Jaeckle, Kurt

Abstract Background Isocitrate dehydrogenase (IDH)-mutant gliomas are infiltrative tumors with limited treatment options at recurrence. Early studies suggest IDH inhibition has therapeutic activity. We evaluated clinical outcomes associated with IDH-1 inhibitor ivosidenib in recurrent IDH-1-mutant gliomas and molecular predictors of response. Methods We retrospectively analyzed adults treated with ivosidenib from January 2021 to August 2025 with predominantly recurrent, pretreated CNS WHO grade 2-4 astrocytoma IDH-mutant or grade 2-3 oligodendroglioma, IDH-mutant and 1p/19q codeleted. Prior anticancer treatments, toxicities, enhancement status at ivosidenib initiation, and genomic alterations were collected. The primary endpoint was progression-free survival (PFS); secondary analyses evaluated associations between PFS, genomic complexity, and CDKN2A/B homozygous deletion. Results Ninety-two adults, median age 43, were included: 61 astrocytomas and 31 oligodendrogliomas, mostly grade 2. Before ivosidenib, 69 had surgery, 64 chemotherapy, and 64 radiation. Median time from diagnosis to ivosidenib was 4.8 years, with median of two prior progressions. Median treatment duration was 5.8 months. Median PFS was 15.2, 4.6, and 2.1 months for astrocytoma grades 2-4, 14.0 and 6.9 months for oligodendroglioma grades 2-3. Increasing genomic complexity was associated with shorter PFS in univariate analysis. Patients without CDKN2A/B homozygous deletion had median PFS of 19.2 months. Two patients with homozygous deletion had median PFS of 0.6 months. Conclusions In this retrospective analysis of predominantly recurrent IDH-1-mutant glioma, ivosidenib was associated with longer PFS in lower-grade, non-enhancing tumors that received little or no prior anticancer treatment and less complex genomic profiles. These findings support a context-dependent benefit of IDH inhibition in recurrent disease.

Abstract Background Cognitive function is an important outcome in brain-tumor clinical trials. Cognitive examiners are often needed across multiple sites, many of whom have no prior testing experience. To ensure quality, we looked at examiner errors in administering a commonly used cognitive test battery, determined whether the errors were correctable upon central review, and considered whether the same errors would be detected using onsite electronic data entry. Methods We looked at 500 cognitive exams administered for brain-tumor trials led by the Alliance for Clinical Trials in Oncology (Alliance). Of 2277 tests examined, 32 noncorrectable errors were detected with routine central review (1.4% of tests administered), and thus removed from the database of the respective trial. The invalidation rate for each test was 0.8% for each part of the Hopkins Verbal Learning Test-Revised, 0.8% for Controlled Oral Word Association, 1.8% for Trail Making Test-A and 2.6% for Trail Making Test-B. It was estimated that, with onsite data entry and no central review, 4.9% of the tests entered would have uncorrected errors and 1.3% of entered tests would be frankly invalid but not removed. Conclusions Cognitive test results are useful and robust outcome measures for brain-tumor clinical trials. Error rates are extremely low, and almost all are correctable with central review of scoring, which is easy to accomplish. We caution that many errors could be missed if onsite electronic entry is utilized instead of central review, and it would be important to mitigate the risk of invalid scores being entered. ClinicalTrials.gov identifiers NCT01781468 (Alliance A221101), NCT01372774 (NCCTG N107C), NCT00731731 (NCCTG N0874), and NCT00887146 (NCCTG N0577).