Epcoritamab Shines in Third-Line Follicular Lymphoma With the Potential to Move into Earlier Lines

As clinical trial data demonstrated that over 80% of patients with relapsed or refractory follicular lymphoma responded to treatment with the bispecific antibody epcoritamab-bysp (Epkinly) in the third-line setting, resulting in its accelerated approval by the FDA on June 26, 2024, the agent offers a very efficacious option for patients, according to Grzegorz S. Nowakowski, MD, who added it has potential to later move up in lines of therapy.¹

“[Since] we have such an active therapy in the relapsed/refractory setting, [it] will move up in the lines of [treatment] in follicular lymphoma. We have studies [examining] second-line treatment and will be [evaluating] front-line therapy with bispecific antibodies, including epcoritamab,” Nowakowski said in an interview with OncLive^®. “I believe that bispecific antibodies, including epcoritamab, will let us develop chemotherapy-free combinations resulting in excellent efficacy, minimal toxicity, and very durable responses for patients, and hopefully one day [may] cure follicular lymphoma.”

The bispecific CD20-directed CD3 T-cell engager, which was examined in the phase 1/2 EPCORE NHL-1 trial (NCT03625037), elicited a median overall response rate (ORR) of 82.0% (95% CI, 74.1%-88.2%), including a 60.0% complete response (CR) rate, in patients (n = 127) with relapsed/refractory follicular lymphoma.¹ Previous data from the trial in patients with relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma showed that patients treated with epcoritamab achieved an ORR of 61.0% (95% CI, 52.5%-68.7%), with a 38.0% CR rate; this led to the agent’s accelerated approval by the FDA in this patient population in May 2023.^2,3

In the interview, Nowakowski, a consultant in the Division of Hematology and enterprise deputy director of Clinical Research at Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, detailed safety as well as efficacy data that have been observed with epcoritamab. He also highlighted remaining unmet needs the agent could fill for patients with follicular lymphoma.

OncLive: What is the significance of this accelerated approval?

Nowakowski: Despite the progress [made] in the treatment of follicular lymphoma, most patients will relapse and require second- and third-line therapy. We have effective frontline and second-line therapies, however, when we look at the third line therapies and beyond patients tend to do poorly and have limited treatment options. The approval of epcoritamab in this space provides a new treatment option for patients in the third-line [setting]. It’s also important that this is a different modality than some of the other agents approved in this space, [such as] signaling PI3K inhibitors [which have] faced some issues with infections in the past. [Therefore], it opens up new treatment options, and is highly effective in this space.

What was the rationale for the EPCORE NHL-1 trial?

Epcoritamab is a bispecific antibody and bispecific antibodies have been active in a variety of B-cell lymphomas, including aggressive B-cell lymphomas. Considering this unmet need [for] therapy in the third-line treatment of follicular lymphoma, the rationale for this trial was to introduce this antibody and learn about the efficacy of this treatment in the relapsed/refractory [setting]. Preliminary data from phase 1 studies and from preclinical studies indicate that this therapy may be very active in those patients.

[EPCORE NHL-1] was a single-arm study where patients with follicular lymphoma treated with at least 2 lines of therapy were eligible to enter. Patients were treated with epcoritamab [in] 28-day cycles until disease progression or unacceptable toxicity. The end points of the study were focused on efficacy, capturing ORR, CR rate, and also duration of response [DOR] which is very important for patients with low-grade lymphomas.

What were key efficacy findings with epcoritamab?

The efficacy data show that this therapy is extremely effective in this space. Considering patients relapsed after first- or second- line therapy [and were] frequently double refractory—refractory to rituximab [Rituxan] and alkylating [agents, which are the] more standard therapies in this space—the ORR in the study was over 80% despite this. [One-hundred-four out of 127] patients had a benefit from treatment. Importantly, their responses were quite deep, as 60% of the patients had a CR, which showed that this therapy is very effective.

When you see such an effective therapy, the next question is how durable the responses are. This is exciting news for [epcoritamab] because during the follow-up of this study, the median DOR was not reached [at] a median follow-up of 14.8 months. The estimated DOR at 12 months [showed that] nearly 70% of patients were still responding. Not only are the response rates high— the treatment is highly effective—they are durable and sustained [responses].

How could epcoritamab fill an unmet need in this patient population?

There are developments in follicular lymphoma with new treatments coming but we are also facing some setbacks. For example, PI3K inhibitors previously [received] accelerated approval in this space, [but] randomized studies showed some detriment in terms of overall survival due primarily to infections, [which] has led to the withdrawal [of approval] and less enthusiasm to use PI3K inhibitors in the third line setting.

The other approved agents have lower response rates, there’s another bispecific antibody mosunetuzumab-axgb [Lunsumio] which is active in this space as well, but nevertheless, [there] remains an unmet need. Therefore, having epcoritamab approved expands our treatment options for patients with follicular lymphoma. Additionally, epcoritamab is approved for the treatment of patients with aggressive relapsed/refractory lymphomas, including diffuse large B-cell lymphoma and high-grade B-cell lymphoma; this makes it a bit easier to implement this treatment, develop it, and [treat] patients with relapsed/follicular lymphoma because the providers who were involved in the care of those patients are quite familiar with epcoritamab.

What is key to note about the safety profile of epcoritamab?

Overall, the treatment is quite well tolerated. With all bispecific antibodies and T-cell engagers we worry about cytokine release syndrome [CRS] and neurotoxicity, [and] this treatment can cause some cytopenias, primarily neutropenia. Those toxicities are typically of low grade—CRS was grade 1-2, so very mild. Similarly, neurotoxicity was rare and of low grade. Although neutropenia may occur in approximately a third of the patients, it is typically of low grade as well, [and patients] usually respond to temporary interruption of therapy or growth factor support.

A number of patients also had infections [as] this study was done during the COVID-19 era and some of those were related to COVID-19. Hopefully, we are past COVID now and we’ll see those [adverse effects] much less. Considering that this is the relapsed/refractory disease setting, patients are typically already immunocompromised [because of] previous therapies [received, but] the safety profile of this therapy is extremely favorable.

How can physicians monitor patients for immune effector cell-associated neurotoxicity and CRS?

That’s very well captured in the package insert and I would encourage everybody to review it in detail because that’s something that needs to be very closely monitored. Physicians should monitor patients for signs of fever and constitutional symptoms associated with CRS like they would do with other bispecific antibodies or CAR T-cell therapies. The rate and grade are much lower [with epcoritamab] than what we see with CAR T-cell therapy.

But physicians are now comfortable in recognizing this complication and managing it with steroids, fluids, and therapy interruptions. It’s one of those pivotal moments in the development of treatment—particularly in hematological malignancies where we see the use of bispecific antibodies increasing and this is across the indications, [it is] also approved in multiple myeloma, [and there are] a lot of clinical trials coming in solid tumors. The medical teams who are taking care of these patients are getting increasingly more comfortable recognizing those complications.

Patient education is extremely important [as well]. There are booklets available for patients—they should be aware when to call if any of those complications are developing. The same is true about neurotoxicity. Typically, mental status changes or confusion would be the symptoms. This is happening in very few patients, and it is usually low grade, but it’s something we also have to monitor and manage very promptly.

What unmet needs remain for patients with relapsed/refractory follicular lymphoma?

Looking at the landscape, unfortunately there is a continuous risk of relapse for these patients and with each relapse the outcome [for] patients tends to be worse. Focusing on the treatments which can further increase the depth of response and durability of response will be important. One of the most exciting things about epcoritamab [is] it can be combined with many other treatments in contrast to CAR T-cell therapy, which is difficult to combine [as] it’s quite intensive [treatment].

For bispecific antibodies, including epcoritamab, this is just the beginning. Studies have been done [and] you can clearly imagine adding epcoritamab to lenalidomide [Revlimid], to rituximab, or to other agents active in the space to further improve the response and durability of response.

The other area under exploration is [with] more of a fixed duration of therapy. Here, because it’s the third line of therapy and patients have relapsed/refractory disease, the therapy is ongoing until disease progression or unacceptable toxicity. But in the future with the addition of new agents, we may see more of a fixed duration therapy which is able to induce durable responses for patients and be less bothersome in terms of returns to the clinic for ongoing therapy. Even with epcoritamab with subsequent [treatment] cycles, 10 and beyond, that’s typically given once a month; it’s manageable for most of the patients and it’s a subcutaneous therapy which is also very convenient in the infusion center.

References

1. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory follicular lymphoma. FDA. June 26, 2024. Accessed July 11, 2024. bit.ly/3XVzMTP
2. Epkinly. Prescribing Information. Genmab US, Inc; 2024. Accessed July 8, 2024. bit.ly/3LdLYrJ
3. FDA grants accelerated approval to epcoritamab-bysp for relapsed or refractory diffuse large B-cell lymphoma and high-grade B-cell lymphoma. FDA. May 19, 2023. Accessed July 11, 2024. bit.ly/3XZl6mJ