Antibody-Drug Conjugate Targeting ROR1 Shows Activity in DLBCL

Among patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), early phase II trial data that was presented at the American Society of Clinical Oncology (ASCO) annual meeting suggested that zilovertamab vedotin may have antitumor activity.

MedPage Today brought together three expert leaders in the field: Moderator Ian Flinn, MD, PhD, from the Sarah Cannon Research Institute in Nashville, Tennessee, is joined by Caron A. Jacobson, MD, from the Dana-Farber Cancer Institute in Boston, and Jason Westin, MD, from the University of Texas MD Anderson Cancer Center in Houston, for a virtual roundtable discussion. This last of four exclusive episodes focuses on the waveLINE-004 study.

Following is a transcript of their remarks:

Flinn: We’re always in need of new targets, and ROR1 has been a relatively hot topic, I think, for the last few years in terms of both antibodies and CAR [chimeric antigen receptor] T-cells. At ASCO this year, there was a presentation on zilovertamab vedotin, an antibody-drug conjugate targeting ROR1. It looked like there was about a 30% overall response rate, not a huge trial, 30% overall response rate. Jason, do you think that’s going to get us home? Do you think that’s high enough in terms of efficacy to want to be excited about that therapy and maybe what about the target itself?

Westin: First off, the target ROR1 is a great target and I’m very glad to see the therapeutic armamentarium beginning to take advantage of ROR1 as a target in B-cell malignancies. We’ll see CAR T-cells begin to move into this space as well, but zilovertamab as our antibody-drug conjugate targeting this, it’s difficult to know what to make of this waveLINE dataset that was presented at ASCO.

The trial is proposing to have 100 patients enrolled, and their efficacy data, I believe, was on 40 patients, somewhere in that neighborhood. It was a relatively small data cut, as you mentioned. And overall response rate of 30% in 2023 is much less attractive than it was a few years ago. We saw selinexor [Xpovio] be approved for large cell lymphoma, with response rates that were in this neighborhood. And it’s not widely utilized in part because of toxicities, but also there’s other options out there.

And so if the final result of this trial was an overall response rate of 30%, I think that would have a hard time finding a place as a single agent in the landscape for large B-cell lymphoma. But we don’t want to prejudge a trial based upon a subset and maybe the next 60 patients that are enrolled, that number moves higher into the 40% or 50% range, which will be more in line with what we’ve seen recently for other agents.

And so I think the jury’s still out on what to make of this abstract as of yet. Of course, combinations are always a preferred approach if we can find the right dance partner for a novel agent.

Flinn: Thank you. And Caron, what about data with CAR T-cells in this setting? While it wasn’t specifically addressed in that abstract, it’s certainly been a topic previously.

Jacobson: Yeah, so I think actually, the data, the response rate in this study, the waveLINE-004 study, was actually only in the first 20 patients to reach 3 months of follow-up. So it’s an even smaller subset of patients. And I think, as you know, a single-agent antibody-drug conjugate target in large cell lymphomas, you’re asking the drug to do quite a bit. And there are other diseases that highly overexpress ROR1, including mantle cell lymphoma. And we’ve seen some preliminary data of the drug in mantle cell lymphoma, which looks quite good. And also CLL [chronic lymphocytic leukemia].

So I think there are other places to continue to test the target. But I think a 30% response rate in large cell lymphoma is proof of concept that the target is interesting.

And we’re excited to see CAR T-cells targeting ROR1 start to enter the clinic. And these are going to be trials that include patients with large B-cell lymphoma and mantle cell lymphoma following autologous CD19 CAR T-cell therapy. So this is going to be sort of a CAR rescue for CD19 CAR failures, which again is an unmet need. And I think using a target that at least on its face just without the T-cell behind it, that leads to a 30% response rate is really encouraging to me.

Flinn: Okay.

Jacobson: And I also think that maybe combining this drug with other drugs could have legs as well. My only concern is that there seems to be a pretty significant toxicity of diarrhea and I just don’t know how well that will combine with other agents. But perhaps I’ll be wrong.

Flinn: And then maybe, Jason, I can go back to ask you one quick follow-up question on this. Does it really matter what the target is in terms of an ADC [antibody-drug conjugate] if the drug is internalized and so forth? Does it matter whether you’re targeting ROR1 or CD79b? I mean, as long as there’s enough expression and you get binding of the drug to the malignancy and it’s internalized, and I get it in CAR T-cells where there may be antigen escape that you would want an alternative target, but how do you think about that when you’re approached to be an investigator on the next ADC? I mean, what drives your decision making in that?

Westin: Well, I think we’ve seen a lot of therapies that have been targeting the same antigens. And so there’s a lot of drugs out there, including CAR T-cells, loncastuximab [Zynlonta], tafasitamab [Monjuvi] targeting CD19. And as you mentioned, some therapies may have a greater selection pressure to make a relapse or an escape of a disease be truly null for that. That’s rare. I think that these antigens that are commonly expressed are likely to be expressed [as] multiple lines as we’ve done with rituximab, where we’ve recycled that to be a therapy added on to many things over and over again.

But I think in terms of combination strategies, it’s nice to have a wide diversity of targets to go after. So I take your point that if the targets expressed and the chemotherapy warhead is delivered, does it really matter how that bounds to the cell? Probably not. But having the ability to combine that with other therapies, I do think there’s advantages in having ROR1-targeting therapies in addition to CD79b and CD19 and all the other different targets that are being evaluated for antibody-drug conjugates.

Flinn: Well, Caron and Jason, thank you for joining me today on this roundtable on diffuse large B-cell lymphoma, looking at some of the ASCO abstracts.

Click here to watch the other videos from this ASCO roundtable series on diffuse large B-cell lymphoma.

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