Review of the SELECT-AML-1 Trial and the Future of Newly Diagnosed AML

Daniel Pollyea, MD, MS: This select AML [acute myeloid leukemia] study is a randomized study looking at newly diagnosed patients with AML who overexpress RARA. Ultimately, patients will be randomly assigned to receive either venetoclax plus azacitidine plus a placebo, or venetoclax plus azacitidine plus tamibarotene. This is a promising study design because monocytic AML is often resistant to venetoclax, and we also know that monocytic AML often overexpresses RARA. There seems to be some overlap in the diagrams that would allow us to hypothesize that patients who overexpress RARA are also less likely to respond to venetoclax in HMA [hypomethylating agent] onload. The idea behind this study is to try to select from those patients who are going to be less likely to respond to venetoclax and add tamibarotene to their treatment. That’s what the study is doing, and it’s looking at response rates, survival, and the toxicity profile. It’s a promising strategy as a way to potentially have a triplet therapy for a newly diagnosed unfit patient with AML.

If a patient is resistant to venetoclax combinations because of a mechanism that overlaps with increased RARA expression, which we think is possible, then adding tamibarotene could allow a patient to have their response to a venetoclax-based regimen restored. The idea is that if you find a population of patients less likely to respond to venetoclax, and they have some other weakness or target, if you can exploit that target as well, you might be able to overcome the resistance. That’s 1 of the fundamental hopes of this randomized clinical trial.

We’re all really excited, based on our recent history in this field of AML and drug development, that we can continue the momentum we’ve had. New investigational therapies in our field may come in the form of immunotherapies or new targeted therapies against particular gene mutations and chromosome abnormalities. I’m especially thinking of the Menin inhibitors, which are showing so much promise for patients with MLL [mixed lineage leukemia] gene rearrangements and ATN1 mutations. Those are really promising, and we should all be very enthusiastic about watching how things unfold.

There are many new, exciting biomarkers that have potential. We might be able to inhibit MCL1 in some patients with therapeutic effect. There’s a monocytic target called LILRB4 that might be an appealing target for patients with AML with monocytic differentiation who have a lessened response to venetoclax regimens. Then there are more traditional targets, perhaps a new FLT3 inhibitor, based on some data that we’ve seen on quizartinib. There’s a lot of exciting stuff here and right around the corner.

Transcript edited for clarity.