INDIGO Trial Supports Vorasidenib as Effective Targeted Therapeutic in IDH1/2+ Low-Grade Glioma

Rimas V. Lukas, MD

Practice-changing safety and efficacy findings from the phase 3 INDIGO trial (NCT04164901) underscore the value of adding vorasidenib (AG-881) to the treatment armamentarium in IDH1/2-mutant glioma, potentially leading to its approval as the first viable targeted therapy for patients with this tumor type, according to Rimas V. Lukas, MD.

Primary results from the trial presented at the 2023 ASCO Annual Meeting demonstrated that the IDH1/2 inhibitor delayed tumor growth, resulting in a 61% decrease in the risk of disease progression or death vs placebo. Specifically, the median progression-free survival (PFS) was 27.7 months (95% CI, 17.0-not estimated [NE]) with vorasidenib compared with 11.1 months (95% CI, 11.0-13.7) with placebo (HR, 0.39; 95% CI, 0.27-0.56; 1-sided P =- .000000067). Vorasidenib also significantly lengthened time to next intervention (TTNI) vs placebo in this population; the median TTNI was not yet reached vs 17.8 months (95% CI, 15.0-NE), respectively (HR, 0.26; 95% CI, 0.15-0.43; 1-sided P = .000000019).

“It’s great to see a large, international positive phase 3 study that demonstrated a clear, efficacious benefit [with a targeted therapeutic] for patients with low-grade gliomas,” said Lukas in an interview with OncLive®during the 2023 Best of ASCO Meeting. Lukas is a neuro-oncologist at Northwestern Medicine and associate professor of Neurology, Northwestern University Feinberg School of Medicine in Chicago, Illinois.

In the interview, Lukas reflected on the key points of his presentation delivered at the 2023 Best of ASCO Meeting, which comprised existing unmet needs in low-grade glioma, key efficacy and safety findings from the INDIGO trial, and the viability of vorasidenib-based combination regimens for future investigation.

OncLive: Could you briefly highlight the main points of your presentation delivered at the Best of ASCO Meeting on the INDIGO trial?

Lukas: I was lucky to have the opportunity to present at the Best of ASCO [Meeting] this year on the phase 3 INDIGO trial. The trial looked at the use of the IDH1/2 inhibitor, vorasidenib, within the context of patients who have IDH1/2-mutated low grade, or World Health Organization grade 2 gliomas. Some of the key points to stress are that this [agent] demonstrated efficacy in this trial, specifically with respect to improved PFS and TTNI. Both [were] clinically relevant end points. In addition, the treatment was well tolerated and seems like something that could be broadly used.

What unmet needs currently exist for patients with central nervous system (CNS) tumors, specifically those with low-grade glioma?

For patients with infiltrating gliomas in general, we’re looking for treatments that can extend survival, improve time to progression, and do all this while maintaining a reasonable quality of life. [We don't want] the treatments causing any major deleterious issues, both in the short term or the long term, for the low-grade glioma population.

That last part is of particular importance [because] our traditional therapeutics—surgery, radiation, and chemotherapy—all have the potential for long-term toxicities. Some of those toxicities related to radiation, for example, can evolve over time. Patients who did okay at the beginning may be suffering the consequences 10 years later.

Please expand on the rationale for investigating vorasidenib in the INDIGO trial.

The rationale for the INDIGO trial was to take patients with low-grade IDH1/2-mutated gliomas who had some degree of residual disease or progressive disease that necessitated intervention but did not necessitate additional surgery or the initiation of radiation chemotherapy, to look at whether a systemically delivered IDH inhibitor could be beneficial.

The patient population investigated within that trial would often be followed clinically and radiographically for some time interval. It has been somewhat unclear what the optimal tipping points should be for moving forward with treatment. The INDIGO study took this unique patient population and was able to demonstrate that the intervention had value.

Could you expand on the key efficacy findings that were presented at this year’s ASCO Meeting?

[We] observed a clear improvement in PFS, or living without evidence of radiographic tumor growth, with a fairly impressive hazard ratio of 0.39 in favor of the investigational arm with vorasidenib. The other secondary end point that was looked at was TTNI, [defined as] the time [from initiation of study treatment] until the patient underwent something else to treat their tumor, whether that’s surgery, radiation, or the initiation of chemotherapy. TTNI also had an impressive hazard ratio of 0.26 in favor of the investigational arm. [Those] end points were presented at ASCO and [were] highlighted again at the Best of ASCO Meeting.

Were any notable toxicities observed with vorasidenib in the INDIGO study?

The agent is very well tolerated. When you look at the toxicity, the primary thing that stood out was elevation in liver enzymes; that was seen in a subset of patients. In the patients with grade 3 or [higher] adverse effects [AEs] related to the liver, [the toxicity] was somewhere in the realm of 3% to 10% compared [with] close to 0% in the placebo [or] control arm.

What might the future use of vorasidenib look like in this population? Is there a possibility of investigating the use of this agent in future combination regimens?

From my perspective, the data regarding vorasidenib in the INDIGO trial are very favorable. They’re potentially practice-changing if the drug receives regulatory approval, which it hopefully will. One could imagine that it will be utilized in the patient population described in the INDIGO trial, and it may be more broadly generalized, as well. Patients who have recently undergone surgical resection, for example, and have some residual tumor but no obvious evidence of growth may be good candidates for this drug. Patients who have progressive disease may also be considered.

This is a space where we still don’t know whether this type of approach has value or not. It’s going to be important for us to begin exploring this in a systematic fashion. It’s reasonable to assume that there may be a need to use IDH inhibition in combination with other therapies for some of these tumors that have either progressed on vorasidenib in the future, or have progressed on traditional therapeutic [approaches like] radiation, chemotherapy, etc.

There are several potential candidates [for combinatorial exploration]. From my perspective, those would include PD-1 inhibition with IDH inhibition, or PARP inhibition with IDH inhibition. The last [option] is the traditional cytotoxic chemotherapies that we already use, whether that’s temozolomide or [procarbazine, lomustine and vincristine] combination therapy. Lastly, radiation therapy [could be an alternative]. Those are some of the top candidates for next steps in the investigation [of combination regimens].

What is your main message for colleagues regarding this presentation?

It’s a very exciting time in the field of neuro-oncology. This is the first time that we’ve seen a targeted therapy be of substantial value in this patient population, and in infiltrating gliomas more broadly. The overall tolerability of this therapeutic easily lends itself to potential combinations with other agents. It’ll be the job of investigators to be thoughtful about what the optimal pairing will be. That will involve a lot of preclinical work that will hopefully spur rapid translation into the clinical realm.

Were there any other exciting presentations on CNS tumors at this year’s meeting that you’d like to highlight?

INDIGO is the biggest potential game-changer in our field, and I think it really stands out amongst the work that was presented at [this year’s ASCO meeting]. There are plenty of other high-quality studies, as well. Some of these include the utilization of tumor-treating fields in conjunction with PD-1 blockade in the [phase 2] 2-THE-TOP study [NCT03405792], presented by David Tran, MD, of Norris Comprehensive Cancer Center. [The ETERNITY study (NCT03770468)] looked at long-term survivors with glioblastoma; [this] was presented by Michael Weller, MD, of University Hospital and University of Zurich. [Thost data were] also quite interesting. Beyond that, there were innumerable excellent-quality presentations that are going to hopefully help change and define the field over time.

References

Mellinghoff IK, van den Bent MJ, Blumenthal DT, et al. INDIGO: A global, randomized, double-blinded, phase 3 study of vorasidenib versus placebo in patients with residual or recurrent grade 2 glioma with an IDH1/2 mutation. J Clin Oncol. 2023;41(suppl 17):LBA1. doi:10.1200/JCO.2023.41.17_suppl.LBA1