In The Lancet Oncology, Patrick Y Wen and colleagues present interim results from the Rare Oncology Agnostic Research (ROAR) study,1 an ongoing phase 2, open-label, single-arm, multicentre basket ...trial of targeted therapies in BRAF-mutant cancers, showing positive results for dabrafenib plus trametinib in patients with high-grade glioma and low-grade glioma. Durable radiographic response rates were seen not only in the low-grade glioma population (nine 69%; 95% CI 39–91 of 13 patients), but also in the high-grade glioma population (15 33%; 95% CI 20–49 of 45 patients), with most of those patients having histology consistent with glioblastoma (WHO grade 4). ...median overall survival in the high-grade glioma patients was 17·6 months (95% CI 9·5–45·2), with a median overall survival of 13·7 months (8·4–25·6) when one considers only the 31 patients with glioblastoma. Next-generation sequencing of the tumour tissue is now needed to aid in diagnosing, prognosticating, and guiding therapeutic options. ...genetic information must now be included in the inclusion and exclusion criteria to appropriately design and implement clinical trials.
Lower grade gliomas (LGGs) are malignant brain tumors. Current therapy is associated with short- and long-term toxicity. Progression to higher tumor grade is associated with contrast enhancement on ...MRI. The majority of LGGs harbor mutations in the genes encoding isocitrate dehydrogenase 1 or 2 (
). Vorasidenib (AG-881) is a first-in-class, brain-penetrant, dual inhibitor of the mutant IDH1 and mutant IDH2 enzymes.
We conducted a multicenter, open-label, phase I, dose-escalation study of vorasidenib in 93 patients with mutant
(m
) solid tumors, including 52 patients with glioma that had recurred or progressed following standard therapy. Vorasidenib was administered orally, once daily, in 28-day cycles until progression or unacceptable toxicity. Enrollment is complete; this trial is registered with ClinicalTrials.gov, NCT02481154.
Vorasidenib showed a favorable safety profile in the glioma cohort. Dose-limiting toxicities of elevated transaminases occurred at doses ≥100 mg and were reversible. The protocol-defined objective response rate per Response Assessment in Neuro-Oncology criteria for LGG in patients with nonenhancing glioma was 18% (one partial response, three minor responses). The median progression-free survival was 36.8 months 95% confidence interval (CI), 11.2-40.8 for patients with nonenhancing glioma and 3.6 months (95% CI, 1.8-6.5) for patients with enhancing glioma. Exploratory evaluation of tumor volumes in patients with nonenhancing glioma showed sustained tumor shrinkage in multiple patients.
Vorasidenib was well tolerated and showed preliminary antitumor activity in patients with recurrent or progressive nonenhancing m
LGG.
A replication-defective poliovirus was injected directly into recurrent glioblastoma tumors, and dexamethasone and bevacizumab were used to control edema. A total of 20% of the treated patients have ...survived beyond 3 years.
Cancer care disparities among rural populations are increasingly documented and may be worsening, likely because of the impact of rurality on access to state-of-the-art cancer prevention, diagnosis, ...and treatment services, as well as higher rates of risk factors such as smoking and obesity. In 2018, the American Society of Clinical Oncology undertook an initiative to understand and address factors contributing to rural cancer care disparities. A key pillar of this initiative was to identify knowledge gaps and promote the research needed to understand the magnitude of difference in outcomes in rural vs nonrural settings, the drivers of those differences, and interventions to address them. The purpose of this review is to describe continued knowledge gaps and areas of priority research to address them. We conducted a comprehensive literature review by searching the PubMed (Medline), Embase, Web of Science, and Cochrane Library databases for studies published in English between 1971 and 2021 and restricted to primary reports from populations in the United States and abstracted data to synthesize current evidence and identify continued gaps in knowledge. Our review identified continuing gaps in the literature regarding the underlying causes of rural-urban disparities in cancer outcomes. Rapid advances in cancer care will worsen existing disparities in outcomes for rural patients without directed effort to understand and address barriers to high-quality care in these areas. Research should be prioritized to address ongoing knowledge gaps about the drivers of rurality-based disparities and preventative and corrective interventions.
Several immunotherapy clinical trials in recurrent glioblastoma have reported long-term survival benefits in 10-20% of patients. Here we perform genomic analysis of tumor tissue from recurrent WHO ...grade IV glioblastoma patients acquired prior to immunotherapy intervention. We report that very low tumor mutation burden is associated with longer survival after recombinant polio virotherapy or after immune checkpoint blockade in recurrent glioblastoma patients. A relationship between tumor mutation burden and survival is not observed in cohorts of immunotherapy naïve newly diagnosed or recurrent glioblastoma patients. Transcriptomic analyses reveal an inverse relationship between tumor mutation burden and enrichment of inflammatory gene signatures in cohorts of recurrent, but not newly diagnosed glioblastoma tumors, implying that a relationship between tumor mutation burden and tumor-intrinsic inflammation evolves upon recurrence.
Purpose
Brain tumours are associated with neurocognitive impairments that are important for safe driving. Driving is vital to maintaining patient autonomy, despite this there is limited research on ...driving capacity amongst patients with brain tumours. The purpose of this review is to examine MVC risk in patients with brain tumours to inform development of clearer driving guidelines.
Methods
A systematic review was performed using Medline and EMBASE. Observational studies were included. The outcome of interest was MVC or measured risk of MVC in patients with benign or malignant brain tumours. Descriptive analysis and synthesis without meta-analysis were used to summarise findings. A narrative review of driving guidelines from Australia, United Kingdom and Canada was completed.
Results
Three studies were included in this review. One cohort study, one cross-sectional study and one case–control study were included (19,135 participants) across United States and Finland. One study evaluated the incidence of MVC in brain tumour patients, revealing no difference in MVC rates. Two studies measured MVC risk using driving simulation and cognitive testing. Patients found at higher risk of MVC had greater degrees of memory and visual attention impairments. However, predictive patient and tumour characteristics of MVC risk were heterogeneous across studies. Overall, driving guidelines had clear recommendations on selected conditions like seizures but were vague surrounding neurocognitive deficits.
Conclusion
Limited data exists regarding driving behaviour and MVC incidence in brain tumour patients. Existing guidelines inadequately address neurocognitive complexities in this group. Future studies evaluating real-world data is required to inform development of more applicable driving guidelines.
Systematic review registration number
PROSPERO 2023 CRD42023434608.
Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma Mellinghoff, Ingo K.; van den Bent, Martin J.; Blumenthal, Deborah T. ...
The New England journal of medicine,
08/2023, Volume:
389, Issue:
7
Journal Article
Peer reviewed
Mutations in isocitrate dehydrogenase 1 or 2 are common in low-grade glioma. The IDH inhibitor vorasidenib improved progression-free survival as compared with placebo.
Recent studies identified distinct genomic subtypes of lower-grade gliomas that could potentially be used to guide patient treatment. This study aims to determine whether there is an association ...between genomics of lower-grade glioma tumors and patient outcomes using algorithmic measurements of tumor shape in magnetic resonance imaging (MRI). We analyzed preoperative imaging and genomic subtype data from 110 patients with lower-grade gliomas (WHO grade II and III) from The Cancer Genome Atlas. Computer algorithms were applied to analyze the imaging data and provided five quantitative measurements of tumor shape in two and three dimensions. Genomic data for the analyzed cohort of patients consisted of previously identified genomic clusters based on IDH mutation and 1p/19q co-deletion, DNA methylation, gene expression, DNA copy number, and microRNA expression. Patient outcomes were quantified by overall survival. We found that there is a strong association between angular standard deviation (ASD), which measures irregularity of the tumor boundary, and the IDH-1p/19q subtype (p < 0.0017), RNASeq cluster (p < 0.0002), DNA copy number cluster (p < 0.001), and the cluster of clusters (p < 0.0002). The RNASeq cluster was also associated with bounding ellipsoid volume ratio (p < 0.0005). Tumors in the IDH wild type cluster and R2 RNASeq cluster which are associated with much poorer outcomes generally had higher ASD reflecting more irregular shape. ASD also showed association with patient overall survival (p = 0.006). Shape features in MRI were strongly associated with genomic subtypes and patient outcomes in lower-grade glioma.
In this retrospective, IRB-exempt study, we analyzed data from 68 patients diagnosed with glioblastoma (GBM) in two institutions and investigated the relationship between tumor shape, quantified ...using algorithmic analysis of magnetic resonance images, and survival. Each patient’s Fluid Attenuated Inversion Recovery (FLAIR) abnormality and enhancing tumor were manually delineated, and tumor shape was analyzed by automatic computer algorithms. Five features were automatically extracted from the images to quantify the extent of irregularity in tumor shape in two and three dimensions. Univariate Cox proportional hazard regression analysis was performed to determine how prognostic each feature was of survival. Kaplan Meier analysis was performed to illustrate the prognostic value of each feature. To determine whether the proposed quantitative shape features have additional prognostic value compared with standard clinical features, we controlled for tumor volume, patient age, and Karnofsky Performance Score (KPS). The FLAIR-based bounding ellipsoid volume ratio (BEVR), a 3D complexity measure, was strongly prognostic of survival, with a hazard ratio of 0.36 (95% CI 0.20–0.65), and remained significant in regression analysis after controlling for other clinical factors (
P
= 0.0061). Three enhancing-tumor based shape features were prognostic of survival independently of clinical factors: BEVR (
P
= 0.0008), margin fluctuation (
P
= 0.0013), and angular standard deviation (
P
= 0.0078). Algorithmically assessed tumor shape is statistically significantly prognostic of survival for patients with GBM independently of patient age, KPS, and tumor volume. This shows promise for extending the utility of MR imaging in treatment of GBM patients.
Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase ...1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
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