ASH 2025 | Evorpacept, lenalidomide and rituximab for high tumor burden indolent B-NHL: a Phase II trial

This year I’m also very excited to present for the first time results from an investigator-initiated trial that I wrote a few years ago. It’s a phase two trial looking into the combination of evorpacept, previously known as ALX148, which is a very novel and potent anti-CD47 targeting agent, in combination with standard of care lenalidomide and rituximab, also referred to as R-square, for patients with previously untreated follicular lymphoma and marginal zone lymphoma with advanced stage and high tumor burden disease. As a clinical background, there was years ago a very large randomized phase three trial called the RELEVANCE trial comparing frontline R-square to frontline chemoimmunotherapy for patients with previously untreated follicular lymphoma and unfortunately the primary endpoint of superiority was not met and so currently we cannot utilize immunotherapy as a frontline treatment for follicular and marginal zone lymphoma. So there’s been a study of interest in trying to increase the activity of R-square, and we demonstrated that tumor-associated macrophages may mediate resistance to R-square, providing the rationale for combining R-square with agents targeting tumor-associated macrophages, such as evorpacept or ALX148. And we were able in a phase one trial that we very recently published on Clinical Cancer Research to demonstrate that the combination of evorpacept and R-square, what I will call moving forward E-R-square, is very safe, but most importantly quite effective. In the relapsed/refractory setting, where historically R-square is able to induce a complete remission in about 20 to 30% of patients, we saw 80% or more of patients experiencing a complete remission. So once the phase one trial in a relapsed/refractory patient was completed, we moved to this phase two in previously untreated. Once again, we demonstrated that there was no synergistic toxicity combining evorpacept to R-square. We saw a little bit more liver function test elevation that was transient, did not result in any liver damage, and was actually a surrogate marker of efficacy. Because as a reminder, our liver is the organ that has the most macrophages, so it makes sense that if the treatment was working, macrophages would get more activated, that may translate into some minor ALT and AST elevation, and these patients tended to do quite well. The efficacy data are also very promising. 100% of patients responded to treatment. 92% had a complete remission. The only limitation at this time is that even if the primary endpoint has been met, we were hoping for a complete remission rate higher than 80%, and in this case was 92%. Of course, because we understand that indolent B-cell lymphoma patients have a very slow natural history, we need to wait for a longer follow-up. At the time of this initial presentation, the median follow-up was close to a year, but in the next couple of years, we should be able to make a final determination whether this treatment also translates into durable remissions. As a final step, we’re now also working with Foresight, trying to analyze samples collected on this trial and to understand whether this regimen may be able to eradicate minimal residual disease, utilizing a very sensitive assay called PhaseSeq, on which we already published on Nature Communications with another regimen. And ultimately if we were able to demonstrate that this regimen can eradicate MRD that could be an indirect sign that this regimen may be curative and finally challenge the paradigm that follicular lymphoma cannot be cured.

This transcript is AI-generated. While we strive for accuracy, please verify this copy with the video.