IDH Mutations Offer Hope as a Prognostic Indicator and Treatable Target in Gliomas

Ingo K. Mellinghoff, MD

Several presentations at the 2019 American Society of Clinical Oncology Annual Meeting highlighted a hopeful new direction in the treatment of gliomas, demonstrating the relevance ofIDH1/2mutational status and its feasibility as a target of therapy.

Mutations in theIDH1andIDH2genes, which encode isocitrate dehydrogenases 1 and 2, result in disruption of the enzyme’s normal catalytic activity and production of 2-hydroxyglutarate (2-HG), an oncometabolite, which leads to genetic and epigenetic dysregulation and subsequent tumorigenesis.¹IDH1mutations serve as an ideal target of therapy because they are found throughout the tumor beginning in early gliomagenesis and persist through all stages of disease progression.²

“The mutant enzyme acquires the novel ability to catalyze the reduction of α-ketoglutarate to 2-HG, which then builds up in the tumor and inhibits a whole suite of α- ketoglutarate—dependent enzymes [that are believed to be] responsible for the cellular differentiation of oncogenic effects associated with this mutation,” Ingo K. Mellinghoff, MD, chief of brain tumor service at Memorial Sloan Kettering Cancer Center in New York, New York, told an audience at the meeting. Subsequent development of novel targeted agents forIDHmutations may provide a highly anticipated treatment modality for patients with glioma.

Data presented by Enrico Franceschi, MD, and colleagues characterized the critical need for assessingIDH1/2mutational status as it predicts prognosis in patients with gliomas.³Exon 4 mutations in theIDH1orIDH2gene are fundamental in glioma classification, withIDH1mutations occurring more frequently and accounting for 70% to 80% of World Health Organization (WHO) grade 2/3 gliomas.⁴

In the single-institution study, the investigators assessed 493 patients who recently received diagnoses of WHO grade 2 through 4IDH-mutant gliomas, with a median follow-up of 80.5 months. Of the patients assessed, 428 were classified as having canonicalIDH1R132H mutations and 65 with noncanonical mutations, including inIDH2and other variants ofIDH1(FIGURE). Baseline characteristics were well balanced between the groups, except that the patients with noncanonical mutations were found to have a lower median age, 32 years versus 39 years (P<.001). Most patients (86.2%) had either partial or total surgical resection of their disease, and more than half had postsurgical therapy with radiation, chemotherapy, or both.³

Median overall survival (OS) was improved in patients with noncanonical mutations compared withIDH1R132H (198.6 vs 145 months; P = .013). These differences in survival could be predictive of outcomes in all patients with gliomas. &ldquo;Detecting noncanonical IDH1 mutations is essential for diagnosis and for prognosis in patients with gliomas. Differential enzymatic activity of noncanonical IDH1 mutations, resulting in different levels [of] 2-hydroxyglutarate, could be the reason [for] improved survival,&rdquo; the authors wrote in the study.³

The recent phase III CATNON trial focused on the efficacy of 4 treatment regimens involving radiation with or without concurrent and/or adjuvant temozolomide (Temodar) in anaplastic gliomas. The trial was terminated at the second interim analysis due to treatment futility. However, analysis of patients in the overall cohort based on IDH mutational status demonstrated improved median OS among patients with mutated IDH compared with wild-typeIDH(117 vs 19 months [HR, 0.14; 95% CI, 0.11-0.18]). In a subgroup analysis, patients withIDH-mutant anaplastic astrocytoma treated with concurrent (HR, 0.63; 95% CI, 0.43-0.91) or adjuvant (HR, 0.46; 95% CI, 0.32-0.67) temozolomide had improved rates of 5-year OS versus patients without temozolomide treatment.⁵

Based on the results of the trial, the investigators led by Martin J. Van Den Bent, MD, PhD, concluded that adjuvant temozolomide with radiation therapy could become the standard of care in IDH-mutant anaplastic astrocytoma. Additionally, they found that the combination of concurrent and adjuvant temozolomide showed a nonsignificant trend toward improving 5-year OS (84.8%) versus adjuvant therapy alone (80.4%; HR, 0.71; 95% CI, 0.40-1.28;P= .258) in IDH-mutant patients.⁵

&ldquo;In [IDH-mutant] anaplastic astrocytoma, there was a benefit from both adjuvant and concurrent temozolomide,&rdquo; Van Den Bent said. Although the benefit of adding concurrent therapy to adjuvant temozolomide failed to reach statistical significance because of the small study size, using both treatment modalities led to a small added value of about 5%, he said.⁵

In a phase I study of the mutant IDH1/2 inhibitor vorasidenib (AG-881), Mellinghoff and colleagues evaluated patients (n = 52) with recurrent or progressive IDH-mutant low-grade glioma using a Bayesian model to determine dose escalation. Other study objectives included analysis of pharmacokinetics (PK) and pharmacodynamics (PD) in blood samples. At the time of data cutoff, 32.7% of patients remained on treatment, with 90.4% experiencing grade 2 or 3 adverse events (AEs). Five initial dose levels were tested, with the maximum tolerated dose (MTD) and recommended phase dose (RP2D) not reached by Bayesian model. Because the MTD was not reached, the investigators recommended proceeding with doses <100 mg in patients with gliomas.⁶

Subsequently, Mellinghoff and colleagues evaluated patients in the perioperative setting with vorasidenib and a small molecule inhibitor of mutantIDH1, ivosidenib (Tibsovo). The investigators&rsquo; primary objective was to determine the 2-HG concentration in resected tumors following treatment with vorasidenib or ivosidenib compared with the untreated control group in the phase I study. Both agents previously showed favorable 2-HG suppression in orthotopic glioma models and safety in patients with glioma.⁷

Secondary objectives included assessing the safety profiles of both agents, PD of 2-HG in plasma, PK of both drugs in plasma and tumor, and preliminary clinical activity assessment by response assessment in neuro-oncology for low-grade glioma (RANO-LGG) criteria. Patients had to have WHO grade 2 or 3 oligodendroglioma or astrocytoma with anIDH1R132H mutation; have measurable nonenhancing disease; be eligible for tumor resection within 2 to 4 months after screening; have adequate bone marrow, renal, and hepatic function; and have no previous treatment with an IDH inhibitor or bevacizumab (Avastin).⁷

Patients were randomized 2:2:1 to vorasidenib 50 mg daily (n = 14), ivosidenib 500 mg daily (n = 13), or a control group for 4 weeks. Tumors were resected after the initial 4-week assessment. Postoperatively, patients had the option to continue vorasidenib or ivosidenib until disease progression. Patients in study drug arms showing tumor 2-HG suppression underwent subsequent randomization to receive additional treatment with either vorasidenib or ivosidenib in a second cohort.⁷

Plasma 2-HG and drug concentrations were evaluated predose on days 1, 8, and 15; both pre- and postdose on day 22; and within 30 minutes of tumor resection. Additionally, 2-HG and drug concentrations in the resected tumor were determined.⁷

The median duration of treatment was similar in both study drug arms, and most patients (26 of 27 in the total cohort) remained on treatment at the time of data cutoff. Both agents had favorable toxicity profiles, with grade &ge;3 AEs occurring in 35.7% of the vorasidenib group and 23.1% of the ivosidenib group; most of the AEs in both groups were related to postoperative complications. Diarrhea was the most common AE for both vorasidenib and ivosidenib, occurring in 35.7% and 38.5% of patients, respectively. Alanine transaminase (ALT) elevations of grades 1 and 3 occurred in 2 patients in the vorasidenib group. The patient with grade 3 ALT elevation had resolution to grade 1 with dose interruption. No patients in either group discontinued therapy due to AEs.⁷

Vorasidenib and ivosidenib demonstrated brain penetration in the surgically resected tumors. &ldquo;The mean concentration of 2-hydroxyglutarate was reduced by 92% for each of the 2 drugs,&rdquo; said Mellinghoff, with vorasidenib demonstrating more consistent 2-HG suppression. In light of this consistency in 2-HG suppression, the investigators plan to test vorasidenib in a phase III study in IDH-mutant low-grade glioma.⁷

The agent DS-1001b was examined in a phase I trial of patients with recurrent or progressiveIDH1R132X—mutant gliomas following standard therapy. DS-1001b is an oral selective inhibitor of the IDH1 R132X enzyme that is capable of penetrating the blood&ndash;brain barrier. Study investigators used a modified continual reassessment model after standard therapy for patients with an ECOG performance status of 0 to 2. The investigators, led by Atsushi Natsume, MD, PhD, sought to determine the MTD and RP2D, with secondary objectives of safety and tolerability, PK profile of the drug, PD effect on 2-HG, and preliminary antitumor effect using RANO criteria for enhancing gliomas and RANO-LGG criteria for nonenhancing gliomas.²

Six dose levels, ranging from 125 mg twice daily to 1400 mg twice daily, were tested in 47 patients, most of whom were in the contrast-enhancing glioma group (n = 35). At the time of data evaluation, the majority (68%) of patients had discontinued treatment, with disease progression causing 84% of the discontinuations. The MTD was not reached, and 1 dose-limiting toxicity was observed at 1000 mg twice daily, which consisted of a grade 3 white blood cell count decrease. The most common (>20%) AEs observed were skin hyperpigmentation (53.2%), diarrhea (46.8%), pruritus (29.8%), alopecia (25.5%), arthralgia (25.5%), nausea (25.5%), headache (21.3%), and rash (21.3%). No drug-related serious AEs were observed.²

The median treatment duration in the enhancing group was 2.3 months, with 20% continuing on treatment at the time of data cutoff. Although the majority (48.6%) of patients in the enhancing group had progressive disease, it is important to note that 2.9% of these patients had a complete response, 14.3% had a partial response, and about one-third (31.4%) had stable disease.²

In the nonenhancing group, the median duration of treatment was 9.1 months, with 67% continuing on treatment at the time of data cutoff. Additionally, the majority of these patients (66.7%) had stable disease and one-third (33.3%) had a minor response. These results led the investigators to conclude that single-agent DS-1001b is effective and safe in this population and warrants further clinical studies.6 Additionally, DS-1001b demonstrated good brain penetration in an optional exploratory study of tumor samples obtained from 6 patients who developed progressive disease and had plans for salvage surgery.²

In addition to the potential for prognostic use,IDHmutations appear to be an encouraging target of novel agents in patients with glioma, with the potential to revolutionize the landscape of treatment for a malignancy that has limited pharmacologic options.

References:

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2. Natsume A, Wakabayashi T, Miyakita Y, et al. Phase I study of a brain penetrant mutant IDH1 inhibitor DS-1001b in patients with recurrent or progressive IDH1 mutant gliomas.J Clin Oncol.2019;37(suppl 15; abstr 2004). doi: 10.1200/JCO.2019.37.15_suppl.2004.
3. Franceschi E, De Biase D, Pession A, et al. Survival outcomes in glioma patients with noncanonical IDH mutations: beyond diagnostic improvements.J Clin Oncol.2019;37(suppl 15; abstr 2028). doi: 10.1200/JCO.2019.37.15_suppl.2028.
4. Suzuki H, Aoki K, Chiba K, et al. Mutational landscape and clonal architecture in grade II and III gliomas.Nat Genet.2015;47(5):458-468. doi: 10.1038/ng.3273.
5. Van Den Bent MJ, Erridge S, Vogelbaum MA, et al. Second interim and first molecular analysis of the EORTC randomized phase III intergroup CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q codeletion.J Clin Oncol.2019;37(suppl 15; abstr 2000). doi: 10.1200/JCO.2019.37.15_suppl.2000.
6. Mellinghoff I, Penas-Prado M, Peters K, et al. ACTR-31. Phase 1 study of AG-881, an inhibitor of mutant IDH1 and IDH2: results from the recurrent/progressive glioma population.Neuro-Oncol.2018;20(suppl 6):vi18. doi: 10.1093/neuonc/noy148.064.
7. Mellinghoff IK, Cloughesy TF, Wen PY, et al. A phase I, open label, perioperative study of AG-120 and AG-881 in recurrent IDH1 mutant, low-grade glioma: results from cohort 1.J Clin Oncol.2019;37(suppl 15;abstr 2003). doi: 10.1200/JCO.2019.37.15_suppl.2003.