Transforming FL Treatment: Inside the EPCORE FL-1 Trial Results

AbbVie’s Al Fakhoury, PharmD, and Genmab’s Brian Elliott, MD, share how the EPCORE FL-1 trial results position epcoritamab + R2 as a chemo-free, highly effective option poised to shift the treatment paradigm in follicular lymphoma.

Please state your name, title, and any relevant experience you’d like to share.

Al Fakhoury, PharmD, RPh: My name is Al Fakhoury. I'm the therapeutic area lead for lymphoma at AbbVie. I've been in hematology/oncology for about almost 25 years now in various roles.

Brian Elliott: I am Brian Elliott. I'm a hematologist/oncologist. I'm the clinical development lead for epcoritamab at Genmab here in Princeton. I've been in pharma for a little over 10 years now.

The EPCORE FL-1 trial demonstrated an impressive 79% risk reduction in disease progression or death. What do you believe are the key biological or mechanistic drivers behind such a profound treatment effect with epcoritamab in combination with R2?

Elliott: First, this demonstrates the power of harnessing a patient's innate immune system—specifically, the benefit of T-cell engager mechanism for treating hematologic malignancies. The standard of care, rituximab + lenalidomide (also known as R2) has a mechanism based on immunology. Combining R2 with epcoritamab yields a triplet with 3 different and complimentary modalities. Epcoritamab targets the B-cell antigen CD20 and the T-cell antigen CD3, stimulating T-cell proliferation and activation and facilitating T-cell-mediated cytoxicity only upon simultaneous binding to CD20-expressing cells.

Although epcoritamab and rituximab both target CD20, they utilize different mechanisms to induce cytotoxicity. Our previous studies have demonstrated that epcoritamab and rituximab can not only be combined effectively but may even have synergistic effects. Rituximab is known to induce NK cell-mediated antibody-dependent cellular cytotoxicity. In our prior clinical trials, epcoritamab has been shown to increase both NK cell numbers and levels of NK cell activation.

The third component, lenalidomide, enhances the proliferation and activation of both T cells and NK cells. So, in this triplet regimen, each of the agents not only has a distinct mechanism of action but also may augment the antilymphoma effects of the other agents.

Additionally, rituximab has the effect of reducing the incidence and severity of cytokine release syndrome (CRS) related to epcoritamab, likely by achieving some degree of debulking of the disease prior to the first full dose of epcoritamab, and perhaps also via direct effect on cytokine production.

Putting all of that together, we were not surprised that we had such a large benefit over the standard of care.

From a clinical perspective, how do you envision these results reshaping the current treatment paradigm for relapsed/refractory follicular lymphoma (FL), particularly in earlier lines of therapy?

Fakhoury: The current treatment paradigm in follicular lymphoma is based on rituximab-based regimens, and R2 is one of the key treatment modalities that is given in earlier lines. However, this triplet actually offers a chemo-free option that is available to patients, because the current standards of care include bendamustine plus rituximab (BR), which is very toxic as well. There is also R-CHOP. So, chemotherapy is actually a concern with patients and clinicians, and giving patients an opportunity to have a treatment regimen with such amazing efficacy is a great option to get them out of a chemo regimen.

When using a triplet, you are treating patients in the earlier lines with much more effective medicines so that you can consider what you're going to use in later lines of therapy as well. If you have a re-treatment option available, that is something that we could consider by giving R2 with epcoritumab upfront or bispecific with epcoritumab upfront, with R2 and then the bispecific upfront. I think it's going to change the treatment paradigm in earlier lines of therapy to consider triplet upfront and earlier and avoid chemo regimens in the earlier lines of therapy.

Elliott: The only thing I'd add is, like you said, with chemotherapy we're in the relapsed/refractory setting. These patients have basically all received chemoimmunotherapy with an anti-CD20 agent combined with chemotherapy. Patients, particularly those who have progressed within 24 months of that initial chemoimmunotherapy, don't respond well to another chemoimmunotherapy in the relapsed/refractory setting, and they don't respond very well to R2 alone either. They don't get long-term benefit from it.

We're really hoping that the addition of epcoritumab to that can allow the chemo-free alternative option that those patients need to, at least, delay the need for further treatment and reduce morbidity and mortality.

With the US Food and Drug Administration (FDA) accepting the sBLA for priority review, what considerations are being taken to ensure swift real-world adoption should approval be granted—especially regarding administration, patient selection, and physician education?

Elliott: Assuming the new indication is approved, our companies are working diligently to ensure that we can deliver epcoritumab to patients with relapsed/refractory FL who are in need of new treatment options, as we said.

This includes continuing and bolstering our collaborations with treatment centers to ensure smooth integration into their practices and equipping providers with the information and data they need to feel confident treating appropriate patients.

The hematologists and oncologists are already comfortable using lenalidomide for the treatment of a number of different hematologic malignancies. The R2 regimen, as we said, is already approved in the US and Europe for relapsed/refractory FL, and the dosing and schedule of R2 in the EPCORE FL-1 trial was the same as those of the approved regimen used in clinical practice, based on the AUGMENT study.

There's also growing familiarity and comfort with the use of epcoritamab itself in its currently approved indications, as monotherapy in third-line and later diffuse large B-cell lymphoma (DLBCL) and FL.

In the phase 3 study, the dosing and administration of epcoritamab were the same as those currently approved for the third-line FL indication, except with an earlier transition to the less frequent every-4-week dosing after only the first 3 cycles. That makes this regimen even more convenient for patients and providers.

The toxicity profile for the combination will also be familiar to providers who've used both R2 and epcoritamab separately, since it reflects the profiles of those individual regimens without the need for additional monitoring or any new safety signals observed within our phase 3 study.

Can you share insights on how the EPCORE FL-1 data might influence ongoing or future trials investigating epcoritamab in other B-cell malignancies or combination regimens?

Fakhoury: Epcoritamab is approved already in the third-line and later setting for DLBCL and FL as monotherapy with treatment to progression. This trial is the first time we're actually combining with other agents, such as R2, for follicular lymphoma, using a fixed-duration treatment regimen. This is a great opportunity to have a regimen that is fixed for stopping therapy and having an amazing result afterwards.

In terms of the combination, this study is the first one, but there are other trials that will look at combinations with R-CHOP as well. This sets the stage for combinations with chemo and other agents like lenalidomide with rituximab.

These fixed-duration treatment and combination studies are going to be the wave of the future for epcoritamab in the earlier-line settings as well. We're also looking at other histologies, like chronic lymphocytic leukemia, in the future. The focus is on expanding into earlier-line settings with combinations of epcoritamab and chemotherapy, as well as combining epcoritamab with other regimens such as R2 for follicular lymphoma. It's setting the stage for fixed-duration treatment as well as combinations. It's an amazing opportunity to look at that in other histologies as well, like CLL.

Is there anything else you hope audiences will take away from this?

Elliott: There is one other thing that may come up, and we haven't shared our complete data yet, but we do have a publication recently published in Blood. It has the epcoritamab plus R2 data from our phase 2 study. If people go and see that publication and want to reference it for efficacy and toxicity, they need to keep in mind that, overall, patients in that study received more epcoritamab than they did in the phase 3 trial.

That regimen not only had a monotherapy maintenance component up to 2 years but also had a cohort with more frequent dosing. In addition to that, we didn't have our optimized CRS mitigation in that study. We expect that with our enhanced CRS mitigation there will be even less of an issue when these data come out from our phase 3 study, once they're presented.

We're also talking about R2 and the AUGMENT study. Other data on R2 from subsequent trials have shown underperformance compared with results observed in the AUGMENT trial. That speaks to the first question of distinct biology. Patients who enrolled to AUGMENT were randomized to rituximab plus or minus lenalidomide. The investigators had to consider rituximab monotherapy as a reasonable treatment option for those patients.

Patients who were refractory to rituximab were not eligible for that study. So, it is a very different population, a different biology, and a much higher-risk disease. We wouldn't expect R2 to perform as well in our study or similar studies as it did in the pivotal AUGMENT trial for R2.

Fakhoury: Stay tuned for the American Society of Hematology (ASH) annual meeting. There will be a presentation there and a publication shortly thereafter. We're really excited. It's going to be great timing for us to show you that epcoritamab is considered a core therapy.

As we're thinking about combinations and fixed-duration treatment in the future, that's the message that we want to make sure that we are relaying to clinicians out there and patients as well.