Investigational Bispecific Antibody Signals Safety and Efficacy in B-Cell NHL

Rajat Bannerji, MD, PhD

Rajat Bannerji, MD, PhD

REGN1979, an investigational antiCD20 x anti-CD3 bispecific IgG4 antibody, demonstrated early antitumor activity in patients with heavily pretreated relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), according to data from a dose-escalation study presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

“In terms of what we have seen as clinicians, we have been impressed with how active and well-tolerated the drug was in patients who have gone through very active treatments and are either refractory to them or relapsed very quickly,” Rajat Bannerji, MD, PhD, lead investigator ofthe phase I study of REGN1979  in B-cell NHL, said.

The overall response rate (ORR) was 95.5% with a complete response (CR) rate of 77.3% in patients with relapsed/refractory follicular lymphoma (FL) who were treated with at least 5 mg of REGN1979 (n = 22). In patients who received at least 80 mg of the study drug, the ORR was 100%. Median progression-free survival (PFS) was 11.4 months (95% CI, 6.7-not evaluable). Fourteen out of 21 responses remained ongoing, and out of 17 patients with CRs, 12 patients had ongoing CRs at the last tumor assessment.

With treatment of at least 80 mg, the ORR rate in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) was 57.9% with a CR rate of 42.1%. In patients who had not received a prior chimeric antigen receptor (CAR) T-cell therapy (n = 7), the ORR was 71.4% with all CRs. The ORR rate in patients who had received a prior CAR T-cell therapy was 50% with a 25% CR rate; all CRs were ongoing at the last tumor assessment in this cohort.

The most common treatment-emergent adverse events (AEs) included pyrexia (80%), cytokine release syndrome (59.1%), and chills (50.9%). The most common grade 3/4 AEs included anemia (21.8%), hypophosphatemia (19.1%), lymphopenia (19.1%), and neutropenia (19.1%). No dose-limiting toxicities (DLTs) occurred in the study.

In an interview withTargeted Oncology, Bannerji, associate professor of Medicine at Rutgers Robert Wood Johnson Medical School and chief of hematologic malignancies at the Rutgers Cancer Institute of New Jersey, discussed the safety and efficacy findings from the phase I trial of a bispecific antibody in patients with heavily pretreated NHL, including cohorts of patients with FL and DLBCL.

TARGETED ONCOLOGY: Could you provide some background to this study?

Bannerji:This was a first-in-human study of this bispecific antibody, REGN1979. The main goals of this study were to find a safe dose of this drug and to define the safety and toxicity profile. Along those lines, an important point of our presentation is that we did not encounter any DLTs in our dose-finding and dose-escalation cohorts. We were able to dose up to the maximal planned dose that was written into the protocol without experiencing any DLTs.

TARGETED ONCOLOGY: Why did you look at CD20 and CD3 as targets?

Bannerji:CD20 as a target has been well defined, and we know that from the context of the unconjugated antibodies rituximab (Rituxan) and obinutuzumab (Gazya), so it’s a validated target. The concept of a bispecific, whether it’s this or any other bispecific, is typically having 1 antigen-binding site that specifies the target, in this case CD20 specifying B-cell lymphomas, and a binding site that activates an effector cell, in this case CD3 which activates CD3-expressing T cells. There have been data presented for other types of bispecifics which can activate other types of effector cells, including macrophages, natural killer cells, and T cells. With this particular molecule, we are targeting B cells in relapsed/refractory lymphomas, and our effector cells are T cells.

TARGETED ONCOLOGY: How was this trial designed?

Bannerji:The trial was designed in a typical 3+3 dose-escalation cohort design. As I said, we did not encounter any DLTs. What we did do, though, to get more experience in our dose levels was while we were waiting for a higher-level dose cohort, which had already been filled in the safety period, we had patients available who wanted to enroll in the study. We enrolled them at already-proven safe lower dose levels to get additional information at lower dose levels. Even though we did not encounter any DLTs, many of our cohorts are more than 3 patients to give us more experience with the drug.

TARGETED ONCOLOGY: What were the patient characteristics for this study?

Bannerji:Our patients were very chemotherapy-refractory and heavily pretreated. To give you 2 specific data points on that, 88% of the patients enrolled in the study were refractory with the definition that either they had not responded at all to their previous therapy or they had relapsed in a very short of within 6 months. In terms of prior therapies, the median number of prior therapies for patients in this study was 3. They had gone through at least 3 regimens, which constitutes a very treatment-refractory population.

TARGETED ONCOLOGY: What were the findings?

Bannerji:We are looking at the safety data and efficacy data, and I would like to point out what we have seen in the efficacy, though that was not the primary endpoint of a dose-escalation study. However, we have seen a fair bit of activity.

In relapsed/refractory FL, we had a number of our dose cohorts that had 100% response rates with a 100% CR rate. If we look at all our patients with FL above a 5 mg dose level, we see a 95% ORR with a CR rate of 77%. This is a very active regimen. With a relatively short follow-up of just over 6.5 months, we looked at the PFS, and the median PFS in the FL group was about 11.5 months, which is a reasonable PFS in this heavily pretreated population.

In terms of the other large group of patients that we saw in DLBCL, we saw a clear dose-response. As we went up higher in doses, we had higher response rates. Once we were above an active dose of about 80 mg and some higher dose levels in the large cell lymphoma patients, we looked at them in terms of patients who had prior CAR T-cell therapy and patients who had not had prior CAR T-cell therapy. In those who did not have prior CAR T-cell therapy, our ORR was 71%, and all of those responses were CRs. In the patients who had prior CAR T-cell therapy, our ORR was 50%, and 25% of those patients had CRs. We thought we have a pretty favorable signal.

This is not limited to FL or large cell lymphoma. It included any CD20-positive B cell lymphoma, so we had some other diagnoses. The ones where we had a couple of patients included mantle cell lymphoma and marginal zone lymphoma. In both of those lymphomas, we saw an ORR of 67% and a CR rate of about 33%.

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

Bannerji:The dose-escalation and dose-finding part of this study has been completed. In the context of the phase I study, we have some available expansion cohorts, and we are just trying to define our activity a little bit more in detail in FL and in large cell lymphoma.

Separately, the sponsor has opened their phase II study. It will eventually incorporate several different B cell lymphomas, but it is currently open for FL. That should be an international phase II study. In Europe, there is also a combination study with the bispecific and a checkpoint inhibitor. Moving forward, I think the plan is to look at this drug in populations where we think it will be active as a monotherapy but also future studies to look at it in various combinations.

TARGETED ONCOLOGY: How can this bispecific antibody compete with other agents in this space?

Bannerji: