Bispecific Antibody Is Highly Active in Relapsed/Refractory Non-Hodgkin Lymphoma

Rajat Bannerji, MD, PhD

REGN1979, a CD20- and CD3-directed bispecific antibody, led to a high objective response rate (ORR) and complete remission (CR) rate in patients with heavily pretreated, relapsed/refractory non-Hodgkin lymphoma (NHL), according to phase 1 results, explained lead study author Rajat Bannerji, MD, PhD.

In the trial, patients with diffuse large B-cell lymphoma (DLBCL; n = 53), follicular lymphoma (n = 25), mantle cell lymphoma (MCL; n = 6), marginal zone lymphoma (MZL; n = 6), or other (grade 3b follicular lymphoma, unknown follicular lymphoma, ungraded follicular lymphoma, or Waldenström macroglobulinemia; n = 6) had received a median 9 doses of REGN1979, as of the data cutoff in June 2019.

Patients received REGN1979 intravenously for 12 weekly cycles followed by another 12 cycles of REGN1979 every other week. Patients must have received prior CD20-directed therapy to be eligible for enrollment.

"Eighty-eight percent of patients enrolled on the study were refractory, meaning either they had not responded to their previous therapy, or they had relapsed within 6 months of their prior therapy," said Bannerji. "Patients had a median of 3 prior therapies, so this was a very refractory population."

In the follicular lymphoma cohort, results showed that the ORR was 95.5% and the CR rate was 77.3% at a ≥5-mg dose. At a dose of ≥80 mg, the ORR was 100%.

In the DLBCL cohort, the ORR was 57.9% and the CR rate was 42.1% at a dose of ≥80 mg. Among patients who had not received prior CAR T-cell therapy, the ORR was 71.4%, all of which were CRs. In patients who had not received prior CAR T-cell therapy, the ORR was 50% and the CR rate was 25%. The ORR and CR rate in the MCL and MZL cohorts were each 67% and 33%, respectively.

In an interview with OncLive, Bannerji, a hematologist/oncologist and chief of hematologic malignancies at the Rutgers Cancer Institute of New Jersey, discussed the clinical activity of the bispecific antibody REGN1979 in patients with NHL.

OncLive: Could you provide some background on the trial?

Bannerji: This was a first-in-human study of the bispecific antibody, [REGN1979]. The main goals of this study were to find a safe dose of the drug and to define the safety and toxicity profile [of the agent]. Patients were very refractory to chemotherapy and were heavily pretreated.

What makes CD20 and CD3 optimal targets in NHL?

CD20 is a well-defined and validated target, which we know in the context of the unconjugated antibodies rituximab (Rituxan), obinutuzumab (Gazyva), and ofatumumab (Arzerra). Bispecifics typically have 1 antigen binding site that specifies the target—in this case, CD20-specific B-cell lymphomas—and a binding site that activates an effector cell, which in this case is CD3, which activates CD3-expressing T cells.

[At the 2019 ASH Annual Meeting], data were presented with 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're targeting B cells in relapsed/refractory lymphoma, and the effector cells are T cells.

What was the design of the trial?

The trial was conducted in a 3+3 dose-escalation cohort design. We did not encounter any dose-limiting toxicities (DLTs). To get more experience in our dose levels, while we were waiting for higher dose cohorts which had already been filled [to mature], we enrolled more patients at lower dose levels that have already been proven safe, to get additional information. Many of our cohorts included more than 3 patients, which gave us more experience with the drug.

What were the results of this trial?

We presented safety and efficacy data. We did not encounter any DLTs in our dose-finding and dose-escalation cohorts. In fact, we reached the maximum planned dose that was written into the protocol, without experiencing any DLTs.

Efficacy was not the primary endpoint of the study, but we did see a fair amount of activity. In relapsed/refractory follicular lymphoma, a number of cohorts had a 100% ORR, with a 100% CR rate.

If we look at all the patients with follicular lymphoma who received a >5-mg dose of the drug. We saw a 95% ORR, with a CR rate of 77%, so it's very active regimen. With a relatively short follow-up of just more than 6.5 months, we looked at progression-free survival (PFS). The median PFS in the follicular lymphoma group was about 11.5 months, which is a reasonable PFS in a heavily pretreated population.

We also saw a clear dose response in patients with DLBCL, so as we increased the dose, we saw higher response rates. Once we were above an active dose of about 80 mg, and some higher dose levels in patients with DLBCL, we looked at [responses] in terms of those who had had prior CAR T-cell therapy and patients who had not had prior CAR T-cell therapy. In the patients who had not had prior CAR T-cell therapy, the ORR was 71%, and all of those responses were CRs. In patients who had prior CAR T-cell therapy, the ORR was 50%, and half of those were CRs.

The study was not limited to patients with follicular lymphoma or to DLBCL. We included patients with any CD20-positive B-cell lymphoma, so we had a couple patients with MCL and MZL. In both of those cohorts, we saw an ORR of 67% and a CR rate of 33%.

What are the next steps for this research?

The dose-escalation and dose-finding portion of this study is complete. In the context of the phase I study, we have some expansion cohorts that are available. We're trying to define the activity a little bit more in follicular lymphoma and in large cell lymphoma.

The sponsor has opened the phase II study, which will incorporate a number of different B-cell lymphomas. Currently, it's open in follicular lymphoma. That’s going to be an international, phase II trial. In Europe, there's also a combination study of this bispecific antibody and a checkpoint inhibitor. Moving forward, the plan is to look at this drug in populations where we think it will be active as monotherapy, but also in various combinations.

Is there anything else about the trial you want to highlight?

We have been impressed by how active and well-tolerated this drug is in patients who are refractory to or relapsing on very active treatments. Initially, I think it will be used in a highly refractory space. That's where a lot of the immune therapies are active, whether it's CAR T-cell therapy, bispecifics, etc., in these very chemotherapy-refractory patients. If a drug this like ends up showing promising activity and safety in combination, it may move further forward in treatment sequence.

Bannerji R, Allan JN, Arnason JE, et al. Clinical activity of REGN1979, a bispecific human, anti-CD20 x anti-CD3 antibody, in patients with relapsed/refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). Blood. 2019;134(suppl_1; abstr 762). doi: 10.1182/blood-2019-122451