Emerging Agents Poised to Transform AML Landscape

Jeffrey E. Lancet, MD

Following the April 2017 FDA approval of the FLT3 inhibitor midostaurin (Rydapt) for patients with acute myeloid leukemia (AML), additional antibodies have emerged that are expected to advance the field.

“We have to give the message to patients that there is more to offer,” said Jeffrey E. Lancet, MD, chair and program leader for the Department of Malignant Hematology, Moffitt Cancer Center. “We are still striking the tip of the iceberg. What we are doing right now and the new drugs that are out there are still so new that there’s a lot to learn.”

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Lancet discussed these exciting new discoveries in the treatment of AML and challenges that remain in improving patient outcomes.

OncLive: You gave a presentation on AML. What were the main points that you highlighted?

Lancet: We have a lot of novel therapies that are in development and likely to gain approval in the very near future for AML, and that is something that we haven’t had in many years—longer than I've been practicing. It's refreshing to see some of the scientific breakthroughs at the molecular and genetic level finally leading to meaningful treatments for patients.

We recently saw the approval of midostaurin. Can you speak to the impact of that approval?

It’s an important advance in the field. It reflects how we can translate the knowledge about genetic events in leukemia to therapies that actually modify that specific genetic event. In the case of midostaurin, there is going to be a large population of patients who benefits from that drug because FLT3 is a frequently mutated gene in AML, and there are certainly a lot of patients who are going to be able to receive it as part of their induction therapy.

I’m excited about where it’s going to lead. It’s exciting to think about the next-generation FLT3 inhibitors coming right behind, which are even more potent and selective. It’s also exciting to think about where we might be 3 or 5 years from now with some of these new drugs.

Can you shed light on what a couple of those emerging agents are?

For the FLT3 inhibitors, we have agents such as gilteritinib, crenolanib, and quizartinib. All of them are felt to be much more selective and potent against FLT3. They show a lot more single-agent activity than midostaurin ever did. It’s really encouraging that these drugs are eventually going to make their way into the mainstream and frontline therapy and really have an impact.

Can you speak to the efficacy of enasidenib (AG-221) and the impact it can have if it gets approved?

That’s another example of a drug that has been developed on the basis of an important mutation that was discovered in this disease. It’s been showing very interesting and promising results as a single agent. We’ve seen over 30% response rates—patients who are able to get into remission and then go on to transplant for potentially curative purposes, and patients who have fewer options to consider receive a single targeted agent, such as enasidenib, and do very well for some period of time.

We’ve heard a lot about CPX-351 (Vyxeos) at prior meetings. What potential does it have?

CPX-351 is a novel delivery mechanism for conventional chemotherapy drugs given in a fixed molar ratio. The phase III study was positive for improved survival. We saw that several patients did very well after transplant, as well, suggesting that this drug could serve as an effective bridge to a curative transplant. In the case of secondary, or otherwise high-risk AML, CPX-351 will emerge as the new standard of care…That’s very exciting because we haven't had anything to improve upon in 7+3 in many years.

What are some of the biggest challenges in AML that you think we can possibly tackle in the next couple of years?

Being able, for the first time, to target minimal residual disease is another such challenge. That's clearly an unmet need in this disease when it comes to dealing with patients with leftover leukemia. There is very little that we can do that is effective, and we’re waiting for the other shoe to drop in most cases. If we have a targeted agent that may be able to impact minimal residual disease, that’s going to be a very important step forward. I know a lot of studies right now are focusing on the use of these targeted therapies in the MRD setting and in maintenance in general.

What do you hope community oncologists took away from your lecture that they can apply to clinical practice?

We’re still striking the tip of the iceberg. What we are doing right now and the new drugs that are out there are still so new that there’s a lot to learn. We need to focus on the continuation of clinical trials to advance the field because that’s where the progress is made.

Now that we have the onslaught of new treatments, it changes the way we approach patient care. In the past, we might have told patients that there is very little to offer. Now, we have to give the message to patients that there is more to offer. We should be looking more deeply and carefully at any 1 individual patient’s profile, both at the clinical level and at the molecular genetic level, to better understand that patient’s disease so that we can give the appropriate therapy based upon whatever target may be present.

The biggest challenges are going to be understanding how to best utilize targeted therapies earlier on and how to combine those therapies in the most effective way. As single agents, these drugs are active, but they are still relatively limited. The real potential is the ability to combine agents and to get the maximum effect out of inhibiting multiple pathways.