IDH-mutant glioma: A new IDH1 inhibitor moves forward

IDH-mutant gliomas are a distinct subclass of gliomas defined by a cancer-associated mutation in the IDH1 or IDH2 enzyme. The IDH mutation arises early during gliomagenesis and, in most cases, persists throughout the lifespan of the tumor. Mutant IDH-mediated accumulation of the oncometabolite R-2-hydroxyglutarate is thought to drive glioma development,¹ and, as such, inhibition of this oncogenic activity has been viewed as a potential therapeutic strategy. Several IDH inhibitors have been under clinical investigation in patients with glioma. Ivosidenib, an IDH1-specific inhibitor, and Vorasidenib, a dual IDH1 and IDH2 inhibitor, are the farthest along in development. In phase I studies, both compounds demonstrated favorable safety profiles and preliminary evidence of anti-glioma activity in patients with recurrent, non-enhancing glioma on MRI.^2,3 Vorasidenib is now being tested in a randomized phase III trial in patients with low-risk IDH-mutant gliomas (NCT04164901).

Here, Natsume and colleagues report on a first-in-human, open-label, dose-escalation phase I study of DS-1001, a brain-penetrant small molecule inhibitor specific for the IDH1 R132H mutation.⁴ The investigators enrolled 47 patients with recurrent or progressive glioma of any grade with IDH1 R132H mutation to investigate the maximum tolerated dose, safety, pharmacokinetics, pharmacodynamics, and efficacy of the drug. Twenty-eight percent of the tumors exhibited 1p/19q codeletion. The majority of patients had experienced 2 or more prior recurrences. All patients had received at least prior radiation and over 80% had received either alkylating chemotherapy or bevacizumab. The drug was reasonably tolerated with no serious adverse events (AEs) reported. Skin hyperpigmentation was the most frequent AE, experienced by 53% of subjects, followed by diarrhea (47%), pruritis (30%), alopecia (28%), arthralgia (28%), and nausea (26%). Grade 3 neutropenia was observed in 12.8% of patients, leading to dose interruption or dose modification in some cases. In addition, dose reductions due to grade 1 or 2 pain-related events were required in a subset of patients treated long-term at a dose of 500 mg BID or higher. An appropriate pharmacodynamic response was observed with doses as low as 125 mg BID, as evidenced by a significantly lower level of measured R-2-HG in tumor tissue from treated patients compared to archival tumor tissue. Ultimately a dose ≤250 mg BID was recommended for future studies based on safety and pharmacodynamic data.

Interestingly, the investigators report impressive responses in patients with enhancing tumors. Of the 35 patients with contrast-enhancing tumors, 2 experienced a complete response (CR) and 4 experienced a partial response (PR). These responders, comprised of 2 oligodendrogliomas and 4 astrocytomas, stayed on treatment for greater than 50 weeks. While it is noted that there exists significant variability in disease course between patients with IDH-mutant gliomas, spontaneous decreases in tumor size are atypical unless there are coexisting treatment-related changes. No CRs were observed in the 12 patients with non-enhancing tumors, although 1 patient experienced a PR, 3 experienced a minor response (MR) and the remaining patients had stable disease as their best response to treatment.

These preliminary signs of efficacy are exciting and certainly warrant further exploration in a larger, randomized setting. While DS-1001 shows signs of anti-glioma activity in a subset of patients with the contrast-enhancing disease, nearly half of patients with enhancing tumors experienced a best response of progressive disease and the median duration of treatment was only 7 weeks. These data make clear that IDH inhibition on its own does not confer clinical benefit for all patients, nor is contrast-enhancement pattern a sufficient indicator of likelihood of response. In the context of stable disease in patients with non-enhancing IDH-mutant gliomas, it is harder to discriminate between drug activity and the natural history of the disease. Nevertheless, all patients in the non-enhancing cohort experienced stable disease or better, with a median treatment duration of 91 weeks.

As DS-1001, Vorasidenib, and other IDH-mutant inhibitors move into larger clinical trials, it will be critical to incorporate a multi-omics approach to profile responders and non-responders, to better inform treatment decisions and trial design moving forward.

Declaration

The text is the sole product of the authors and no third party had input or gave support for its writing.

Funding

JJM is supported by NIH K08 NS119796, U19 CA264504, Richard B. Simches Scholars Award and a Semaan Family MGH Scholar in Neuro-Oncology Award.

Conflict of Interest

The authors have no financial or competing interests to declare.

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