from July 2020 to May 2021. Significantly, the researchers found that up to 56% of patients reported financial hardships due to their brain tumour diagnosis and half of patients reported feeling moderately to extremely anxious or depressed. Racial disparity was prominent among non-whites and Hispanics who reported greater financial burden compared with whites. Furthermore, participants who were unemployed had a worse financial burden than those who were employed. Lastly, worse financial toxicity scores strongly correlated with worse overall symptom burden, in particular anxiety and depression. The authors noted that future studies are needed to assess financial toxicity across time and especially post-pandemic. Read more
Rare CNS tumours as a paradigm to expedite progress in CNS cancers and diseases
A review article published in Neuro-Oncology
details the essential aspects of basic, translational, and clinical research in rare central nervous system (CNS) tumours. The article covers preclinical models, advances in tumour classification and molecular analysis and options for clinical trial design. It also includes incorporation of patient outcome measures in clinical care and clinical trials, and current models of multidisciplinary care in rare tumours of the CNS. Read more
Children’s Brain Tumor Network and genetic research on childhood tumours
The Children’s Brain Tumor Network (CBTN), a multi-institutional brain tumour research programme with funding from the Childhood Cancer Data Initiative of the National Cancer Institute (NCI), USA, is collecting tumour samples from patients at 26 member institutions all over the world. CBTN will procure molecular characterization for thousands of these brain tumour samples to provide an insight into brain cancers so that future therapeutic interventions can be developed.
This programme will support molecular characterization of greater than 3,000 germline samples and more than 1,500 tumour samples across all paediatric brain tumour types that have been collected by CBTN since 2011. Because childhood brain tumours are rare, collaborations like CBTN are crucial in advancing development of treatments. The more data that is available to researchers, the higher is the potential for novel insights leading to breakthroughs in treatment. Read more
Study on nivolumab plus ipilimumab in patients with asymptomatic melanoma brain metastases: CheckMate 204 results announced
The final results of the landmark CheckMate 204 trial were published in TheLancet Oncology
on November 10th. In patients with melanoma that has metastasized to the brain, combination treatment with immune checkpoint inhibitors nivolumab and ipilimumab showed an improved overall survival. About 40% of patients with stage IV melanoma have brain metastases at diagnosis, whereas around 75% of melanoma patients will develop brain metastases at some point during the disease course. Historically, patients with brain metastases have been excluded from clinical trials and hence treatment options for this patient population were not studied. Combination checkpoint inhibitors have changed the landscape of treatment for melanoma with brain metastasis: prior to its introduction, the one-year survival rate for these patients was dismal at about 20%.
According to the study results, the overall survival rate from melanoma brain metastases is around 72% in asymptomatic patients at three years and in those who responded to treatment within 12 weeks, the overall survival was 92%. The overall survival was lower at around 36% in patients with symptomatic brain metastasis but remained durable. The intracranial progression-free survival was noted to be 54.1% at three years in asymptomatic patients and 18.9% in symptomatic patients. The checkpoint combination toxicity was similar to previous trials in advanced melanoma patients without brain metastases. Common treatment-related adverse events noted by the researchers were colitis, diarrhea, pituitary inflammation and elevated liver enzymes. Immune-mediated adverse events were hepatitis, rash and hypothyroidism. Read more (subscription/payment needed for full paper).
Experimental imaging approach using FET-PET in patients with glioblastoma
Researchers in Australia have announced a new trial, FIG
, investigating an experimental imaging approach using FET-PET imaging technology in patients with glioblastoma. MRI plays a central role in diagnosis, radiation planning, and treatments in glioblastoma but can have certain limitations, especially with determining tumour progression. The aim of the FIG study is to accomplish a more accurate assessment of a glioblastoma and its response to treatments with the aim to improve outcomes. The primary goal of the trial is to find whether the imaging modality can provide any additional information to distinguish between treatment related changes (sometimes called ‘pseudoprogression’) and true tumour growth after initial treatment. TROG Cancer Research in Australia will be coordinating the multi-site prospective trial which will enroll up to 210 patients at ten sites.
The technique works by imaging a novel radiotracer (FET) that can detect the metabolic activity of cancer cells. The participants will receive standard of care radiotherapy and temozolomide chemotherapy. The participants will get the FET-PET scans at the time of starting treatments and after completing chemoradiation. In addition, study participants will be followed-up with a quality-of-life questionnaire in their clinical assessment at regular, pre-specified intervals and at the time when the routine FET-PET imaging is performed. Read more
Potential role of oral drug arginine to enhance radiation therapy for brain metastases
A paper has been published in Science Advances
looking at the use of arginine to enhance the effect of radiation treatment in patients with brain metastases. Arginine, also called L-arginine, is an amino acid that is inexpensive and widely available. Arginine is used by the body to produce nitric oxide (NO). The researchers hypothesised that overloading a high-nitric acid (NO) tumour with more NO before radiation treatment could impair the tumour’s ability to repair radiation-induced DNA damage.
The researchers further report that arginine is generally considered safe and has a noticeable blood-brain barrier permeability. The researchers administered arginine to the 31 study participants who had brain metastases prior to standard radiation therapy. They found that only 22 percent of the 32 patients who received a placebo prior to radiotherapy had a complete or a partial response in their brain tumours over the follow-up period of up to four years whereas those patients who received arginine had a 78 percent response over a similar timeframe. The trial was designed as a proof-of-concept that arginine can be used as a radiosensitizer that enhances the effects of radiation treatment. The researchers also highlight that the results of the trial suggest that arginine could be useful more broadly in anticancer therapy. Read more here and here.
Barrow Neurological Institute to evaluate niraparib, a PARP inhibitor, in a Phase 0 clinical trial for patients with glioblastoma
In a collaboration between The Ivy Brain Tumor Center
at Barrow Neurological Institute and the University of California San Francisco (UCSF), United States, niraparib, a PARP inhibitor, will be tested in a Phase 0 clinical trial in partnership with pharmaceutical company GSK. PARP inhibitors are a type of cancer drug. PARP stands for ‘poly adenosine diphosphate-ribose polymerase’, a type of enzyme that helps repair DNA damage in cells. These drugs are a form of targeted therapy. Niraparib is an orally administered, once-daily medication that is FDA-approved for advanced ovarian, fallopian tube, or primary peritoneal cancer. Niraparib has been shown to have a good bioavailability (the ability of a drug or other substance to be absorbed and used by the body) and a strong synergy with temozolomide in preclinical studies.
Enrolment will be open for patients with either a newly diagnosed glioblastoma or recurrent glioma (grades II – IV). The goal of the study, which is expected to recruit 42 participants, is to evaluate the medication’s pharmacokinetics (a drug’s absorption, distribution, metabolism and excretion from the body) and pharmacodynamics (the body’s response to a drug). Read more.
Antiseizure medication levetiracetam use during glioblastoma treatment may be correlated with a higher overall survival rate, study reports
A retrospective study published in Neurology
reported that patients with glioblastoma who used antiseizure medication levetiracetam during treatments with chemotherapy or radiation therapy may have a higher overall survival rate. Seizures are common in brain tumours, ranging from 30% to 60% of patients. These are more common in patients with isocitrate dehydrogenase (IDH) mutant brain tumours than in IDH wild-type brain tumours. The researchers reviewed charts of 460 patients with IDH wild-type from 2010 to 2018. They found that among the patients who were on levetiracetam for the entirety of chemoradiation, median overall survival was 21 months whereas in patients who were on this medication part-time and those not on it, the overall survival was 16.8 months and 16 months, respectively. In conclusion, the researchers claim that only using levetiracetam for the entire duration or part of the chemoradiation was an independent factor in prolonging overall survival and the daily dose did not influence the outcome.
Furthermore, they found that O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and amount of tumour resection (partial or gross total resection) were also independent factors determining overall survival. The authors, however, noted that their study had limitations including the study design, clinical diagnosis of epileptic seizures, missing data for methylation status of MGMT promoter and absence of specifics on levetiracetam use. They also commented that further prospective multicentric controlled trials to investigate survival benefit of antiseizure medications would be required. Read more
Combining repurposed disulfiram and copper shows activity in medulloblastoma
Researchers at Johns Hopkins University School of Medicine, USA, and Italy’s Catholic University of the Sacred Heart School of Medicine have published a study in PLOS One
which describes combining copper ions with disulfiram (DSF) in the treatment of medulloblastoma. The treatment for pediatric medulloblastoma has been surgery, radiation, and chemotherapy used individually or in combination. Disulfiram has traditionally been used to treat chronic alcoholism and has shown promise repurposed as an anti-cancer agent particularly when combined with copper ions [Cu++
Researchers tested the anti-cancer activity of DSF-Cu++
in cell cultures and in mice. The researchers found that DSF-Cu++
is lethal to medulloblastoma cells and also to its precursor stem cells in these cell cultures and mice. They also found that DSF-Cu++
impairs the DNA-repair machinery of medulloblastoma cells. Damage to DNA, if not repaired, promotes apoptosis which is a biological mechanism to remove dysfunctional cells. It also blocks the two common biological pathways that medulloblastoma cancer cells use to remove toxic proteins making them more prone to lethal damage. When tested in mice implanted with medulloblastoma tumours, the combination also showed a significant improvement in survival, according to the researchers. Read more
Study reports new drug combinations identified with activity in highly aggressive childhood DIPG brain tumours
In a pre-clinical study published in Cancer Discovery
, researchers have identified a combination of MEK inhibitor drug trametinib and multi-kinase inhibitor drug, dasatinib that slowed the growth of cancer cells obtained from patients with diffuse intrinsic pontine glioma (DIPG). These two drugs are already approved for treating other cancers. DIPG is a rare pediatric brain cancer which is universally fatal with a majority of patients dying within a year of diagnosis. DIPG tumour cells often develop resistance to targeted therapies. Trametinib alone had little effect in mice experiments however when dasatinib was used in combination with it, there was a slowing of tumour growth in cells resistant to trametinib. The combination will be tested in further animal studies and if it shows promising results, will be tested in clinical trials. Trametinib is approved for use in adults for melanoma skin cancer and non-small cell lung cancer. Dasatinib is used in chronic myeloid leukemia. Read more
Yale School of Public Health researchers awarded US $13 Million to study low grade gliomas
Low grade gliomas (LGGs) are brain tumours that are a challenge to manage because of slow and gradual growth. Researchers at Yale School of Public Health in the United States have been awarded US $13 million to study the biology of these tumours in a large-scale research project. The scientists plan to enroll 500 patients with LGGs and will perform a comprehensive genomic characterization of the tumours and investigate their evolution. The research effort, named “OPTimIzing engageMent in discovery of molecular evolUtion of low grade glioMa, (OPTIMUM)” is funded by the National Cancer Institute (NCI).
The goal of this multi-institutional study is also to learn more about the effect of this diagnosis and its associated treatments on daily life including the ability to work, drive, sleep, exercise, or take care of oneself and/or a family member. The current study will build upon the existing International Low Grade Glioma Registry but focus on people with recurrent low grade glioma to understand how treatment may change the genetic makeup of these tumours. Read more.