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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.

Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against m IDH 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 m IDH1 -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 m IDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197. The dual IDH1/IDH2 inhibitor vorasidenib exhibited better brain permeability and target engagement than ivosidenib in a pilot perioperative randomized clinical trial in patients with IDH1-mutant glioma.

Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P<0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P<0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention. (Funded by Servier; INDIGO ClinicalTrials.gov number, NCT04164901.).

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.

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. Recurrent glioblastomas (rGBM) have dismal outcomes, but long-term survival has been observed in subsets of patients after immunotherapy. Here the authors report a positive association between low tumor mutation burden, inflammatory gene signatures, and survival after immunotherapy in rGBM patients.

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.

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 a phase 3 trial, vorasidenib, an oral brain-penetrant inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2), resulted in improved progression-free survival (primary endpoint) and time to next intervention (key secondary endpoint) at second interim analysis, resulting in study unblinding. We report 6 months of additional double-blind data, from second interim analysis (Sept 6, 2022) to unblinding (March 7, 2023), and the effect of vorasidenib on volumetric tumour growth rate, health-related quality of life (HRQOL), neurocognitive function, and seizure control. INDIGO was a randomised, double-blind, placebo-controlled, phase 3 trial done in 92 hospitals in Canada, France, Germany, Israel, Italy, Japan, the Netherlands, Spain, Switzerland, the UK, and the USA. Patients aged 12 years or older with residual or recurrent grade 2 IDH1/2-mutant diffuse glioma, a Karnofsky performance-status score of 80 or higher, at least one previous surgery, and no other previous anticancer treatment were eligible. Patients were randomly assigned (1:1; stratified according to locally determined chromosome 1p/19q codeletion status and baseline tumour size) to oral vorasidenib (40 mg) or placebo once a day in continuous 28-day cycles until disease progression or unacceptable toxicity. Progression-free survival per masked independent review committee was the primary endpoint, and time to next intervention was the key secondary endpoint. Prespecified secondary endpoints included tumour growth rate (6-monthly change in tumour volume) and HRQOL (Functional Assessment of Cancer Therapy–Brain [FACT-Br]). Prespecified exploratory endpoints included neurocognitive function (cognitive performance instruments) and seizure activity (self-reported). The full analysis set was used for all efficacy analyses and included all randomly assigned patients, and the safety analysis set was used for all safety analyses and included all patients who received one or more doses of vorasidenib or placebo. The trial is registered with ClinicalTrials.gov, NCT04164901. Recruitment is complete and the trial is ongoing. Between Jan 9, 2020, and Feb 22, 2022, 331 patients were enrolled and randomly assigned to vorasidenib (n=168) or placebo (n=163). 187 (56%) patients were male, 144 (44%) were female, and 257 (78%) were White. Median follow-up was 20·1 months (IQR 15·9 to 23·8). With an additional 6 months of follow-up, median progression-free survival (not reached [95% CI 22·1 to not estimated] vs 11·4 months [95% CI 11·1 to 13·9]; hazard ratio [HR] 0·35 [95% CI 0·25 to 0·49]) and time to next intervention (not estimated [not estimated to not estimated] vs 20·1 months [17·5 to 27·1]; HR 0·25 [0·16 to 0·40]) remained substantially improved with vorasidenib versus placebo. Tumour growth rate was –1·3% (95% CI –3·2 to 0·7) with vorasidenib and 14·4% (95% CI 12·0 to 16·8) with placebo (difference 15·9% [95% CI 12·6 to 19·3]). Mean FACT-Br total scores were similar between the vorasidenib and placebo groups (158·2 [SD 26·4] and 158·8 [23·3]) at baseline and remained high (154·2 [29·8] and 153·2 [29·4]) by the end of treatment. There was no difference between vorasidenib or placebo in neurocognitive functions of verbal learning, executive function, attention, working memory, and psychomotor function from baseline through to end of treatment. The vorasidenib group had lower rates of seizures than the placebo group (18·2 seizures per person-year [95% CI 8·4 to 39·5] vs 51·2 seizures per person-year [22·9 to 114·8]). The most common grade 3 or worse treatment-emergent adverse events (TEAEs) in the vorasidenib and placebo groups, respectively, were increased alanine aminotransferase (17 [10%] and two [1%]), increased aspartate aminotransferase (eight [5%] and none), seizures (seven [4%] and five [3%]), and increased γ-glutamyltransferase (five [3%] and two [1%]). Serious TEAEs occurred in 20 (12%) patients in the vorasidenib group and ten (6%) in the placebo group; the most common were seizures. There were no treatment-related deaths. Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or neurocognition. Additional follow-up supported the robustness of progression-free survival and time to next intervention in patients with grade 2 IDH1/2-mutant diffuse glioma. These findings support the use of vorasidenib in patients with grade 2 IDH1/2-mutant gliomas who only had surgical intervention and are not in immediate need of radiotherapy or chemotherapy. Servier.

Cancer-related cognitive impairment (CRCI) is commonly experienced by individuals with non-central nervous system cancers throughout the disease and treatment trajectory. CRCI can have a substantial impact on the functional ability and quality of life of patients and their families. To mitigate the impact, oncology providers must know how to identify, assess, and educate patients and caregivers. The objective of this review is to provide oncology clinicians with an overview of CRCI in the context of adults with non-central nervous system cancers, with a particular focus on current approaches in its identification, assessment, and management.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating condition associated with a number of chemotherapeutic agents. Drugs commonly implicated in the development of CIPN include platinum agents, taxanes, vinca alkaloids, bortezomib, and thalidomide analogues. As a drug response can vary between individuals, it is hypothesized that an individual’s specific genetic variants could impact the regulation of genes involved in drug pharmacokinetics, ion channel functioning, neurotoxicity, and DNA repair, which in turn affect CIPN development and severity. Variations of other molecular markers may also affect the incidence and severity of CIPN. Hence, the objective of this review was to summarize the known biological (molecular and genomic) predictors of CIPN and discuss the means to facilitate progress in this field.