Targeted Therapies Could Revolutionize AML Treatment

Raoul Tibes, MD, PhD

A host of novel agents that target distinct molecular targets are pushing complete remission rates beyond historical boundaries for patients with acute myeloid leukemia (AML), with further promise anticipated for these agents in various combinations and therapeutic sequences increasingly guided by genomic information and biomarkers, according to Raoul Tibes, MD, PhD.

Chief among the next wave of therapies are FLT3 inhibitors, like quizartinib, which has shown efficacy and tolerability as a monotherapy or in combination with chemotherapy and is currently in 2 ongoing phase III studies for patients with FLT3-ITD-positive AML.

The ongoing phase III randomized QuANTUM-R study (NCT02039726) is determining whether quizartinib monotherapy prolongs overall survival (OS) compared with chemotherapy for patients with relapsed/refractory FLT3-ITD—positive AML. The phase III randomized, double-blind, placebo-controlled QuANTUM-First trial (NCT02668653) will examine quizartinib combined with chemotherapy and then as a maintenance therapy in newly diagnosed elderly patients with AML who are also FLT3-ITD–positive.

In an interview with OncLive during the 2016 Congress of the European Hematology Association, Tibes, a physician-scientist at the University Hospital Head Myeloid Malignancies, Department of Internal Medicine II at the University Hospital in Würzburg & Adjunct Consultant at Mayo Clinic in Arizona, , discussed these ongoing studies, the potential of quizartinib, and the rapidly evolving treatment landscape for patients with AML.

OncLive: What is the potential role for FLT3 inhibition in AML?

Tibes: FLT3 is one of the most commonly mutated genes in AML. It occurs in roughly 20% to 30% of patients in mostly the diploid karyotype AML, but we also have seen it in the relapsed/refractory setting, as well. The exciting part is that we have several first-, second-, and almost third-generation FLT3 inhibitors in the clinic. All of those have shown good results and clinical activity and validated FLT3 is a target in AML. We have several drugs available, and we have exciting results from clinical trials, he added.

The way I approach FLT3 inhibition in AML is to add a FLT3 inhibitor in the upfront/1^st line treatment combined with cytotoxic chemotherapy. For example, the first drug was sorafenib, which has been approved for other cancers, but when added to chemotherapy can achieve very high response rates—up to 90% and even 100% in some of the initial trials.

Now we have even more potent FLT3 inhibitors and the largest trial to date was presented at the 2015 ASH Annual Meeting, with an update at the 2016 ASCO Annual Meeting. This is the RATIFY trial, which uses the combination of midostaurin (also PKC-412) and chemotherapy in FLT3-ITD and TKD (tyrosine-kinase domain) positive patients. It was a large, international collaboration where 3,279 patients were screened and 717 enrolled based on FLT-3 as the biomarker .

The results were positive, in terms of the complete response (CR) and complete response with incomplete platelet recovery (CRi) rates being higher when midostaurin was added. More importantly, the primary endpoint of OS rate was significantly higher in patients who received midostaurin versus patients who received placebo added to chemotherapy (hazard ratio = 0.77 P=0.0074), with a 23% improvement in OS. . This is the first biomarker mutation-targeted trial in AML with a positive OS benefit.

There are also several other FLT3 inhibitors being studied in clinical trials. The ones that come to mind are quizartinib—or AC220—crenolanib, and gilteritinib (ASP2215). All of those drugs have shown single-agent activity in relapsed/refractory AML as first- or second-line salvage, and now these medications are also being tested in large phase III trials in the upfront/1^st line treatment setting, similar to the RATIFY trial. We will have several other trials that will tell us how these second-generation inhibitors will do in the upfront setting in FLT3-positive AML when added to chemotherapy. Importantly, crenolanib and gilteritinib also target the FLT3-TKD, important when considering a trial.

Similar trials are now also ongoing in the relapsed/refractory setting using the same FLT-3 inhibitor chemotherapy salvage combination——and all of the mentioned drugs are in large phase III studies now. If I have a patient, and I have suspicion that the patient has FLT3 (often these patients have very high weight blood cell counts) I think they should be enrolled in one of the clinical trials.

We do have some internal data as well that FLT3- mutations may actually occur at a higher frequency in relapsed AML patients and test all of our patients who relapse for FLT3 mutations, especially if patients are older and they don’t want to have more intensive salvage chemotherapy. But regardless, if they have a FLT3 mutation, we preferentially channel them and enroll them on a clinical trial.

There are also trials of FLT3 inhibitors plus low-intensity therapies—such as azacitidine and decitabine—that have also shown a benefit in terms of achieving responses and potentially longer-term responses, but these studies are ongoing and we need to await more data..

You mentioned that quizartinib has shown some promising early results. Can you discuss the phase III QuANTUM-R and QuANTUM-First studies that are ongoing?

Initially, a lot of the FLT3 inhibitiors were used as a single agent. Single-agent responses for example with quizartinib in relapsed/refractory AML are generally in the range of 40% to 50%; they are CRs but mostly CRis. That in itself is a clinical benefit, but the responses do not last as long as we hoped. Often, after 6 to 9 months, patients unfortunately relapse; therefore, we have to do something else—especially in the relapsed/refractory setting when the goal is and the only chance of cure is to get a patients to an allogeneic stem cell transplant (ASCT).

As for a combination, quizartinib has been tested in phase I trials with a cytotoxic chemotherapy regimen of daunorubicin plus cytarabine. The responses were very good. You saw remissions from the phase I trial that were very high.

Based on these datat, there are several trials ongoing. One is QuANTUM-First, where quizartinib is being combined with cytotoxic chemotherapy in the upfront setting, for FLT3-ITD positive patients with AML. Then, there is the QuANTUM-R trial, where quizartinib is compared with chemotherapy as a first-line salvage option. Both are large randomized phase III trials and allow ASCT.

I think that adding a FLT3 inhibitor with chemotherapy may be a more promising, and the responses will hopefully last longer than using these drugs as single agents.

What other agents are on the horizon for AML, and how is the treatment landscape evolving?

It is actually very exciting these days. In my opinion, we have maximized cytotoxic dose intensity by dose escalation for anthracyclins or other cytotoxic drugs. We now need to focus on improving treatment regimens in the first-line setting for newly diagnosed AML, by adding novel therapies to a chemotherapy backbone. We have several examples.

There are FLT3 inhibitors from sorafenib to quizartinib, and now some of the others—gilteritinib or crenolanib—combined with chemotherapy. One abstract shows that crenolanib plus chemotherapy demonstrates good response rates, as well and this combination will move forward.

In the wake of deciphering the genome and mutation analysis, there are also many other mutations detected for which we now have panel sequencing tests specifically for AML. Importantly, olver the last years, several novel drugs have become available for mutations we commonly find in AML patients.

The other important class of drugs are IDH1 and IDH2 inhibitors. There are several IDH1 inhibitors in clinical development , and one IDH2 inhibitor so far. Both IDH2 and IDH1 inhibitors have also shown rather promising results as a single agent. The response rates for AG-120—the most advanced IDH1 inhibitor—are between 30% and 40%. For the IDH2 inhibitor AG-221, the response rates are in the range of 40% to 50%. And those responses can last as a single agent. These are mutations that change the metabolism of leukemia cells, and thus we are arriving at targeting tumor metabolism, or oncometabolism. with promising results as a single agent.

Those drugs can now be added to concventional chemotherapy to the first-line indcutin treatment based on mutation sequencing, that is if a patient’s AML harbors an ID1 or IDH2 mutation. The mutation frequency for IDH1/IDH2 is in the range of 4% to 8%, maybe 10%, based on several sequencing papers that have been published. Thus now we have another group of AML patients where, all of a sudden, you may add a targeted drug to a chemotherapy backbone.

Unfortunately, we don’t have inhibitors and drugs against all or most of the comon mutations in AML available yet, but with the development of new drugs, over time we will stratify our patients and add a specific drug to our chemotherapy in the first-line setting based on mutation and genomic markers, which I foresee coming.

The second strategy is in patients who are ineligible for intensive chemotherapy, these patients require low-intensity therapies. The backbone have been, historically, hypomethylating agents such as 5-Azacytidine or Decitabine or less common outside trails, low-dose Cytarabine. It is actually very exciting and encouraging that there are several combinations being presented at the last several meetings, where we push the response rates in these chemotherapy ineligible often elderly AML patients. Response rates have been in the order of 15% to 25% response rates for most of the single-agent trials with azacitidine and decitabine. Now we are pushing CR, CRi, and PR rates up to 50% to 75%. It is very exciting, as a leukemia physician who has been involved in many of those treatments, to be breaking the wall and passing 50% CR/CRi rates. As to the durability of those responses, we need longer follow up.

Looking at the various investigational agents, how do you think sequencing will look in the future?

One question that always comes up is, “How do you sequence all of these therapies in the future?” In the first-line treatment setting, if we routinely do gene panels sequencing for the relevant mutations in AML and we have appropriate drugs available, we can add them to cytotoxic chemotherapy. For that we have to do sequencing systemically; we than have to follow the patients and repeat the sequencing at relapse because mutations may change Or new ones may occur, so called clonal evolution. I would favor to add a novel agent based on mutations or a combination of drugs based on the constellations of mutations. Thus, we should start to combine different targeted therapies based on mutations and incorporate biomarker studies for all of our patients.

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