BTK Degraders and Other Targets in Mantle Cell Lymphoma

Transcript:

Alexey V. Danilov, MD, PhD: I’m excited about BTK [Bruton tyrosine kinase] degraders. There was an exciting proof-of-principle presentation by Anthony Mato, MD, MSCE. We participated actively in that trial of NX-2127. While BTK degraders have the same target, they work very differently. They belong to a class of agents called PROTACs [proteolysis-targeting chimeras]. The molecule consists of 2 parts. There’s a hook that attaches to the kinase of interest—in this case BTK, but you can choose anything you like. Then there’s a harness that shuttles the whole thing to an E3 ligase. As a result, the whole complex gets degraded. They are BTK degraders. We enrolled quite a few patients on NX-2127, which is a BTK degrader. We’ve seen good efficacy post-ibrutinib, in CLL [chronic lymphocytic leukemia] in particular. The trial also enrolls patients with mantle cell lymphoma [MCL]. Toxicities were characteristic mostly of what we see with BTK inhibitors: contusion, atrial fibrillation. All these patients were heavily pretreated. Some even had prior noncovalent BTK inhibitors. I’m looking forward to more data from that study. Matt, are there any targets you find exciting in MCL?

Matthew J. Matasar, MD: I agree with you on degraders, and that isn’t the only 1 in the space. Others are developing similar approaches. I’ve always been jealous of our prostate cancer brethren because they can attack testosterone 18 ways. They address androgen until they exhaust that target. Part of me wonders if we’re going to end up there with BTK, where we’re going to have covalent and noncovalent degraders. We’re going to have multiple ways to address BTK in earlier lines of therapy before we’re required to expose patients to the toxicities of other approaches, such as chemotherapy or other treatments we’ve been discussing.

Beyond BTK, I’m invested in the bispecific story personally and professionally, and I’ve been encouraged by those data. One target that we haven’t talked about yet is ROR1, which is a ubiquitously expressed surface antigen. There’s an antibody-drug conjugate targeting ROR1 delivering MMAE [monomethyl auristatin E], which is the same payload as brentuximab and polatuzumab vedotin. The ROR1 MMAE-delivering agent has activity in mantle cell lymphoma, which isn’t surprising because it expresses the target. But the toxicity profile is what you would expect from MMAE-delivering treatment. We don’t have a lot of experience with polatuzumab in mantle cell lymphoma. It’s nice to have some evidence that we can use an MMAE-delivering system as another tool for these patients when we’re trying to get them out of hot water.

Alexey V. Danilov, MD, PhD: My lab has been working on CDK9 inhibitors, and now we have more selective CDK9 inhibitors. In the past, it was a problem for the therapeutic window with nonselective CDK inhibitors, but now we might find the therapeutic window. We have pretty good preclinical data, and clinical data are emerging as well with these drugs. There are also alternative targets for allogeneic CAR Ts. There are a lot of exciting developments in our field.

I’d like to thank everyone for participating.Thank you, Dr Shah, Dr Hu, and Dr Matasar for this rich and informative discussion. To our viewing audience, thank you for joining us. We hope you found this OncLive® Peer Exchange® to be useful and valuable to the treatment of patients with mantle cell lymphoma.

Transcript edited for clarity.