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ASH 2020 | DTRM-555: combining a BTK inhibitor, mTOR inhibitor and IMiD in B-cell lymphomas

Anthony Mato, MD, Memorial Sloan Kettering Cancer Center, New York, NY discusses the results of a Phase I trial of DTRM-555 (NCT02900716), a novel triplet combination therapy for use in Richter’s transformation (RT) and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The triplet is comprised of DTRM-12, an irreversible Bruton tyrosine kinase inhibitor (BTKi); the mTOR inhibitor everolimus (EV); and pomalidomide (POM), an immunomodulatory drug (IMiD). Pre-clinical studies have shown that the combination can kill malignant B-cells via a synthetic lethality approach. The trial followed a standard 3 + 3 design to determine the optimal DTRM-555 dose. The results showed that adverse events were tolerable and fitted with those reported for each therapy given as a single agent. This interview took place during the 62nd American Society of Hematology (ASH) Annual Meeting and Exposition, 2020.

Transcript (edited for clarity)

I’ll be presenting a unique study called DTRM, which is a triple combination of a covalent BTK inhibitor with everolimus and pomalidomide and taken together the molecule or the regimen is called DTRM-555. And the whole premise of this study is that with targeted agents particularly in full doses, we can hit one pathway and then cancer cells are smart. They overcome it and they develop mechanisms of resistance...

I’ll be presenting a unique study called DTRM, which is a triple combination of a covalent BTK inhibitor with everolimus and pomalidomide and taken together the molecule or the regimen is called DTRM-555. And the whole premise of this study is that with targeted agents particularly in full doses, we can hit one pathway and then cancer cells are smart. They overcome it and they develop mechanisms of resistance.

Here we’re talking about using what we follow synthetically validate concept, hitting multiple key pathways and ancillary pathways simultaneously to try to induce deeper and more durable remissions in cancer cells. It’s not a new concept, it’s actually an old concept in medicine but more recently in the context of oncology you’ve seen many studies now presented with multiple targeted therapies given together for that very purpose. This is a very unique study in that the concept was developed by looking at in vitro studies to come up with the best triple combo testing it with in vivo studies and then bringing it to patients.

And so at the meeting, I’m going to be presenting data on patients with Richter’s transformation and diffuse large B-cell lymphoma heavily pretreated patient population of whom by protocol definition really could not have standard options available to them and demonstrate a near 50% response rate in the Richter’s cohort and DLBCL with responses that do appear to be ongoing.

So again, very early data from the phase I study, but it does appear that this combination is active. Now the way this study was conducted is that patients received these molecules all separately, so three pills once daily. But the point of the study was to come up with the appropriate low-dose, fixed-dose combination strategy. And then the next phase of the trial, the sponsor is now developing single tablets that will either have two of the compounds together or all three of the compounds together. So, a first-in-class attempt to develop multi-targeted combination therapies with one tablet, which may be very convenient for patients and may also help with adherence. So, very excited about it early on and certainly in Richter’s for example, where when you start to get out to three and four prior therapies there are certainly no standard of care and survival is measured in weeks to months. This potentially could represent an advance for select patients.

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