Targeted Therapies Could Revolutionize AML Treatment

Gina Columbus @ginacolumbusonc
Published: Saturday, Jun 11, 2016

Dr. Raoul Tibes

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/1st 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/1st 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.

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