Targeted Therapies Transform Outlook of FLT3- and IDH-Mutant AML

Lyndsey Runaas, MD

FLT3 and IDH1/2 mutations carry prognostic significance, and now therapeutic implications for patients with both newly diagnosed and relapsed/refractory acute myeloid leukemia (AML), explained Lyndsey Runaas, MD, an assistant professor at the Medical College of Wisconsin.

Most recently, ivosidenib (Tibsovo) received regulatory approval as a frontline therapy for adult patients with IDH1-mutant AML, as identified by an FDA-approved test, who are ≥75 years old or are unable to tolerate intensive chemotherapy. Now that the agent is approved in this setting, as well as alongside enasidenib (Idhifa) in the relapsed/refractory setting, Runaas said that researchers will put more focus on sequencing strategies.

In FLT3-positive AML, there are several agents in the relapsed/refractory space, including gilteritinib (Xospata) and quizartinib, which showed sustained activity in the ADMIRAL and QuANTUM-R trials, respectively. Follow-up data from the phase III ADMIRAL trial showed a significant prolongation in overall survival (OS) with gilteritinib in patients with relapsed/refractory FLT3 mutation—positive AML.¹ Specifically, patients in the gilteritinib arm experienced a 9.3-month median OS versus 5.6 months with salvage chemotherapy (HR, 0.637; 95% CI, 0.490-0.830; P = .007).

Similarly, at a median follow-up of 23.5 months, data from the QuANTUM-R trial indicated a median OS of 6.2 months with quizartinib versus 4.7 months with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).² The FDA scheduled an Oncologic Drugs Advisory Committee (ODAC) meeting to discuss a new drug application (NDA) for quizartinib on May 14, 2019.

“It's a bit of a whole new world. It used to be a bit more straightforward,” said Runaas. “It is certainly more complicated, but I think that's for the better of all of our patients.”

In an interview during the 2019 OncLive^® State of the Science Summit™ on Hematologic Malignancies, Runaas discussed the newfound outlook for patients with FLT3- and IDH1/2-mutant AML given recent regulatory approvals and trial data.

OncLive: What have been the most impactful targeted therapies for patients with mutated AML?

Runaas: A lot has changed in the field of AML in just the past few years. We're learning more about mutations that matter not just prognostically but [therapeutically]. FLT3-mutant AML is not an uncommon subtype of AML. We see it in one-third of patients. Historically, it has been associated with a pretty poor prognosis. Luckily, in the past few years, we've had a variety of FLT3 inhibitors arrive in the market. There are a lot more in the pipeline.

The next question is, “How do we best to use these agents—in what order and for what population?” We have to learn whether it matters which FLT3 inhibitor we give to patients at which time. To try and further that understanding, we have the results of the RATIFY trial, which looked at the oral FLT3 inhibitor midostaurin (Rydapt) in combination with our standard of care, 7+3 chemotherapy for patients with newly diagnosed AML. I found that trial particularly exciting. While there wasn't a difference in response rates, the OS difference between patients who were treated with midostaurin versus those who received placebo is really quite dramatic, especially when you consider that the survival data were censored for the patients who went on to get transplant. This is a really important agent for us.

In the relapsed/refractory setting of FLT3-positive AML, gilteritinib is FDA approved based on data from the ADMIRIAL trial. Quizartinib is another agent being studied in the QuANTUM-R trial. More thorough data will be reported soon. Both agents might be very reasonable options for clinicians treating a patient with relapsed/refractory FLT3-positive AML. We'll have more to learn, as there are many FLT3 inhibitors actively being studied. We’re continuing to combine FLT3 inhibitors with other chemotherapy backbones and look at them both before and after transplant. There is a lot more ahead for patients with FLT3-positive AML.

What targeted therapies are available to patients with IDH1/2 mutations?

For patients with IDH1/2 mutations, we have ivosidenib and enasidenib. Both agents were FDA approved for patients with IDH1- or IDH2-mutated AML. Currently, we're using these medications in the relapsed/refractory setting as that's where they’ve been studied, but I look forward to looking at these medicines in combination with standard induction chemotherapy, or with other agents to learn whether or not we might be able to move those to the frontline setting as well.

Are there concerns regarding sequencing strategies now that these agents are being studied in the frontline setting?

Absolutely. For example, how should we approach a patient with a FLT3 and an IDH mutation? We might consider a drug like venetoclax (Venclexta), but we have to better understand which drug you should use and when. Additionally, which drugs are safe to use in combination? It's nice that these are not traditional cytotoxic chemotherapies. Their side effect profiles are not identical, but that doesn't necessarily mean that we can combine these medicines without having studied them and not expect to see some increased toxicity.

The FDA scheduled an ODAC meeting to discuss the NDA for quizartinib. What are your thoughts on the scheduled hearing?

If quizartinib and gilteritinib are approved for patients with relapsed/refractory FLT3-mutant AML, it's going to be very difficult for a clinician to choose between the 2 agents. Neither of the drugs have data that are particularly mature. I worry that it may be become what clinicians are familiar with in terms of side effects profiles and affordability.

Are there other targets being explored beyond FLT3 and IDH1/2?

CD33 is an interesting target. We have some antibodies, such as antibody-drug conjugates (ADCs) like gemtuzumab ozogamicin (Mylotarg), and antibodies coupled with radiolabeled antibodies like lintuzumab (SGN-33). I reported on some very preliminary data with bispecific T-cell engagers or ADCs looking at CD33 as a target from the 2018 ASH Annual Meeting. Those are very exciting. I would like to have the equivalent of blinatumomab (Blincyto) in AML to help with measurable residual disease. We know it’s a problem, and we don’t know what to do with it.

References

1. Agios Announces FDA Approval of Supplemental New Drug Application (sNDA) for TIBSOVO as Monotherapy for Newly Diagnosed Adult Patients with IDH1 Mutant Acute Myeloid Leukemia (AML) Not Eligible for Intensive Chemotherapy. Agios. Published May 2, 2019. https://bit.ly/2DNjOkV. Accessed May 2, 2019.
2. Perl AE, Martinelli G, Cortes JE, et al. Gilteritinib significantly prolongs overall survival in patients with FLT3-mutated (FLT3mut+) relapsed/refractory (R/R) acute myeloid leukemia (AML): Results from the Phase III ADMIRAL trial. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CTPL04.