2023 Top Story in Oncology: Vorasidenib for IDH1- or IDH2-Mutant Low-Grade Glioma
At this year’s ASCO plenary session, with simultaneous publication in The New England Journal of Medicine, Ingo Mellinghoff reported on an interim analysis of a novel brain-penetrant IDH-inhibitor as primary therapy (other than surgery) in patients with IDH-mutant grade 2 (low-grade) glioma (INDIGO trial, NCT04164901).1 A total of 331 patients with residual measurable (defined as at least one target lesion measuring ≥1 cm × 1 cm) IDH-mutant grade 2 glioma were randomized to receive vorasidenib or placebo once daily until disease progression. Disease evaluation with MRI was performed every 12 weeks (three cycles), and progression was determined by a centralized blinded radiological assessment. After a median follow-up of only 14.2 months, the median progression-free survival was 27.7 months with vorasidenib versus 11.1 months with placebo (HR, 0.39; 95% CI, 0.27–0.56; P < .001). The follow-up period is too short for a survival analysis, as the estimated median survival in such a patient population is in excess of 7 years. Furthermore, the trial allowed for a crossover for patients in the placebo arm. The treatment was well-tolerated, with an increased incidence of elevated transaminases (increased alanine aminotransferase levels of 38.9%, of which 9.6% were grade ≥3 vs 14.7%). Interestingly, there was no decrease (!) in seizure frequency in the experimental arm.
Mutations in the IDH gene in low-grade glioma as an early event in gliomagenesis were identified some 15 years ago. These mutations lead to a neomorphic enzymatic activity in the Krebs cycle. The “new” metabolite 2-hydroxyglutarate leads to epigenetic changes and drives the methylator phenotype (favorable) as well as stimulates proliferation and impairs cell differentiation (unfavorable). It was, thus, uncertain whether the pharmacological inhibition of mutant IDH would be clinically beneficial or detrimental. Furthermore, the absence of tumor shrinkage of higher-grade glioma after IDH inhibitor treatment (ie, response) further led to doubt on the value of an IDH-inhibition strategy. The results of this trial now unequivocally demonstrate that targeting IDH mutations in patients with low-grade glioma results in a true antitumor effect. Indeed, secondary volumetric analyses show a decrease in the tumor growth rate compared with the growth rate established on serial pretreatment MRIs. On average, the tumor volume increase prior to treatment was 13% over a period of 6 months; on vorasidenib therapy, the tumor started shrinking by 3% over a period of 6 months.2 These differences are not appreciable by standard routine MRI comparison; yet, here, they clearly indicate that the IDH inhibitor exerts a quantifiable antitumor effect.
So why are these results not practice-changing (yet)?
The trial was well-designed and provided a clear answer with regard to the efficacy of the intervention. Yet, the trial neither addresses the timing of the intervention nor the sequence or combination with currently established treatments — namely, radiotherapy and cytotoxic chemotherapy with either temozolomide or PC(V) [procarbazine and lomustine; vincristine is nowadays commonly omitted as it has poor CNS penetration]. The INDIGO trial enrolled largely asymptomatic patients with a good performance status who had been diagnosed months to years earlier and were simply followed clinically and radiologically (watchful waiting as the treatment of choice). Many patients were offered trial participation upon the activation of this trial, including many patients who otherwise may have been followed for months to years prior to needing the introduction of any treatment. The time from initial diagnosis to surgery was 2.9 years in the vorasidenib arm and 2.5 years in the placebo arm, with a range of 1 to 20 years (!). For comparison, in our randomized trial (EORTC 22033-26033)3 aiming at high-risk patients for whom treatment is “clinically indicated,” the median time from initial diagnosis to treatment start was only 5 to 6 months, with a range of 3 months to 2.5 years.
Vorasidenib is going to be a very welcome additional treatment option for patients with IDH-mutant glioma. The absence of activity in patients with higher-grade glioma remains somewhat puzzling, and there may be a benefit in combination with other treatments. Providing treatment earlier in the disease course and allowing the delay of subsequent interventions — namely, delaying radiation therapy and/or cytotoxic chemotherapy by more than 1 year, is remarkable; yet, is it meaningful enough in this overall young and functional patient population?
The optimal duration of treatment has been studied very little. Do we need to treat continuously until disease progression; that is, longer than 2 years in half of the patients in the current trial or even lifelong? Active treatment with potentially hepatotoxic agents will require regular (monthly as in the trial?) clinical and biological follow-up.
Vorasidenib is a welcome new addition to our therapeutic armamentarium, but the true work begins now in establishing its optimal role, timing, and treatment duration for patients with low-grade glioma. It will require discipline in enrolling patients in well-designed clinical trials rather than prescribing vorasidenib to every (anxious) patient diagnosed with an IDH-mutant glioma.
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Additional Info
- Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma. N Engl J Med. 2023;389(7):589-601.
- Wen PY, Mellinghoff IK, van den Bent MJ, et al. LTBK-06. Impact of Vorasidenib Treatment on Mutant IDH1 or IDH2 Diffuse Glioma Tumor Growth Rate: Results From the Randomized, Double-Blind, Phase 3 Indigo Study. Neuro Oncol. 2023;25(Suppl_5):v310–v311.
- Baumert BG, Hegi ME, van den Bent MJ, et al. Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study. Lancet Oncol. 2016;17(11):1521-1532.
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