Therapies for IDH-Mutant Gliomas

Isocitrate dehydrogenase (IDH) mutant gliomas are a distinct type of primary brain tumors with unique characteristics, behavior, and disease outcomes. This article provides a review of standard of care treatment options and innovative, therapeutic approaches that are currently under investigation for these tumors. Extensive pre-clinical data and a variety of clinical studies support targeting IDH mutations in glioma using different mechanisms, which include direct inhibition and immunotherapies that target metabolic and epigenomic vulnerabilities caused by these mutations. IDH mutations have been recognized as an oncogenic driver in gliomas for more than a decade and as a positive prognostic factor influencing the research for new therapeutic methods including IDH inhibitors, DNA repair inhibitors, and immunotherapy

The Role of Molecular Genetics of Glioblastoma in the Clinical Setting

The rapid evolving knowledge of glioblastoma molecular biomarkers and their association to prognosis and treatment calls for clinicians to keep abreast of the latest literature on the recommendations that have an impact on clinical practice. The presence or absence of IDH mutations and MGMT methylation continue to be essential molecular markers that indicate prognosis and response to treatment. New emerging data on the presence of other alterations such as TERT promoter mutation, EGFR amplification, and/or the combination of gain of entire chromosome 7 and loss of entire chromosome 10 (+7/−10) in the case of IDH-wildtype astrocytomas and the presence of CDKN2A/B in IDH-mutant astrocytomas have become significant as these mutations are associated with more aggressive tumor behavior. Other mutations such as EGFRvIII expression, FGFR-TACC gene fusions, PTEN deletion, PDGFRA and BRAF V 600E have elucidated important pathways for targeted therapies and aid in prognosis assessment

Phase 1 LITESPARK-001 study of belzutifan in advanced solid tumors: Results of the glioblastoma cohort

2054 Background: Patients with progressive/recurrent glioblastoma (GBM) have very poor prognosis, and novel treatments are urgently needed. Hypoxia is a prominent feature of the tumor microenvironment in GBM and has been implicated as a potential mechanism of resistance to radiation therapy, which is a key part of standard-of-care treatment for GBM. HIF-2α has been suggested as a key therapeutic target because it plays a role in stabilizing the hypoxic environment in GBM tumors. Belzutifan, a first-in-class HIF-2α, has shown efficacy in advanced renal cell carcinoma and in von Hippel-Lindau disease–related renal cell carcinoma, pancreatic neuroendocrine tumors, and central nervous system hemangioblastomas. The phase 1 LITESPARK-001 trial (NCT02974738) was designed to evaluate belzutifan across solid tumors. Here, we report results from the GBM expansion cohort of LITESPARK-001. Methods: Patients enrolled in the GBM cohort had histologically confirmed, IDH wild type GBM that is first recurrent following radiation therapy and temozolomide according to the Response Assessment in Neuro-Oncology (RANO) criteria and had a measurable contrast-enhancing lesion by MRI imaging and a Karnofsky performance scale score ≥60%. Patients received belzutifan 120 mg by mouth twice daily. End points for this cohort included objective response rate (ORR), clinical benefit rate (CBR, CR + PR + SD of any duration), and progression-free survival (PFS) per RANO criteria by investigator assessment and safety. Results: Overall, 25 patients were enrolled in the GBM cohort. Median age was 63 years (range, 35-75), and most patients were male (n = 15; 60%). Median follow-up was of 1.9 months (range, 0.7-5.1). ORR was 0% (95% CI, 0.0-13.7) and CBR was 8% (95% CI, 1.0-26.0). Median PFS was 1.4 months (95% CI, 1.1-1.8). All patients (100%) experienced ≥1 adverse event and 15 (60%) experienced a grade 3-5 adverse event. The most common adverse events were anemia (n = 16 [64%]), fatigue (n = 13 [52%]), headache (n = 8 [32%]), muscular weakness (n = 8 [32%]). Two patients (8%) died from adverse events (both disease progression). No deaths were considered related to treatment. Conclusions: Antitumor activity was not observed with belzutifan for patients with GBM who received prior radiation therapy and temozolomide. The safety profile was similar to previous studies with belzutifan. Further efforts are warranted to identify therapies for patients with glioblastoma to improve outcomes. Clinical trial information: NCT02974738

Interim analysis of ABM-1310, a blood-brain barrier-penetrant BRAF inhibitor, in patients with BRAF V600 -mutated solid tumors

3107 Background: ABM-1310 is a novel, small-molecule BRAF inhibitor with preclinical evidence of high blood-brain barrier penetration. Here we report interim results from a Phase 1 study of ABM-1310 in patients (pts) with BRAF V600 mutations (NCT04190628). Methods: This multicenter, open-label, two-part study enrolled adult pts with advanced BRAF V600-mutated solid tumors, including those with recurrent or metastatic solid tumors or primary CNS tumors. Pts who failed previous BRAF ± MEK inhibitor treatment were eligible. In the dose-escalation (Part 1), pts received either ABM-1310 monotherapy (25–250 mg bid) continuously or ABM-1310 (100–200 mg bid) + cobimetinib (60 mg QD on d1–21) q28d. Escalation followed a “3+3 design” with dose-limiting toxicities assessed during Cycle 1. Part 2 was cohort expansion (ABM-1310 150–200 mg bid). Primary objectives were maximum tolerated dose (MTD) of ABM-1310 ± cobimetinib. Secondary objectives included safety, tolerability, pharmacokinetics, and anticancer activity. Results: As of 28 Nov 2023, 51 pts (36 male; median age 56 years; 38 pts refractory to BRAF ± MEK inhibitors) were enrolled. Of these, 74.5% (38/51) experienced treatment-related adverse events (TRAEs). The most frequent (≥10%) TRAEs were skin rash (n=15) and asymptomatic electrocardiogram QT prolongation (AQTP, n=18), most (97.4%) of which were grade (G) 1–2. Nine pts (17.6%) had G3 TRAEs including AQTP, rash, neutropenia, nausea, vomiting, lipase increased and myalgia. There were no treatment-related early discontinuations, G4 AEs, or treatment-related deaths. Among 28 efficacy-evaluable pts who received any dose of ABM-1310 monotherapy, the ORR was 21.4% and disease control rate (DCR) was 60.7%, including 6 partial responses (PR) (glioblastoma multiforme n=2, pleomorphic xanthoastrocytoma n=2, papillary thyroid carcinoma [PTC] n=1, and pancreatic cancer [PC] n=1). Eleven pts had stable disease (SD). Among 16 efficacy-evaluable pts treated with ABM-1310 + cobimetinib, the ORR was 12.5% and DCR was 68.8% including 2 PR (1 each with melanoma and PTC) and 9 SD. Among 10 pts with primary CNS tumors treated with ABM-1310 monotherapy, the ORR was 40% (4 PR, 4 SD), and the median PFS was 4.6 months. In 6 pts with PTC, the ORR was 33.3% (2 PR, 4 SD), and the median PFS was 6.0 months. In 4 pts with PC treated with ABM-1310 monotherapy, the ORR was 25% (1 PR for >6 months; pt remains on study treatment). The MTD for ABM-1310 either as monotherapy or in combination with cobimetinib was 200 mg bid. Preliminary assessment of ABM-1310 drug exposure vs. dose showed a linear dose-proportional relationship. Conclusions: ABM-1310, either alone or in combination with cobimetinib, was well tolerated without new or unexpected side effects or safety issues. Preliminary efficacy of ABM-1310 was seen in pts with BRAF V600-mutated solid tumors, including those who were refractory to prior BRAF ± MEK inhibitors. Clinical trial information: NCT04190628

Survival benefit of lobectomy for glioblastoma: moving towards radical supramaximal resection

Extent of resection remains a paramount prognostic factor for long-term outcomes for glioblastoma. As such, supramaximal resection or anatomic lobectomy have been offered for non-eloquent glioblastoma in an attempt to improve overall survival. Here, we conduct a propensity-matched analysis of patients with non-eloquent glioblastoma who underwent either lobectomy or gross total resection of lesion to investigate the efficacy of supramaximal resection of glioblastoma. Patients who underwent initial surgery for gross total resection or lobectomy for non-eloquent glioblastoma at our tertiary care referral center from 2010 to 2019 were included for this propensity-matched survival analysis. Propensity scores were generated with the following covariates: age, location, preoperative KPS, product of perpendicular maximal tumor diameters, and product of perpendicular FLAIR signal diameters. Inverse probability of treatment weighting (IPTW) with generated propensity scores was used to compare progression-free survival and overall survival. Sixty-nine patients were identified who underwent initial resection of glioblastoma for non-eloquent glioblastoma from 2010 to 2019 (GTR = 37, lobectomy = 32). Using IPTW, overall survival (30.7 vs. 14.1 months) and progression-free survival (17.2 vs. 8.1 months were significantly higher in the lobectomy cohort compared to the GTR group (p < 0.001). There was no significant difference in pre-op or post-op KPS or complication rates between the two groups. Our propensity-matched study suggests that lobectomy for non-eloquent glioblastoma confers an added survival benefit compared to GTR alone. For patients with non-eloquent glioblastoma, a supramaximal resection by means of an anatomic lobectomy should be considered as a primary surgical treatment in select patients if feasible