The Role of Bispecific Antibodies in Mantle Cell Lymphoma

Transcript:

Alexey V. Danilov, MD, PhD: There are some exciting developments in novel therapeutics in MCL [mantle cell lymphoma]. Bispecifics have been making an impact in lymphoma in generaland MCL in particular. At ASH [American Society of Hematology Annual Meeting], my colleague from City of Hope, Tycel Phillips, MD, presented glofitamab data. Glofitamab is 1 of 2 bispecific antibodies being developed by Genentech. My understanding is that it’s essentially a trispecific. Right, Boyu?

Boyu Hu, MD: Yes. It has 1 arm that reaches for CD3 and 2 arms reaching for CD20, so it’s a trispecific antibody. There were some convincing data. The trial used 2 doses of obinutuzumab, either 1000 or 2000 mg. Using the 2000-mg obinutuzumab not only improved of efficacy but reduced the CRS [cytokine release syndrome] in the neurotoxicity with glofitamab as well. The data were exciting, given that it had a high overall response rate—just like CAR [chimeric antigen receptor] T cells, somewhere in the 80% range. It had a high CR [complete response] rate as well, around 60% to 70%. That’s another tool we can reach for if we need it as a bridging therapy for CAR T. We’d all probably prefer that over chemotherapy, for example. We also had another more targeted-therapy chemotherapy-free strategy for patients who are TP53-mutated.

Alexey V. Danilov, MD, PhD: Not to be provocative, Bijal, but do you think bispecifics will replace CAR T?

Bijal D. Shah, MD: No, and I say this having been in the ALL [acute lymphocytic leukemia] field for a long time. Ultimately, they’ll be complementary, and we’ll be trying to understand how and when to use 1 vs the other in what sequence. There will be a learning process part of that. But I don’t see CAR T going away, and I certainly don’t see bispecifics going away. They’ll have different bridging maintenance things that we can think about after CAR T-cell therapy has been given, which may help improve outputs. We’ll build MRD [minimal residual disease] into our post–CAR T follow-up, so we understand when and where to use some of these instruments. We have something off the shelf that’s incredible. We’re going to see them used together. We really want the boxing match of glofitamab vs epcoritamab vs CAR, but that’s not the reality. As we’ve seen, we’re all reaching for these tools.

Boyu Hu, MD: To that point, it’s going to be taken up in different areas. CAR T is going to remain in these large referral centers and academic centers, whereas glofitamab is going to be taken up more in the community because it’s right off the shelf. Community doctors can give it once they get over that learning curve of how to manage the CRS and the neurotoxicity.

Bijal D. Shah, MD: That’s critical because we haven’t seen that with blinatumomab. Whether it’s the cost or the comfort, it’s hard to say. But we haven’t seen broader community uptake of this bispecific, which we’ve had for years. I’m trying to remember how long it’s been around. It’s fascinating.

Boyu Hu, MD: The continuous infusion scares me a little, but this will be more palatable to give in the community in discrete doses.

Bijal D. Shah, MD: I hope so.

Alexey V. Danilov, MD, PhD: We don’t know yet, but let’s say it requires…all the CRS monitoring. Do you think the community will take up glofitamab?

Boyu Hu, MD: When nivolumab and pembrolizumab came around with immunotherapy, there was some hesitation whether this could be given in the community, given this novel set of drugs and toxicities. It was a big learning curve, but it’s now given routinely in the community. It’s going to be the same thing with glofitamab. Once you use it a couple of times, you learn about CRS and neurotoxicity. We didn’t know about it until we started doing CAR T. We figured it out, but now we have a protocol and algorithm. It’s going to be the same in the community. Some will be comfortable doing it, and some less so. But it’s here to stay, and we’re going to have to learn how to deal with it.

Alexey V. Danilov, MD, PhD: One aspect to think about is we don’t know what bispecifics ultimately do to T cells and how they impact efficacy of subsequent CAR T-cell therapies. If all patients referred to us for CAR T cells have been exposed to bispecific antibodies, what happens? How is that going to go? We don’t know.

Bijal D. Shah, MD: Even more important, what does a bispecific-refractory patient look like? Are they coming in with multiple 10-cm masses that you can’t spot weld your way through? And now we’re coming to CAR T. It’s not necessarily the T-cell impact; it’s the macro impact as well. What does the lymphoma look like? That’s what we learned with blinatumomab. Initially there was a lot of concern about blinatumomab pre-CAR. Is it going to somehow damage the T cells? If you’re resistant, does that mean you’re not going to respond to CAR because your T cells or lymphoblasts don’t respond? It looked like it initially. When we controlled for tumor burden, most of that went away. It was clear that we were selecting the worst of the worst because they’d been through so much before they got to the CAR. That’s scary, and that’s why we have to start thinking prospectively about how we combine rather than how we pivot the 2 against each other.

Matthew J. Matasar, MD: These questions are ultimately going to be answered by real-world evidence. We’re not going to build post-bispecific CAR T clinical trials; that’s a nonstarter. But we’re going to be using bispecifics before CAR T. That’s real world. In large cell lymphoma, we can all say with a straight face that CAR T offers curative potential—words you haven’t heard today about mantle cell lymphoma. Even there, we saw data at ASH that very few patients in the world are getting CAR. [That’s more pronounced with] mantle cell lymphoma, where the same value proposition for CAR T cells may not be present. Now that we’re getting a signal with glofitamab and others that you can mitigate CRS with aggressive obinutuzumab premedication, my guess is that we’re going to find ourselves in a world where there’s community uptake and it’s a preferred treatment. Patients aren’t going to be seeing CAR until they’ve seen bispecifics. That’s my guess.

Alexey V. Danilov, MD, PhD: Let’s say patients progress on bispecifics and come to us. They’ve already seen bispecifics. I’m sure those progressions won’t be pretty. We still need more novel therapies.

Transcript edited for clarity.