Novel Bispecific Antibody Induces Encouraging Activity in B-Cell NHL

Rajat Bannerji, MD, PhD

Findings from a first-in-human phase 1 clinical trial, presented during the 2020 American Society of Hematology (ASH) Annual Meeting, demonstrated encouraging antitumor activity with odronextamab (REGN1979), the novel CD20 x CD3 bispecific antibody odronextamab offering an off-the-shelf, primarily outpatient, therapeutic approach for the treatment of patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). The study showed durable responses in patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), and the benefit-risk profile appeared acceptable.

Complete responses (CRs) were observed among 70% of patients with relapsed/refractory FL, 81% of which were durable and ongoing up to 41 months. Among the patients with relapsed/refractory DLBCL who had no prior chimeric antigen receptor (CAR) T-cell therapy, 55% had CRs, of which 83% were durable and ongoing for up to 21 months, while CRs were observed in 21% of those who received prior CAR T, all of which were ongoing for up to 20 months.

Grade 3 was the highest grade of cytokine release syndrome (CRS) observed in this study, which was mostly transient and occurred with the initial dose or the immediate step-up dose. Immune effector cell-associated neurotoxicity syndrome-like events were grade 3 at the highest, and no TLS was observed. In addition, 3 patients with FL and 3 with DLBCL had discontinued treatment due to treatment-emergent adverse events, but none were due to either CRS or neurotoxicity.

A potentially pivotal global phase 2 study (NCT03888105) is currently recruiting to further explore the role of odronextamab in patients with relapsed/refractory B-cell NHL. The trial will include patients with FL, DLBCL, mantle cell lymphoma, marginal zone lymphoma, and other B-cell NHL and plans to recruit a total of 481 patients across these 5 cohorts.

In an interview with Targeted Oncology, Rajat Bannerji, MD, PhD, associate professor of Medicine at the Robert Wood Johnson Medical School of Rutgers University and chief of the Hematologic Malignancies Clinic at the Rutgers Cancer Institute of New Jersey, discussed the early and encouraging findings from a novel bispecific antibody for the treatment of patients with FL and DLBCL.

TARGETED ONCOLOGY: What research set the stage for this trial?

Bannerji: In terms of preclinical research, I think there has been a body of work looking at bispecific antibodies, and that goes back decades. I'm not an immunologist by training; I'm a clinical oncologist, but you can see papers that are 20 plus years old looking at this idea of bispecifics. In the clinical setting, both for the study I presented and studies that other colleagues presented with other bispecifics, what we're trying to do is redirect T cells. We know that T cells have very specific affinities for certain antigens via the T cell receptor. We know that there are T cells that infiltrate tumors, and there is a whole body of work on infiltrating T cells into tumors, etc. What is often seen in that setting is that those cells are there, but they're not doing anything to fight the tumor. There is a huge body of immunology [data] about different techniques that tumors use to avoid detection by the immune system, and we know now, for example, there are marketed drugs, like nivolumab (Opdivo) and pembrolizumab (Keytruda), that effect 1 of those techniques, which is checkpoint inhibition, preventing activation of T cells. We have a tumor, we have the immune system seeing the tumor, but it's just not doing anything, and then we also have a lot of other T cells that don't have any specificity to the tumor that are in the body. Bispecifics are a way to redirect T cells, whether they were originally against the tumor or not, and have the T cells become activated. Then, the T cells, in very specific way, attack a tumor antigen, and in this case, we're looking at lymphomas, so we're using a well-established antigen, CD20.

We have a number of commercial drugs, rituximab (Rituxan) being the earliest but also ofatumumab (Arzerra) and obinutuzumab (Gazyva) that are in commercial use as monoclonal antibodies against that target. It's a well-validated target, and so we're going to redirect the T cells that are in the tumor already, and maybe even recruit T cells that are not in the tumor. We're going to have them specifically attack the tumor, and the way that's being done in a lot of these bispecifics, certainly for the 1 that I was talking about, is that 1 part of the bispecific antibodies will bind the T cell receptor via CD3, which is an agonistic binding, meaning an activating binding, not antagonistic, not blocking the receptor gradually turning on the receptor. That's the part where we grab the T cell and we turn it on; we activate it. Then the specificity for the tumor comes on the other side of device, specific where it's binding CD20. We see CD20 in normal B cells, and we certainly see CD20 on lymphoma cells. Now you're taking T cells and you're bringing them up to the lymphoma cell adjacent to it, and you're activating the T cell so the T cell ends up killing the lymphoma cell. The T cells own receptor specificity is not relevant in this interaction, the drug is doing that, so the T cell could have been against the same tumor antigen, or the T cell could be against some bacterial viral antigens that happen to be there and in the body. It's recruited and used to attack the lymphocyte, so there's specificity that's determined by the drug itself.

TARGETED ONCOLOGY: With regard to this trial, what were the end points that were evaluated, and ultimately, what are the updated results?

Bannerji: This is a first in human phase 1 study, so the primary purpose of the study is 2-fold. One is to ascertain the safety of the drug, and the other is to determine a dose to then take into phase 2. The dose-escalation part of the study is complete, and in fact, it was completed last year, so we presented that at ASH 2019.

To answer the second part of your question, what we're showing this year are longer follow-up data on our responses, as well as additional patients who were involved in the study in the intervening year, but primarily looking at longer follow-up data. To cut to the chase, the responses that we're seeing are durable, especially the CRs, which seem to be very durable in patients with ongoing remissions. Specifically, in large cell lymphoma patients who had not had a prior immunotherapy or CAR T-cell therapy, our overall response rate was 55%, and our CR rate was 55%, so all of those were responders. Eighty-three percent were durable responses, meaning that the response was maintained for at least 3 months, and the 3-month value comes from when we're doing scans every 12 weeks, every 3 months. There was a scan that showed a CR, and then the next scan 3 months later continued to show a CR, so we would call those durable responses. We have patients who are maintaining that remission out to the longest at the time of our data cut off, 1 was a patient going out to 21 months who is still in remission. These are durable responses, and the update this year allows us to show those longer durations of response because we have a whole new year of data from these patients.

The caveat I want to say is for these large cell patients, these response data are not from the very first patient that was put on the study. This is at, what we feel are, the active doses, so for odronextamab 80 mg or higher and the doses that will be taken into phase 2 steps. That's the data we're looking at here. The other group that people are very interested in are patients who have had prior CAR T-cell therapy, and we know that, at least in the United States, CAR T-cell therapy for diffuse large B-cell lymphoma is FDA-approved, so these are patients who are treated with commercial agents approved for patients who failed 2 prior lines of therapy. These patients have been received CAR T-cell therapy and progressed on CAR T-cell therapy and have been referred to our study.

Our data in large cell lymphoma is an overall response rate of the 33% with a CR rate of 21%, and, again, the caveat that these are at, what we feel are, the active dose of 80 mg or higher. These are durable remissions, so 100% of those CRs are ongoing. The longest follow-up is out to 20 months, still in CR, and so, again, those were the primary points of this update.

TARGETED ONCOLOGY: In terms of safety, were there any late onset or delayed toxicity signals to note?

Bannerji: No. The toxicity that we do see, primarily low grade, grade 1/2 events, CRS, low grade central nervous system toxicities, etc, all tend to occur relatively early. We, of course, have had higher grade toxicities, including infections, so that may be toxicity that we've seen a bit later. However, in terms of very late toxicity for these people who are in remission now and are going into their second year of remission, we have not seen any late toxicities. I have a number of patients, both in these large cell cohorts but also in the follicular lymphoma cohort who have been off treatment for a year or more, and there has not been any late toxicity that's developed.

TARGETED ONCOLOGY: What are the next steps for this research?

Bannerji: They've already started a phase 2 study, and they're looking at specific cohorts of patients at a specific dose. Again, the study that I'm reporting is a dose-escalation study, so they're going to see monotherapy results there. Hopefully, if there's appropriate activity, the sponsor would pursue, presumably, trying to get regulatory approval for the drug, but in general, in the field, the next steps are combinatorial strategies, either with conventional human therapies and perhaps substituting device-specific [therapies] instead of the current anti-CD20 antibody, rituximab, or similar drugs. I think a lot of people think there are going to be much more interesting combinations, pure immunotherapy combinations without any chemotherapy at all, so there are a lot of ways to tweak the immune system. People are thinking of all different combinations between bispecifics, perhaps with checkpoint inhibitors or other bispecifics.

I think that's going to be kind of the exciting next steps, and hopefully, 1 of the many holy grails oncology harnessing the immune system to eliminate the cancer without having to depend on a conventional set of toxic chemotherapies.

TARGETED ONCOLOGY: What are your final thoughts on this study that you would like to include?

Bannerji: Right now, we are doing our dose-escalation, which is a way that we administer the drug safely with hospitalizations for the patients with those doses, and when we get them to a full dose, we go on to outpatient therapy, so I think 1 thing with just tweaking this drug that's going to be important is determining which patients need to be hospitalized and which patients can go through the entire dose escalation process. As an outpatient, I'm making this much more useful drug not in a research setting, but when you eventually get to using either this particular bispecific or any of the bispecifics as a drug that your community oncologists would have access to in the future, you want a drug that can be given in the clinic, and you don't need mandatory hospitalizations. Determining who is at high risk for the early toxicities such as CRS, and who is low risk and can have all of this done in the office, that's going to be something that's important.

_Reference

_{Bannerji R, Allan JN, Arnason JE, et al. Odronextamab (REGN1979), a Human CD20 x CD3 Bispecific Antibody, Induces Durable, Complete Responses in Patients with Highly Refractory B-Cell Non-Hodgkin Lymphoma, Including Patients Refractory to CAR T Therapy. Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract 400.}