Ianalumab/Ibrutinib Combo Shows Promising Activity in CLL

February 26, 2021
Courtney Marabella
Courtney Marabella

Senior Editor, OncLive®
Courtney Marabella joined the MJH Life Sciences team in 2021 and is Senior Editor for OncLive®. Prior to joining the company she worked as the Audience Development Editor for the Asbury Park Press, part of the USA Today Network. Email: cmarabella@onclive.com

Kerry A, Rogers, MD, discusses the rationale behind the phase 1b study of VAY736 combined with ibrutinib in patients with chronic lymphocytic leukemia and the next steps for this research.

The combination of ianalumab (VAY736) and ibrutinib (Imbruvica) demonstrated encouraging clinical activity and an acceptable safety profile in patients with chronic lymphocytic leukemia (CLL) currently receiving ibrutinib therapy, according to preliminary results of a phase 1b study (NCT03400176) that were presented during the 2020 ASH Annual Meeting and Exposition.

The results provide evidence of a potential approach to discontinue ibrutinib, which is generally indefinite treatment, by VAY736 add-on therapy, explained lead study author Kerry A, Rogers, MD. Additionally, no dose-limiting toxicities were observed with the regimen, and the maximum-tolerated dose was not reached.

“I think the most interesting thing about this antibody is just the target [itself,] and it actually is also a blocking antibody. The biology of that is really unique,” said Rogers. “I'm really looking forward to seeing how that translates into the clinical effectiveness of it.”

VAY736 is an investigational Fc-engineered afucosylated monoclonal antibody that targets the BAFF receptor and enhances natural killer (NK) cell mediated antibody-dependent cellular cytotoxicity. Preclinical findings showed that the combination of ibrutinib and VAY736 had synergy, providing rationale to explore the regimen as a way to deepen responses and potentially allow patients to discontinue ibrutinib.

In an interview with OncLive, Rogers, a hematologist/oncologist and assistant professor in the Department of Hematology at The Ohio State University Comprehensive Cancer Center–James, discussed the rationale behind the phase 1b study of VAY736 combined with ibrutinib in patients with CLL and the next steps for this research.

OncLive: What was the rationale to combine VAY736 and ibrutinib in this population?

Rogers: VAY736 is an antibody that is very novel because it has a target that's not something that's currently covered by our approved monoclonal [antibodies], which are targeting anti-CD20. It actually targets the BAFF receptor, and it is unique because it has 2 separate mechanisms. It's engineered to have very potent NK cell-mediated antibody-dependent cellular cytotoxicity. In the preclinical data, [results showed] that this is still very potent compared with the anti-CD20 [antibodies] that are on the market, even in the presence of ibrutinib where it's been previously shown that it decreases the targeting and immune destruction capabilities of those antibodies.

Then, as a separate mechanism, it's a blocking antibody. If it's bound to the cells, it inhibits signaling through the BAFF receptor. That's actually a pro-survival signal that is still active when patients are taking ibrutinib.

That's the rationale for using it in CLL, which expresses the BAFF receptor, but also in combination with ibrutinib, because in preclinical models, it worked in the presence of ibrutinib and also has this other blocking activity. The reason that we chose the patient population we did—which is people who are taking ibrutinib who have not achieved a complete remission [CR] after at least 1 year, or those with mutations known to confer clinical resistance, is because those are patients who have something to gain by adding a second drug. The goal in both of those cases would be to eliminate the residual leukemia in people who don't have a CR—they may not be resistant, but the disease is still detectable—or in those with mutations to eliminate the residual leukemia and the resistant clone, and allow people to successfully discontinue treatment.

This was a phase 1 study, and the goal was to determine the safe dose in combination with ibrutinib and also, hopefully, [a dose] that had some biologic activity, too. It was really exciting to see that we actually had no dose-limiting toxicities, and the maximum-tolerated dose was not reached. Overall, the antibody infusions with the VAY736 were very well tolerated. There were a few grade 3 or higher toxicities—mostly neutropenia—and we didn't observe any infections that would limit the use of this antibody.

The whole point of the phase 1 trial with these cohorts was to determine the optimal dose going forward, but it was great to see that 3 of our 15 patients actually achieved a CR with no detectable CLL, and chose to discontinue all treatment and are now in follow-up. They are being observed on therapy. There was a pretty big variability in the amount of CLL that patients had when they entered the study, so it would be exciting to see, now that we're in the expansion phase, more information on the activity of this combination.

What ultimately will be the dose that will proceed to the expansion phase?

It was not the highest dose we used. We're currently using 3 mg/kg in the expansion phase.

Was there anything from the analysis that surprised you?

I wasn't expecting to see this many patients in a phase 1 trial that actually had elimination of the CLL and were able to stop treatment. That was kind of a surprise, especially because it wasn't what the study was powered to detect, but it was great to see that kind of efficacy already.

What were the parameters by which minimal residual disease (MRD) was assessed?

MRD was assessed in the study using standard 10-color flow cytometry [FC] with the limited detection of 10-4. That's the usual standard parameters for FC in CLL. Patients were treated for 6 cycles—these were 28-day cycles and the antibodies are given every 14 days—and then were assessed 8 weeks after that. They were assessed in both the blood and the bone marrow at that time. We did follow the peripheral blood circulating disease burden during treatment and at the end-of-therapy time point.

Could you elaborate more on the next steps of this research?

We're currently accruing to an expansion study in both those populations: those who have not achieved a CR after ibrutinib, and those with molecular resistance. The next step is to gather more safety data and then some formal preliminary efficacy data in these expansion cohorts. My hope is that, ultimately, this antibody will be tolerated and effective enough that this could be used to facilitate people discontinuing ibrutinib.

As I'm sure everyone knows, BTK inhibitors are just outstanding drugs for CLL and are highly effective, but a major drawback is that they don’t eliminate the leukemia completely. People take them kind of indefinitely, or at least for years, so it would be great to see this antibody as a therapy for people who are tolerating ibrutinib, and to be able to eliminate residual leukemia and stop treatment.

Being off treatment comes with a lot of benefits to our patients, [such as] decreased chronic toxicity [and] decreased financial toxicity. That’s what I hope to see for this, and then beyond that, I hope actually to expand this into different patient populations in CLL. Of course, given the target, it would be nice to see this tested in other B-cell malignancies. That's beyond what we're doing immediately with this study, but that would be really exciting, too, because it's just such an effective antibody.

Reference

Rogers KA, Flinn IW, McGarry C, et al. Phase Ib study of ianalumab (VAY736) and ibrutinib in patients with chronic lymphocytic leukemia (CLL) on ibrutinib therapy. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020. Accessed January 25, 2021. Abstract 1309. https://ash.confex.com/ash/2020/webprogram/Paper137629.html


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