Behind the FDA Approval of Ivosidenib in IDH1-Mutated MDS

The FDA approved ivosidenib (Tibsovo) for the treatment of IDH1-mutated relapsed or refractory myelodysplastic syndromes (MDS) on October 24, 2023, based on data from the AG120-C-001 trial (NCT02074839).^1,2

In the study, 18 adult patients with relapsed or refractory MDS with an IDH1 mutation received oral ivosidenib daily on a 28-day cycle. All responses in the trial were complete responses (CR), and the CR rate was 38.9% (95% CI, 17.3%-64.3%). The median time-to-CR was 1.9 months (range, 1.0-5.6 months), and the median duration of CR was not estimable (range, 1.9-80.8+ months).¹

In an interview with Targeted Oncology^TM, Courtney DiNardo, MD, MSCE, department of leukemia, MD Anderson, Houston, Texas, discussed the mechanism of action of ivosidenib, as well as its potential future indicationsand safety profile.

Targeted Oncology: Could you give some background on ivosidenib?

DiNardo: Ivosidenib is a mutant targeted IDH1 inhibitor. It is a small molecule, and it leads to differentiation of the abnormal cancer cells into the mature normal counterparts they were supposed to be. It is an interesting type of therapy called a differentiating agent therapy where it's not standard cytotoxic therapy that kills indiscriminately—it's actually a targeted therapy specifically for correcting that mutant IDH1.

How does IDH1 mutation play into hematologic malignancies or blood cancers?

IDH1 mutations occur in about 10% of patients with acute myeloid leukemia [AML] and about just under 5% of patients with MDS. The IDH1 mutation in and of itself is not prognostic—it doesn't lead to a more favorable or less favorable outcome compared with the standard. But the standard is unfortunately, especially in the relapse setting, one where there's not great outcomes.

What does the future of ivosidenib look like? Is there potential for future indications?

Ivosidenib has already been approved in in several indications. We now have a new approval for MDS that has failed standard therapy. It's also approved for relapsed IDH1-mutated AML. It's also approved in the frontline, both as a single agent and, importantly, in combination with azacitidine for newly diagnosed AML. We know that it is appropriate, safe, and effective to use in combination. I suspect that will be the evaluation and the future of ivosidenib, and other targeted therapies in general, is moving them into rational combinations where they can be more effective and moving them into the upfront setting.

How does the safety of ivosidenib compare to other drugs for similar indications?

Ivosidenib is a pretty well-tolerated therapy. It’s oral, it’s outpatient. The 2 main [adverse events] to be aware of when you're using ivosidenib is QT prolongation. That is something that can happen when your patients are on multiple different QT-prolonging medicines, as many of our patients who are neutropenic with blood cancers are. Typically, you don't need to hold the therapy or stop the ivosidenib; you just need to stop the other QT-prolonging medications they're on to help address it. But you do need to monitor it, and it is something to be aware of.

The other main adverse event to be aware of is differentiation syndrome. This is more common in patients with AML. There were some patients with MDS that had differentiation syndrome, but it was very few and lower grades. The whole class of IDH1 and IDH2 inhibitors can cause differentiation syndrome, [and that is] something to be aware of. These are nonspecific kind of symptoms, like shortness of breath, edema, culture-negative fevers. That type of nonspecific syndrome, which if you have a patient who is on an IDH1 inhibitor who experiences that, the treatment for that is steroids, corticosteroids, like dexamethasone.

They’re not cytotoxic therapy, so [patients] don't have hair loss, significant myelosuppression, or other things that you typically attribute to standard chemotherapy.

In the MDS population, about three-quarters of patients who were transfusion-dependent of either blood or platelets became transfusion-independent on ivosidenib. That is an important aspect. It's well-tolerated and patients have improvement in transfusion requirements, which helps keep them out of the hospital and improves quality of life.

REFERENCES:

1. FDA approves ivosidenib for myelodysplastic syndromes. News release. FDA. October 24, 2023. Accessed October 24, 2023. https://tinyurl.com/yc562fpp

2. Study of orally administered AG-120 in subjects with advanced hematologic malignancies with an IDH1 mutation. ClinicalTrials.gov. Updated October 11, 2023. Accessed October 25, 2023. https://www.clinicaltrials.gov/study/NCT02074839