Novel CD19xCD3 Bispecific Antibody May Expand Second-Line Options in Follicular Lymphoma

Ryan Jacobs, MD

The encouraging preliminary activity and safety seen with the novel CD19 and CD3 bispecific T-cell engager TNB-486 could address the unmet need for more targets in relapsed/refractory follicular lymphoma, particularly for patients who have previously received prior CD19- or CD20-directed therapy, according to Ryan Jacobs, MD.

Interim analysis of the dose-escalation portion of a phase 1 study (NCT04594642) was reported at the 2023 EHA Congress. Preliminary efficacy data demonstrated that the administration of TNB-486 at dose levels of 2.4 mg or more produced a complete response (CR) rate of 91% in the overall patient population. This high response rate was observed in heavily pretreated subgroups, with 70.6% (n = 12) of patients having received at least 3 prior lines of therapy. Notably, 100% of patients with CD20-negative disease (n = 2), prior exposure to CD20-directed therapy (n = 2), or lymphoma progression within 24 months (POD24; n = 5) achieved a CR. Moreover, the 6-month progression-free survival (PFS) rate was 91%, indicating durable responses.

The agent’s safety profile was deemed manageable with low incidence and severity of neurotoxicity and cytokine release syndrome (CRS) events.

“At this point for follicular lymphoma, our only option [after frontline chemoimmunotherapy] is CAR T-cell therapy, which is not available for all patients and involves a high level of financial toxicity. Perhaps we could target CD19 without CAR T cells [using this agent],” said Jacobs, a hematologist and medical oncologist at Levine Cancer Institute, Atrium Health in Charlotte, North Carolina.

In an interview with OncLive®, Jacobs expanded on the initial efficacy and safety data seen with TNB-486, the need for more data on treatment-related CRS to improve toxicity management, and next steps planned for the investigation of this and other bispecific antibodies in relapsed/refractory follicular lymphoma.

OncLive: What was the rationale for investigating the novel CD19 and CD3 T-cell engager TNB-486 in relapsed/refractory follicular lymphoma?

Jacobs: [TNB-486] is a T-cell engager that is a CD19- and CD3-targeted agent. It has a unique CD3 binding site that seems to, on analyses, bind with less avidity than some of the other bispecific antibodies. Perhaps that’s why the toxicity data have been favorable relative to what would be expected from bispecific antibodies. Its other binding site is a high-affinity binding region for CD19.

[One] question that comes up a lot is: does this bind to the same CD19 location as other CD19 treatments, such as CAR T cells, loncastuximab tesirine-lpyl [Zylonta], or tafasitamab-cxix [Monjuvi]. Preliminary data indicate that it appears to bind at a different site. Interestingly, that provides [the rationale for why] we allowed patients previously treated with CD19-directed CAR T-cell therapy as well as CD20-directed bispecifics [to enroll] onto the study.

What patient population was included in this analysis, and are any baseline characteristics important to note?

We looked at relapsed/refractory adults with follicular lymphoma. They had to have at least 2 prior lines of therapy. They were treatment refractory on enrollment. The median number of prior lines of therapy was 3. Over 70% of the patients had seen at least three prior lines of therapy. Over half of the patients were identified as [having] POD24, and we know that [this] patient population is difficult to treat. In this report, 2 patients were treated with bispecifics, and 2 patients had previously seen treatment with CD19-directed CAR T-cell therapy.

Could you expand on the preliminary efficacy findings reported at the meeting?

When it comes to efficacy, we focused the analysis on patients that had received at least a 2.4 mg target dose. This is a phase 1 study. I treated some of the very early patients and gave the first in-human dose. We started very low at 30 micrograms and worked our way up. When you look at the patients [who received a] 2.4 mg dose and above, we have 11 patients to evaluate for efficacy. Ten out of 11 patients, or 91%, achieved an objective response, and all those patients were complete responders. In sub-populations of interest, particularly those POD24 patients, all 5 achieved a CR. Both patients that had received prior CD19-directed therapies as well as bispecifics also responded. We also had CD20-negative patients in the study, and those patients also showed high overall responses. That is another value of this treatment. If we keep treating patients with CD20-directed therapies in subsequent lines, we see loss of CD20 in some patients, and that is associated with worse outcomes.

The responses [with this agent] do appear to be durable, with a PFS [rate] of 91% at 6 months, and we have 2 patients that have been on treatment for over a year at this time.

What should physicians know about the toxicity profile of TNB-486?

Adverse effects [AEs] and treatment-related AEs [TRAEs] were expected with prior understanding of bispecifics. [Events] were mostly low grade. The most common TRAE was cytokine release syndrome [CRS], and that was [seen] in [64.7]% of patients. No patient discontinued treatment due to a TRAE. There was only one death on the study, and that was due to COVID-19 in a patient [who had achieved] a CR. [The death] was not felt to be treatment related. Of the original [17] patients I mentioned who were evaluable for baseline characteristics, there were only 3 progressors. Of [patients in this group who received] the 2.4 mg dose and above, only 1 patient did not respond to treatment.

What should be known about CRS and neurotoxicity events in the context of other bispecific antibodies? How has the incidence of these treatment-related toxicities influenced dosing and management strategies in this trial?

We need to delve further into the CRS. The CRS was early in onset and low grade. All [events] resolved within cycle 1, so there were no CRS events beyond cycle 1, and the CRS events were all grade 1/2. Interestingly for this report, a substantial proportion of the patients had received a fixed-dose treatment, which was how the trial was initially designed. Since its inception, we have now moved into [an initial] single step-up dose [of the agent]. [This is] modeling off what we are seeing done with CD20 bispecifics to help mitigate CRS and neurotoxicity. That’s primarily what was reported in this study.

In the current phase of the study, we are in a double step-up dose. Those data [were] not included in this report but will be presented at later meetings. Preliminary data have shown that the single step-up dosing and now the double step-up dosing appears to reduce these low-grade CRS events even further. In terms of neurotoxicity, 4 patients experienced neurotoxicity. There was 1 grade 1 event, 2 grade 2 events and 1 grade 3 event.

Of note, the [individual with] grade 3 toxicity was my patient, and he was a young male in his early 30s. He came to me [with] POD24 after bendamustine and rituximab [Rituxan], and I first treated him on a clinical trial with epcoritamab-bysp [Epkinly] and lenalidomide [Revlimid] plus rituximab. He was refractory to that treatment. In the third line, I treated him with TNB-486. His first dose was 1000 micrograms, [although] we’re no longer using that high of a priming dose. He did have what technically qualified as grade 3 neurotoxicity, but [his presentation] was more of a pleasant, altered state, and he was fairly somnolent. It resolved within 2 days, as did all the neurologic toxicity events. That patient has been on treatment for close to a year now and remains in complete remission. I think he feels that it was worth it.

What future avenues of investigation exist for this and other bispecific antibodies in follicular lymphoma?

We continue to look for more targets. We do a good job of treating [patients with] follicular lymphoma with frontline chemoimmunotherapy, but as mentioned, the outcomes become worse in the second line and beyond in terms of shorter PFS. Bispecifics have now come into this area with mosunetuzumab-axgb [Lunsumio], but we need targets other than CD20. CD19 was shown to be an efficacious target in relapsed/refractory follicular lymphoma.

[TNB-486] is an interesting compound that is showing a lot of promise, [but] it is not indefinite therapy. While we’re still looking for the RP2D in this trial, the drug is pharmacokinetically supported at a dose [that is administered] every other week. If patients were in complete remission, they could go to once-a-month dosing starting at cycle 6, and there’s intention to discontinue [treatment] at 2 years.

Disclosures: Dr Jacobs reports receiving research funding from AstraZeneca, Pharmacyclics, Teneobio, and LOXO Oncology; he has served on a speaker’s bureau for AstraZeneca, Pharmacyclics, Janssen, Abbvie, SecuraBio, Beigene, and Eli Lilly; he has worked as a consultant or in an advisory role for AstraZeneca, AbbVie, SecuraBio, Genentech, Adaptive, Beigene, Pharmacyclics, and Janssen. 

Reference

Jacobs R, Nair R, Seok-Goo C, et al. High complete response rate with TNB-486, a novel CD19xCD3 T-cell engager (TCE), in relapsed/refractory follicular lymphoma (FL): interim results from an ongoing phase I study. Presented at: 2023 European Hematology Association Congress; June 8-11, 2023; Frankfurt, Germany. Abstract S224.