Subcutaneous Epcoritamab for R/R DLBCL

The newly approved treatment, subcutaneous epcoritamab-bysp (Epkinly), is indicated for use in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after 2 or more lines of systemic therapy based on finding from EPCORE NHL-1 (NCT03625037) .1

In the phase 2 study, treatment with subcutaneous epcoritamab led to deep and durable responses in this patient population. The overall response rate was 61% with epcoritamab, and the complete response (CR) rate was 38%. The agent also led to a median duration of response of 15.6 months in heavily pretreated patients with R/R DLBCL.

While several targeted therapies have been approved for patients with R/R DLBCL over the past few years, single-agent and ready-available treatment options are limited in this space. Also, chimeric antigen receptor (CAR) T-cell therapy requires patients to travel to tertiary centers for treatment. Considering epcoritamab’s ability to be administered in community practices, the approval of epcoritamab is an important addition to the field, according to Tycel Phillips, MD.

In an interview with Targeted OncologyTM, Phillips, associate professor, Division of Lymphoma, Department of Hematology & Hematopoietic Cell Transplantation at City of Hope, discussed what led to the FDA approval of epcoritamab for patients with R/R DLBCL and how it adds to the current treatment landscape.

Targeted Oncology: Can you discuss the available therapies for relapsed/refractory B-cell non-Hodgkin lymphoma and the need for additional therapies?

Phillips: At the moment, if we look at patients with relapsed/refractory diffuse large B-cell lymphoma, which is the most common non-Hodgkin lymphoma in the United States, in that setting, we have had several approved agents in the last several years. There was an oral medication, lenalidomide [Revlimid], given together with an antibiotic called tafasitamab [Monjuvi] that is approved for patients with second-line or beyond, especially those in the second-line who are unable to tolerate more traditional treatments. In that second-line space, we have historically had salvage chemotherapy, and the complications that we know come with that, followed by autologous stem cell transplantation. For a large number of patients, salvage chemotherapy and autologous transplant was not a great option because these patients had an intrinsic resistance to chemotherapy. More recently, we had the approval of 2 of chimeric antigen receptor therapy treatments or CAR T treatments that have been approved. One is axi-cel [axicabtagene ciloleucel; Yescarta] and the other is liso-cel [lisocabtagene maraleucel; Breyanzi].

Beyond that in the third-line of beyond, there was polatuzumab vedotin [Polivy] and rituximab [Rituxan] may have been the most in rituximab and loncastuximab [Zynlonta], and the oral medication selinexor [Xpovio]. CAR T, as much as we advocate for it, and that is also available in the third-line, is underutilized here in the United States with only about a third of patients who are eligible for CAR T. There is a large number of patients who cannot get to this treatment either because they do not live near a CAR T center or they don’t want to travel to a CAR T center or they can’t keep their disease under control enough to get to CAR T.

Image Credit: © David A Litman – stock.adobe.com

As of right now, CAR T is probably the only treatment that has durable responses in this patient population. With those other treatments that I didn’t mention, there’s probably a minority of those patients who will have a doable response. The vast majority of those patients will likely relapse and die from their cancer.

If they can’t get the CAR T, that does leave a large number of patients who are in need, which prompts the need for more treatments in his patient population. Because even with CAR T and as much as I have advocated for it in this conversation, about half of those patients, if not a little bit more, will fail to respond to CAR T or relapse after treatment with CAR T, and those patients have poor outcomes as well.

Can you give some background on the EPCORE NHL-1 study?

EPCORE NHL-1 was a study looking at epcoritamab, which is a CD20/CD3 bispecific antibody. This bispecific antibody is similar to CAR T and will bind to the B-cell with the CD20 receptor, and then will bind to the T-cell with a CD3 receptor that is joined on that antibody. It sort of forces the 2 together and causes T-cell stimulation and activation, and then uses a patient’s own T cells to try to fight off the cancer. Again, this is like an off the shelf CAR T product, and some people refer to it as [that] because CAR T uses the patient’s own T cells to fight off the cancer. Here, we are trying to do the same thing without the manufacturing process. In this study, they enrolled 157 patients with diffuse large B-cell lymphoma, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, and a few patients afflicted with grade 3B. This was a patient population that was relapsed/refractory, some were CAR T naive, some were CAR T exposed, and the goal was to get an idea of any initial safety signals in this. Then with his dose-expansion in the diffuse large B-cell lymphoma expansion cohort, they were looking to get some gauge of preliminary efficacy of epcoritamab in patients with relapse prior to large cell lymphoma. Epcoritamab was given as a subcutaneous injection.

What were the results from the EPCORE NHL-1 trial?

With all the bispecific antibodies, we see them given in a step-up dosing fashion to reduce some of the adverse events that we know with this type of treatment. Epcoritamab is similar and it was given on day 1 at a dose of 0.16 mg of cycle 1, on day 8 was given at 0.8 mg, and then cycle 1 day 15 and thereafter, it was given at 48 milligrams. It was given weekly from cycles 1 through 3, and then every other week from cycles 4 through 9, and with cycles 10 plus, it was given monthly to maintain response.

We saw an overall response rate in this patient population of 63%. Much more importantly, there was a complete response rate of around 40% in his patient population, indicating that those are the patients we likely would expect to see to have durable responses.

There was not much of a difference if we looked at treatment based on age. As we see, the overall response rate and the CR rate was fairly similar in most of these patients. We saw a slightly higher CR rate in older patients, which probably just reflects their disease and what they received previously.

If we look at patients with primary refractory disease, which is probably our most difficult to treat patient population, there was a slight decrease in the complete response rate from the overall population. There was 30% in our primary refractory group and 39% overall. Then, we looked at those who were CAR T naive and CAR T exposed. The CR rate was 34% in the exposed patient population and 42% in the CAR T naive patient population. Again, probably speaking more to the biology of the disease, we did see a higher CR rate in patients with more treatments, which probably indicates if they’ve received 4 or more lines of therapy, lymphoma was probably not as aggressive as some of the other ones. But overall, there wasn’t a substantial difference in that overall response rate and CR rate across important subgroups that we typically look at in this patient population.

Can you talk about the implications of these findings and the FDA’s approval?

The biggest impact is, these drugs can be given to the community, they don’t have to necessarily be given in a specialized registered CAR T center. It gets dragged into the hands of more physicians, which hopefully gets into the treatment algorithm for more patients. I think the biggest thing moving forward for the community physicians and those who have not prior prior experience with bispecifics or CAR T is getting adjusted to some of the common adverse events that are consistent between bispecifics and CAR T, which are cytokine release syndrome or CRS, immune cell activated neurological symptom, or ICANS, which are neurological complications.

As we get more physicians comfortable with drugs and more comfortable dealing with some of these adverse events, they get more comfortable not having to admit these patients for this type of treatment, we will see a substantial increase in patients treated with these bispecific antibodies, likely because of the ease of giving these compared with what we do with CAR T. They probably will take up a larger share of the market in this patient group at the current time with the community physician’s involvement, if these responses that we’re seeing remain durable, which of you know those who have may or may obtain a complete remission, most of those patients are remaining in remission with longer follow from the study. And those remissions remain durable. And we’re starting to cure a subset of these patients afterwards. Again, it’ll just increase the number of patients, we can give an effective incurable treatment for large cell lymphoma, as the ultimate goal to secure these patients, because again, of how this cancer behaves, patients cannot live with this cancer, so we have to get rid of it or it is fatal.

For those community physicians who may be using this drug for the first time now that it is approved, what advice do you have for them?

I will say from my experience with this agent, most of the patients probably don’t require hospitalization. If they do have any serious events, they are typically low, grade 1 and some great 2. Grade 2 events probably will require some hospitalization and observation, but the grade 1’s typically will not and those just consist of fever, because the epcoritamab was given concurrently with several days of steroids during a step-up dosing. That does help mitigate some of the propagation and escalation of the CRS. Steroids, when we deal with bispecifics, are much more effective at controlling CRS and what we saw with CAR T. Because of that, and because the timing of most of the CR events is kind of predictable. With epcoritamab, a patient gets 2 very small doses. Most of the CRS events do not occur into the first full dose, which is cycle 1 day 15.

You can sort of get an idea of when you expect most of these events and it will allow you to sort of plan things out and predict if you do need to have a hospitalization and allow you to better get things aligned with whatever local hospital that you may patients to and give them some advice about what to expect. Ideally just because of the risk, they will probably need to have some tocilizumab on hand. I will say the majority of the patients probably would not require any treatment, and as I’ve mentioned before, steroids will probably be very effective in mitigating and controlling the CRS events if they do occur in these patients.

I think overall, with time and more experience like what they’ve already done with rituximab, obinutuzumab [Gazyva] or venetoclax [Venclexta], we will get comfortable with the unique [adverse events] that come with these treatments. Again, once that comfortability level is reached, I think the utilization of this bispecific and probably all the other ones may hit the mark, and it will be quite substantial. Overall, it’ll help benefit the patients.

I think the very first is just comfort. And if they don’t necessarily feel comfortable right away, they can work with an academic center or another local center that has more experience with bispecifics just to manage that first cycle of therapy when the step-up dosing is occurring. Because after that first cycle, the vast majority of these patients will not have any more serious events and they can be just treated in a local community center with the subcutaneous injection and then space out eventually those once-a-month injections to keep the disease under control and hopefully cure these patients.

REFERENCE:

1. EPKINLY™ (epcoritamab-bysp) approved by US FDA as the first and only bispecific antibody to treat adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). News release. AbbVie. May 19, 2023. Accessed May 19, 2023. news.abbvie.com/article_display.cfm?article_id=12584

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