Targeted Therapies Continue to Show Promise Against FLT3, IDH1/2 Mutations in AML

Jorge E. Cortes, MD, associate professor of oncology and urology at Johns Hopkins Medicine

Jorge E. Cortes, MD

Anthracyclines and cytarabine have remained the standard of care for most patients with acute myeloid leukemia (AML) over the last 50 years. However, over time, investigators have learned more about the molecular heterogeneity of the disease and are now able to target specific mutations in effort to improve outcomes in these patients.

For patients who harbor FLT3 or IDH1/2 mutations, novel targeted agents have become available for use, explained Jorge E. Cortes, MD, who mentioned FLT3-targeted therapies such as midostaurin (Rydapt), gilteritinib (Xospata), and IDH1/2-targeted agents such as ivosidenib (Tibsovo) and enasidenib (Idhifa).

“FLT3 mutations are important because they are common,” said Cortes. “It’s one of the most common mutations in AML.”

Moreover, quizartinib is an agent moving through the pipeline for patients with FLT3-mutant AML. An update of the phase III QuANTUM-R trial, which evaluated quizartinib in patients with relapsed/refractory AML, was presented at the 2018 ASH Annual Meeting. Results showed that, at a median follow-up of 23.5 months, the median OS was 6.2 months (95% CI, 5.3-7.2) with quizartinib compared with 4.7 months (95% CI, 4.0-5.5) with salvage chemotherapy (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sided P = .0177).

A new drug application (NDA) for quizartinib was granted a priority review designation in November 2018 for the treatment of adult patients with relapsed/refractory FLT3-ITD—positive AML. Under the Prescription Drug User Fee Act, the FDA will decide on the NDA by May 25, 2019.

OncLive: Could you discuss the current treatment landscape for AML?

In an interview with OncLive during the 23rd Annual International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas, and Myeloma^®, Cortes, deputy chair of the Department of Leukemia in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed the current treatment options for patients with AML, including the use of quizartinib in patients with FLT3 mutations, as well as data from the QuANTUM-R trial.Cortes: For the longest time, since around 1970, the treatment with anthracycline and cytarabine was introduced. For nearly 50 years, that standard did not change. Still today, that is the standard for the majority of patients. However, what has happened in recent years is that we started discovering the molecular heterogeneity of the disease, and understanding all of these molecular mutations and changes that happen. Very importantly, [we are] able to translate that into development of new therapeutic strategies.

That led to the discovery of FLT3 mutations, the prognostic implications, and then the development of drugs. Now, we have 3 FLT3 inhibitors approved by the FDA. First, midostaurin [is approved] in combination with chemotherapy for the frontline treatment of patients with FLT3-mutated disease. More recently, gilteritinib [was approved] as a single agent for patients with relapsed/refractory FLT3-mutant AML. Quizartinib is now being reviewed by the FDA, hopefully, to be approved soon.

IDH1/2 mutations are not as common, but each of them still occur in about 8% to 12% of patients. Prognostically, they are not as adverse as the FLT3 mutations. However, they do represent a target, and we have been able to develop both IDH1 and IDH2 inhibitors that are both approved by the FDA. We know patients respond very well, even as single agents, and durable responses are seen with these very well-tolerated drugs.

Those are the 2 main advances in the last few months. Another important drug that has been approved includes venetoclax (Venclexta) in combination with hypomethylating agents. It gives outstanding responses in older and unfit patients in the range of 70%. These responses can be durable. The study was not randomized compared with historical [data], but the median survival in these studies were about 15 months. It’s much better than we expect in that patient population and, again, is very well tolerated. With venetoclax, you need to know how to use it. If you know how to use it properly to minimize the risk of tumor lysis syndrome, it’s a very safe drug.

The other drug was glasdegib (Daurismo), which is a hedgehog inhibitor. These drugs have been used in squamous cell carcinomas of the skin, but in combination with low-dose cytarabine, again in patients [who are older] and with comorbidities, it gave a significant prolongation of survival. This is an additional drug for AML treatment today.

All of a sudden, now we are starting to see that the landscape is changing. We still depend a lot on the chemotherapy, but we are starting to see that adding these drugs to chemotherapy may improve outcomes. Gemtuzumab ozogamicin (Mylotarg) was recently reapproved, and that’s a major advance, but there are many other monoclonal antibodies coming.

Could you discuss the significance of FLT3 and IDH1/2 mutations in AML?

Could you discuss the latest data from the QuANTUM-R trial presented at the 2018 ASH Annual Meeting?

Some of the antibody-drug conjugates, such as gemtuzumab ozogamicin, and bi-specific monoclonal antibodies, such as blinatumomab (Blincyto) for acute lymphoblastic leukemia,[has] the same concept in AML. In the next 2 to 3 years, we will have several of these drugs approved as well.The internal tandem duplication (ITD) implication happens in about 25% to 30% of the patients. The tyrosine kinase domain mutation is a little bit less, at about 5% to 8% at diagnosis. They are associated, particularly the ITD, with a very poor prognosis; their diseases are very proliferative. They do respond to chemotherapy, but their responses are very short, and therefore the survival is very poor. Because it’s a kinase, it’s an important target for development of drugs.This was a study that randomized patients with relapsed/refractory AML to receive either quizartinib or salvage chemotherapy, and there were 3 options in that study. The physicians had to select whether they would give patients either low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and granulocyte-colony stimulating factor with idarubicin (Idamycin; FLAG-IDA). These are the standard salvage therapies that we use in this population. The patients were then randomized and the primary endpoint was overall survival.

The results of the QuANTUM-R trial showed an improvement in survival. The hazard ratio was 0.76, essentially meaning an approximate 24% reduction in the risk of death during the observation period of this study. This, of course, also came with an improvement in the response rate for patients treated with quizartinib. There was a higher response and remission rate. We looked at the composite complete remission (CR) and CR with incomplete hematologic recovery. There were a lot of patients who had a partial remission that didn’t have a CR, but still benefited from the partial remission. Overall, we put them all together, and around 60% of patients responded in some way. This is much better than the chemotherapy arm.

If approved, where will quizartinib fit into the treatment paradigm?

Is this agent being looked at in any other settings in AML?

Importantly, the treatment was very well tolerated. The concern about QTcF prolongation that had been the main dose-limiting toxicity in the phase I study, but at the doses being used in QuANTUM-R, it is at a very low rate and really not associated with serious arrhythmias or any other problems. This was a very well-tolerated, oral, outpatient therapy that beats intensive, aggressive chemotherapy—where patients would spend a lot of time in the hospital. It’s a very positive study.The QuANTUM-R, which would be the basis for the approval now, is in the salvage setting for patients who were refractory or relapsed after prior chemotherapy. That’s where it will be. It’s a similar place to where gilteritinib is approved. The 2 drugs agree very good; they’re both oral, well tolerated, and very effective. Perhaps the population with quizartinib is a little more difficult but generally, they are still similar. You can use either 1 of these 2 drugs, confident that you are going to get a good response for these patients.With quizartinib, additional studies are ongoing for the combination with chemotherapy in the frontline setting in a study called QuANTUM-First. It’s very similar to the study that led to the approval of midostaurin, which means newly diagnosed patients with FLT3 mutations. They are randomized to receive either standard chemotherapy alone or in combination with quizartinib.

In the salvage setting, we are also doing a lot of studies in combination. In the long term, combination therapy will likely be the way we use quizartinib and other drugs, but initially, it will be as a single agent in the salvage setting after resistance or relapse after initial therapy.

Jorge E. Cortes, MD1, Samer K. Khaled, MD2, Giovanni Martinelli, MD. Efficacy and safety of single-agent quizartinib (Q), a potent and selective FLT3 inhibitor (FLT3i), in patients (pts) with FLT3-Internal Tandem Duplication (FLT3-ITD)—mutated relapsed/refractory (R/R) acute myeloid leukemia (AML) enrolled in the global, phase 3, randomized controlled Quantum-R Trial. Presented at: 2018 ASH Annual Meeting; December 4-8, 2018; San Diego, CA. Abstract 563.

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