Perioperative Vorasidenib and Ivosidenib Remain Effective, Safe in IDH1+ Diffuse Glioma

Diffuse Glioma

Vorasidenib (Voranigo) or ivosidenib (Tibsovo) administered before and after surgery demonstrated sustained clinical benefit in patients with predominantly non-enhancing IDH1-mutant diffuse glioma, according to updated findings from a phase 1 trial (NCT03343197) presented at the 2024 Society for Neuro-Oncology (SNO) Annual Meeting.

At a data cutoff date of September 23, 2023, 64% of evaluable patients who received vorasidenib (n = 22) and 45.4% of evaluable patients who received ivosidenib experienced tumor reduction. The overall response rate (ORR) among evaluable patients who received vorasidenib (n = 22) was 45.5%, including partial response (PR), minor response (MR), stable disease (SD), and progressive disease (PD) rates of 18.2%, 27.3%, 36.4%, and 18.2%, respectively. The median time to response in this arm was 9.2 months (range, 2-20), and the median duration of response (DOR) was not evaluable (NE; range, 14.7 months-NE). The median duration of treatment was 44.67 months (range, 0.9-62.7).

The ORR among evaluable patients who received ivosidenib (n = 22) was 31.8%, including PR, MR, SD, and PD rates of 22.7%, 9.1%, 59.1%, and 9.1%, respectively. The median time to response in this arm was 5.6 months (range, 2-13), and the median DOR was 42.4 months (range, 1.8-NE). The median duration of treatment was 23.92 months (range, 0.0-62.7).

“With additional [follow-up of approximately] 3.5 years from previously published results, vorasidenib and ivosidenib continue to show clinical benefit immediately after surgery in patients with predominantly non-enhancing glioma,” presenting author Timothy F. Cloughesy, MD, and coauthors wrote in a presentation of the data. “Vorasidenib resulted in durable disease control including objective responses, consistent with phase 3 INDIGO study [NCT04164901] results.”

Cloughesy is a professor and director in the Department of Neurology, Neurological Services, and the Neuro-Oncology Program, as well as a physician in the Department of Neurology and a member of the Brain Research Institute at the UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles, California.

Background and Trial Design

Vorasidenib, an oral, brain-penetrant dual mIDH1/2 inhibitor, was FDA approved in August 2024 for the treatment of patients at least 12 years of age with grade 2 astrocytoma or oligodendroglioma harboring a susceptible IDH1 or IDH2 mutation who have previously undergone surgery, including biopsy, subtotal resection, or gross total resection.²

Ivosidenib, a first-in-class, oral, small-molecule mIDH1 inhibitor, is FDA approved for the treatment of patients with diseases harboring a susceptible IDH1 mutation as detected by an FDA-approved test, including in combination with azacitidine for patients newly diagnosed acute myeloid leukemia (AML) who are at least 75 years of age or have comorbidities precluding the use of intensive induction chemotherapy; as monotherapy for adult patients with relapsed/refractory AML; as monotherapy for adult patients with relapsed/refractory myelodysplastic syndromes; and as a single agent for adult patients with locally advanced or metastatic cholangiocarcinoma.³

In cohort 1 of the phase 1 perioperative trial, patients with grade 2/3 non-enhancing IDH1 R132H–mutant gliomas were randomly assigned 2:2:1 to receive vorasidenib at 50 mg once daily (n = 12), ivosidenib at either 500 mg once daily or 250 mg twice daily (n = 12), or no treatment (control arm; n = 5) for 4 weeks prior to planned surgery.¹ Patients from cohort 1 with evidence of target engagement could continue to cohort 2, where they were randomly assigned 1:1 to receive either vorasidenib at 10 mg once daily (n = 10) or ivosidenib at 250 mg twice daily (n = 10). Patients had the option to continue treatment with vorasidenib or ivosidenib after surgery.

The primary end point was 2-hydroxyglutarate (2-HG) concentration in tumors that were resected following neoadjuvant treatment with vorasidenib or ivosidenib compared with untreated control tumors. Secondary end points included safety; pharmacodynamics of 2-HG in plasma; pharmacokinetics in plasma and tumor; and preliminary clinical activity per Response Assessment in Neuro-Oncology criteria for low-grade gliomas. Exploratory end points included 2-HG concentration in tumors before and after treatment; and the pharmacokinetic/pharmacodynamic relationship of vorasidenib and ivosidenib in tumor, plasma, and cerebrospinal fluid.

Additional Efficacy Findings

This trial was initiated in March 2018, and enrollment was completed in April 2019. In total, 49 patients were randomly assigned before surgery, all of whom proceeded to surgery without unplanned delays. Forty-six patients (oligodendroglioma, n = 24; astrocytoma, n = 20; anaplastic oligoastrocytoma, n = 1; anaplastic oligodendroglioma, n = 1) received treatment with either vorasidenib (n = 24) or ivosidenib (n = 22) following surgery.

At baseline, patients in the vorasidenib arm had a median age of 49 years (range, 31-75), and most were male (66.7%). Karnofsky performance status (KPS) scores included 100% (33.3%), 90% (54.2%), and 80% (12.5%). Most patients had WHO grade 2 tumors (91.7%). Histological subtypes in this arm included oligodendroglioma (54.2%) and astrocytoma (45.8%). Additionally, 1p19q status was co-deleted, intact, or not determined in 50.0%, 41.7%, and 8.3% of patients, respectively. All patients had received prior surgery. In total, 29.2% and 41.7% of patients had received prior radiation therapy and prior systemic therapy, respectively.

At baseline among patients in the ivosidenib arm, the median age was 37 years (range, 19-66), and most were male (68.0%). KPS scores included 100% (44.0%), 90% (48.0%), and 80% (4.0%); One patient (4.0%) had a missing KPS score. Most patients had WHO grade 2 tumors (84.0%). Histological subtypes in this arm included oligodendroglioma (48.0%), astrocytoma (44.0%), anaplastic oligodendroglioma (4.0%), and anaplastic oligoastrocytoma (4.0%). Furthermore, 1p19q status was co-deleted, intact, or not determined in 52.0%, 36.0%, and 12.0% of patients, respectively. All patients had received prior surgery. In total, 28.0% and 56.0% of patients had received prior radiation therapy and prior systemic therapy, respectively.

Previously reported findings from this phase 1 trial showed that 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 who received vorasidenib at 50 mg once daily or ivosidenib at 500 mg once daily, respectively.⁴ However, the ratios of tumor to plasma were higher in patients who received vorasidenib vs those who received ivosidenib. Reductions in 2-HG were associated with lower tumor cell proliferation, reversal of IDH1/2 mutation–associated gene expression programs, increased DNA 5-hydroxy-methylcytosine, and increased tumor-infiltrating lymphocyte levels. The dose of vorasidenib at 50 mg once daily was associated with the most consistent mutant enzyme inhibition and the most preliminary antitumor activity.

As of the data cutoff date for the updated analysis, 11 patients remained on treatment with vorasidenib, and 5 patients remained on treatment with ivosidenib.¹ Among the patients in the safety analysis set who had received vorasidenib (n = 24), 13 had discontinued treatment due to either disease progression (n = 10), adverse effects (AEs; n = 1), or investigator decision (n = 2). Among the patients in the safety analysis set who had received ivosidenib (n = 25), 20 had discontinued treatment due to either disease progression (n = 14), AEs (n = 2), or investigator decision (n = 1); 3 patients in this group did not continue therapy post-surgery.

The median progression-free survival (PFS) was 41.4 months (95% CI, 9.3-NE) in the vorasidenib arm and 38.6 months (95% CI, 18.3-NE) in the ivosidenib arm. Among patients who had only undergone prior surgery, the median PFS was 55.2 months (95% CI, 2.4-NE) in the vorasidenib arm (n = 9) and 38.6 months (95% CI, 24.0-NE) in the ivosidenib arm (n = 9).

Updated Safety Findings

Investigators reported no new safety signals and noted that the safety profiles of the agents in this analysis were consistent with those observed in previously published studies.

In the vorasidenib arm, any-grade treatment-emergent AEs (TEAEs) occurred in 100.0% of patients, and treatment-related TEAEs were seen in 66.7% of patients. Serious TEAEs and treatment-related serious TEAEs were seen in 41.7% and 4.2% of patients, respectively. Grade 3 or higher TEAEs, treatment-related grade 3 or higher TEAEs, and AEs of special interest were observed in 62.5%, 12.5%, and 12.5% of patients, respectively. TEAEs led to treatment discontinuation, dose reduction, and dose interruption in 4.2%, 4.2%, and 37.5% of patients, respectively.

In the ivosidenib arm, any-grade TEAEs occurred in 100.0% of patients, and treatment-related TEAEs were seen in 72.0% of patients. Serious TEAEs were seen in 32.0% of patients, and no patients had treatment-related serious TEAEs. Grade 3 or higher TEAEs and treatment-related grade 3 or higher TEAEs were observed in 32.0% and 4.0% of patients, respectively. No AEs of special interest were reported. TEAEs led to treatment discontinuation, dose reduction, and dose interruption in 8.0%, 4.0%, and 20.0% of patients, respectively.

Notably, no TEAEs led to on-treatment deaths in either arm.

“Safety profiles remain favorable with no new risk identified for either drug,” the authors concluded.

Disclosures: Dr Cloughesy reported being the cofounder of Katmai Pharmaceuticals; holding stock holder in Katmai Pharmaceuticals, Chimerix, Erasca; serving as a consultant for Katmai Pharmaceuticals, 501c3 Global Coalition for Adaptive Research, Sagimet, Clinical Care Options, Ideology Health, Servier, Jubilant, Immvira, Gan & Lee, BrainStorm, Sapience, Inovio, Viego Therapeutics, DNATrix, Tyme, SDP, Novartis, Roche, Kintara, Bayer, Merck, Boehringer Ingelheim, VBL, Amgen, Kiyatec, Odonate Therapeutics, QED, Medefield, Pascal Biosciences, Tocagen, Karyopharm, GW Pharma, AbbVie, VBI, Deciphera, Agios, Genocea, Celgene, Puma, Lilly, BMS, Cortice, Wellcome Trust, Novocure, Novogen, Boston Biomedical, Sunovion, Human Longevity, Insys, ProNai, Pfizer, Notable Labs, Medqia Trizel, and Medscape; serving as a board member for Katmai Pharmaceuticals, 501c3 Global Coalition for Adaptive Research, Break Through Cancer and Cure Brain Cancer Foundation; receiving milestone payments and possible future royalties from Chimerix; serving as a member of Break Through Cancer and Cure Brain Cancer Foundation; and that the Regents of the University of California have licensed intellectual property coinvented by Dr Cloughesy to Katmai Pharmaceuticals.

References

1. Mellinghoff IK, Wen PY, Taylor JW, et al. A phase 1, randomized, perioperative trial of vorasidenib and ivosidenib in IDH1-mutant diffuse glioma: updated results. Presented at: 2024 SNO Annual Meeting; November 21-24, 2024; Houston, TX. Abstract CTNI-47.
2. FDA approves vorasidenib for Grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation. FDA. August 6, 2024. Accessed November 25, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-vorasidenib-grade-2-astrocytoma-or-oligodendroglioma-susceptible-idh1-or-idh2-mutation
3. Ivosidenib. Prescribing information. Servier; October 2023. Accessed November 25, 2024. https://www.tibsovopro.com/pdf/prescribinginformation.pdf
4. Mellinghoff IK, Lu M, Wen PY, et al. Vorasidenib and ivosidenib in IDH1-mutant low-grade glioma: a randomized, perioperative phase 1 trial. Nat Med. 2023;29(3):615-622. doi:10.1038/s41591-022-02141-2