FLT3 Inhibitors Continue to Move Through AML Pipeline

Catherine Smith, MD

Though the 2017 FDA approval of midostaurin (Rydapt) in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation for the treatment of adult patients with newly diagnosed FLT3-positive acute myeloid leukemia (AML) was an exciting milestone for the field, more selective FLT3 inhibitors are emerging in the pipeline that may improve outcomes even further.

“We need to keep in mind that even though we have a new toy to play with, that it may not be the best toy out there,” said Catherine Smith, MD. “There are newer and better drugs coming down the pike.”

At the 2017 ASH Annual Meeting, a phase I trial of gilteritinib plus induction and consolidation chemotherapy demonstrated high response rates in FLT3-mutant newly diagnosed patients with AML. In FLT3-positive and FLT3-negative patients, end-of-treatment complete composite remission (CRc) rates were 91.3% and 56%, respectively. Among subjects who received more than 80 mg of gilteritinib daily, the end-of-treatment CRc rates were 90% for FLT3-positive and 60% for FLT3-negative patients. The median overall survival (OS) has not been reached.

OncLive: What is important to highlight about FLT3-mutant AML?

Smith, an assistant professor in the Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco (UCSF), spoke to the evolution of FLT3 inhibition in AML and ongoing studies that are poised to potentially change practice in an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies.Smith: FLT3 mutations are actually the most commonly found genetic alterations in AML. They come in 2 “flavors”: activating ITD mutations, and there is another subset of mutations that are point mutations found in the activation loop residue D835. We have known for a long time that FLT3-ITD mutations are a poor prognostic indication in AML. These result in increased relapse rates, decreased relapse-free survival rates, and decreased OS. For a long time, the field has looked for ways to mitigate the poor prognosis of these mutations. As a field, we have moved toward almost uniformly transplanting these patients and this does result in better outcomes for patients who are transplant candidates.

We sought to help these patients by developing targeted therapy in terms of FLT3 inhibitors. There has been a big effort to do this for over a decade now. Unfortunately, the first class of FLT3 inhibitors was not very active when used as monotherapy. These include the recently approved midostaurin.

In recent years, there have been more potent and selective inhibitors developed, such as quizartinib, which was very active and resulted in a composite complete remission (CR) rate of 40% to 50% in a relapsed/refractory FLT3-mutant population but, unfortunately, responses were limited by the rapid development of drug resistance.

Recently, we have been able to develop some targeted therapies that are actually active against these D835 mutations. The most active of these is gilteritinib which, in a phase I/II trial in AML, also resulted in CR rates of about 40%. Unfortunately, even gilteritinib has been limited by the development of resistance. It takes a little bit longer, but it still happens. Really, what we have been trying to do is essentially develop strategies in which we can mitigate resistance. That was evident at the 2017 ASH Annual Meeting, where there were multiple trials that…[attempted] to develop active therapy with combinations.

The benefit of this can actually be seen when you look at the recent approval of midostaurin, which is not at all active as a single agent, but in combination with chemotherapy resulted in an increase in OS in a randomized trial compared with chemotherapy alone in the upfront setting. This was a 7% absolute benefit in 4-year OS. It demonstrates that sometimes even when you have a drug that’s not ideal, if you combine it with the right agents, you may be able to produce better outcomes.

Ongoing trials of these more active second-generation FLT3 inhibitors are currently accruing in both the upfront setting and the relapsed/refractory setting. These include upfront combinations with gilteritinib and quizartinib, with induction chemotherapy as well as the hypomethylating agents. While the efficacy of upfront combinations is not able to be evaluated yet, because these are mostly just phase I tolerability trials, it does seem that they do result in impressive upfront remission rates. This includes gilteritinib; in a preliminary report of the upfront combination trial, results have been 100% remission rates. These data were presented at the 2017 ASH Annual Meeting.

Is there any rationale to add immunotherapy to these combination regimens?

The future is bright for therapies in combination, and we are hopeful that some of these newer drugs in combination with some of the drugs we already have in our armamentarium will be able to improve outcomes for these patients with poor prognosis AML. That is a really good question. We are all very excited about the advent of immunotherapy in oncology, both in solid tumors and liquid tumors. Those combinations are not yet being explored, but they are certainly being talked about. It certainly makes a lot of sense that you can combine agents with differing mechanisms and hopefully achieve better outcomes, but the jury is still out.

For patients with newly diagnosed FLT3-mutant AML, do you automatically give them midostaurin plus chemotherapy, or is there an optimal sequence?

For example, FLT3 signaling is important in immune cells as well, and so it may be that there could be unforeseen effects. Actually, FLT3 is being explored as a potential target for some of the immunotherapies. At the 2017 ASH Annual Meeting, there were preliminary results of the FLT3-targeted chimeric antigen receptor T cells, so it is not clear at this point how to best target FLT3 with immunotherapy. Could it be in combinations with small molecule inhibitors that we are developing, or can it be just a target for immunotherapy itself? That will be a focus of investigation going forward. The RATIFY trial, which was of the upfront combination with midostaurin, was only carried out in patients 60 years and younger. Definitely in the younger population we are considering a new standard of care, but it is an open question of what to do with the older patients—whether or not the upfront combinations are going to have the same kind of benefit. You would think it would, but you don’t know that for sure.

What advice can you give community physicians who are treating their patients who have FLT3-mutant AML?

Some patients are not going to be fit for chemotherapy and that is why a lot of these upfront combination trials are combining FLT3 inhibitors with hypomethylating agents, which we know to be better tolerated in that population. That may end up being a better choice for these older patients, where you are really worried about toxicity. Keep in mind that these patients are at an increased risk for relapse and referring them to a transplant center for consideration for transplant is important. Also, keep in mind the availability of clinical trials. Midostaurin is not that great of a FLT3 inhibitor and so, while I do think it is a new standard of care for the younger patients that fall into that trial, it is not a be-all and end-all.

Sometimes, a tendency when a drug gets approved is to just start using it off-label; that is not necessarily the best thing to do. It is not at all active as monotherapy, so there really is no rationale for using midostaurin off-label as monotherapy—certainly not in a relapsed/refractory setting. You are better off trying to refer that patient to clinical trials.

For example, there is a multinational clinical trial which uses gilteritinib randomized to salvage chemotherapy in patients who are relapsed/refractory or first relapse. That would be a better choice for a patient like that. In patients who are not eligible for that trial, there are also novel inhibitors that are being developed. We also have a phase I trial at UCSF looking at the first-in-class covalent FLT3 inhibitor, which is also active against these drug resistance mutations.

Pratz K, Cherry M, Altman JK, et al. Preliminary results from a phase 1 study of gilteritinib in combination with induction and consolidation chemotherapy in subjects with newly diagnosed acute myeloid leukemia (AML). Presented at: American Society of Hematology 59th Annual meeting; December 9-12, 2017; Atlanta, GA. Abstract 722.