Ongoing Research Targeting FLT3 and IDH1/2 in AML

Lloyd Damon, MD

Lloyd Damon, MD

Identifying an individual patient's genetic abnormalities, such as aFLT3orIDH1/2mutation,can help guide treatment to facilitate remission or ultimate cure, explained Lloyd Damon, MD. There are already FDA-approved agents available for patients with acute myeloid leukemia (AML) who harbor such mutations, and there are others still coming down the pike.

“AML is rapidly advancing in terms of our knowledge of pathophysiology as well as our treatment approach,” said Damon. “Learning more about the genetics and the basic mechanisms of the formation of AML will inform us as to appropriate personalized and targeted therapies. We have had more drugs approved for AML in the last year and a half than in the last decade. Progress is around the corner.”

Quizartinib was granted a breakthrough therapy designation by the FDA in August 2018 for the treatment of adult patients with relapsed/refractoryFLT3-ITD—positive AML based on data from the phase III QuANTUM-R study. Compared with salvage chemotherapy, quizartinib treatment resulted in a 24% reduction in the risk of disease progression or death.

At a median follow-up of 23.5 months, the median overall survival was 6.2 months (95% CI, 5.2-7.2) and 4.7 months (95% CI, 4.0-5.5) with quizartinib and chemotherapy, respectively (HR, 0.76; 95% CI, 0.58-0.98; stratified log-rank test, 1-sidedP= .0177).  

As more potent and specific FLT3 and IDH1/2 inhibitors come to market, Lloyd noted that venetoclax (Venclexta) has shown significant benefit across hematologic cancers and is likely to have an impact in AML, especially in older patients who may be unable to tolerate chemotherapy.

In an interview withTargeted Oncology, Damon, director of the Adult Blood and Marrow Transplant and Hematologic Malignancies Program, and chief of the University of California, San Francisco (UCSF) Hematology Clinic, UCSF Helen Diller Family Comprehensive Cancer Center, discussed novel therapies in AML with a focus on FLT3 and IDH1/2 inhibitors.

TARGETED ONCOLOGY:Could you highlight the novel FLT3 inhibitors in the landscape?

Damon:We currently know over 90% of the genetic lesions involved in the pathogenesis of AML. One's individual genetic findings may direct you to genetic-based therapies that will facilitate entering remission with chemotherapy, or ultimate cure.

FLT3-mutated AML involves 25% of AML cases. It's a great target. We now have a number of drugs, some of which are in development and one that is FDA approved for FLT3-mutated AML. Not all FLT3 inhibitors are created equal. Some of the FLT3 inhibitors are extremely potent and very specific for FLT3. Others are less potent, less specific, and have off-target effects in other tyrosine kinases, leading to excess toxicity.

Midostaurin (Rydapt) happens to be a nonpotent, nonspecific FLT3 inhibitor, which is FDA approved for patients withFLT3-positive AML in conjunction with chemotherapy. The RATIFY trial randomized patients to midostaurin or placebo with conventional chemotherapy and showed a survival advantage with midostaurin. There was a 22% reduction in death, but it's unclear if this benefit was achieved because of the agent’s FLT3 activity.

A more potent and specific drug is quizartinib. Quizartinib was part of a randomized study called QuANTUM-R that was recently presented at the 2018 European Hematology Association Congress. In that trial, patients received quizartinib at relapse or in the primary refractory setting. This was compared with conventional chemotherapy, which could either be low-dose cytarabine; mitoxantrone, etoposide, and cytarabine (MEC) chemotherapy; or fludarabine, cytarabine and GCSF with idarubicin (FLAG-IDA) chemotherapy.

There was a 24% reduction in death with quizartinib compared with chemotherapy, indicating that a potent and specific FLT3 inhibitor may have incredible activity in this disease. [There is more] to come, particularly whether it should be combined with chemotherapy.

One of the take-home points I made was that allogeneic stem cell transplant remains the standard of care for patients withFLT3-mutated AML and should be considered the pathway for an eligible patient. One of the major questions in the transplant community is whether a FLT3 inhibitor after transplant as maintenance is of value.

A large trial known as BMT CTN 1506/2215-CL-0304 is being conducted. We have that available at UCSF. Patients withFLT3-mutated AML in first remission going through allogeneic transplant of any type will then be randomized to 2 years of gilteritinib, another potent and specific FLT3 inhibitor. That is being compared with placebo.

TARGETED ONCOLOGY:What are the available therapies for patients withIDH1/2mutations?

Other things that are moving fast are other targeted therapies. The IDH1/2 story is very interesting.IDH1/2, when mutated. results in an oncometabolite accumulation to hydroxyglutarate. Hydroxyglutarate invokes epigenetic changes that result in the inability of myeloid cells to differentiate. If a cell can't differentiate, it can't go through programmed cell death. IDH1/2 inhibitors trying to correct that abnormality are showing value.

We now have 2 FDA-approved drugs: enasidenib (Idhifa) and ivosidenib (Tibsovo), which are IDH2 and IDH1 inhibitors, respectively. They have a lot of single-agent activity in these diseases. How they will be utilized in the future, whether upfront or with or without chemotherapy, is still to be ascertained.

A practice-changing approval [in 2017] was CPX-351 (Vyxeos), which is liposomal cytarabine and daunorubicin. The theory is if you put these in the liposome and maintain an appropriate molar ratio of 5:1 between the 2 drugs, you get synergistic cell kill. In a large study in patients with secondary AML, CPX-351 had a survival advantage compared with regular 7+3 chemotherapy. At our institution, we use CPX-351 rather than standard treatment in that patient population.

In terms of BCL-2 inhibition, venetoclax, which is an FDA-approved drug for chronic lymphocytic leukemia, is showing activity in virtually every hematologic malignancy in which it is tested. The oral drug is fairly well tolerated. It has extraordinary activity in an older patient population in combination with a hypomethylating agent, such as 5-azacytidine (Vidaza) or decitabine.

Two-thirds of patients enter remission with the combination, which has an extremely tolerable toxicity profile. For patients who are ineligible to receive intense inpatient chemotherapy, this may be standard-of-care changing. [We will hear more on that] in the near future from the FDA.

TARGETED ONCOLOGY:Does immunotherapy have potential to alter the landscape?

AML has been a bit behind the mark with immunotherapy because it's been very difficult to identify targets that are differentially expressed and not found on normal hematopoietic stem cells or hematopoietic myeloid cells. That said, CD123 is a target of interest because it is differentially expressed on what is considered the leukemic stem cell and underexpressed on the normal hematopoietic stem cell. A number of trials using Bi-specific T-cell engagers or dual-affinity re-targeting as immunotherapy directed against CD123 are now in play. We will have trials in both of those spaces open soon at UCSF.

TARGETED ONCOLOGY:What are your thoughts on hedgehog inhibitors?

They are showing great promise. We will be opening a randomized phase III study with glasdegib in combination with either 7+3 chemotherapy or 5-azacitadine in less fit patients. The preliminary data with hedgehog inhibitors have been so encouraging. That could result in a standard practice-changing behavior as well. It isn't quite so targeted at a specific genetic lesion, so it has a broader population to which it could potentially be of benefit.

TARGETED ONCOLOGY:Are there other potential targets in development?

There is some interest in MDM2 inhibitors. If you inhibit MDM2, you force TP53 to be more active. Its normal role is a tumor suppressor gene, and therefore tumor suppressor protein. If you encourage that behavior, you're going to push back bad hematopoiesis and promote hematopoiesis. MDM2 inhibitors are off to a slow start, but are showing activity.

Reference:

Cortes J, Khaled S, Martinelli G, et al. Quizartinib significantly prolongs overall survival in patients with FLT3-internal tandem duplication—mutated (MUT) relapsed/refractory AML in the phase 3, randomized, controlled QuANTUM-R trial. In: Proceedings from the 2018 EHA Congress; June 14-17, 2018; Stockholm, Sweden. Abstract LB2600.