A Flood of Bispecific Antibodies Anticipated in Multiple Myeloma

Scientific developments, particularly in antibody engineering, have led to numerous innovations in cancer immunotherapy.¹ One of the
most promising innovations has been the development of bispecific antibodies (bsAbs).² These specialized therapeutics combine the specificities of 2 antibodies to simultaneously detect 2 separate epitopes or antigens on tumor cells or in the tumor microenvironment.^3,4

“The idea is that the antigen acts as a bridge,” Farhad Ravandi-Kashani, MD, the Janiece and Stephen A. Lasher Professor of Medicine and Chief of Section of Developmental Therapeutics in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, said in an
interview with Targeted Therapies in Oncology™. “It recruits T cells and brings them over to the malignant cells. The T cells then get activated and
destroy the malignant cells.”

In 2014, blinatumomab (Blincyto), a CD19/CD3 bispecific T-cell engager antibody, became the first bsAb approved in the United States to treat relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and Philadelphia chromosome–negative B-ALL.¹ Topp et al analyzed pooled 3 year follow-up data from 2 single-arm phase 2 trials (NCT01209286 and NCT01466179) of blinatumomab therapy in 259 patients with R/R B-cell precursor ALL at high risk for unfavorable outcomes and found that it induced favorable long-term survival rates.⁵

Because of their unique mechanisms of action and growing ease of production, bsAbs have the potential to become a valuable weapon against cancer.⁶ At present, more than 100 bsAb formats have been developed, and 57 bsAb therapies were in clinical trials as of 2019.^6,7 With further technological advancements in bsAb manufacturing and a deeper understanding of target expression on cancer cells, currently retractable disease may someday become manageable.

Antibody vs Immunotherapy

Chimeric antigen receptor (CAR) T-cell treatment for B-cell leukemia and lymphoma has shown impressive clinical success in recent years.⁸ Between 30% and 40% of patients with lymphoma with high-risk features have sustained responses to CAR T cells; however, many obstacles limit
their therapeutic efficacy.⁷ As an alternative to CAR T-cell therapy, bsAbs have shown promising activity in aggressive tumors and can potentially circumvent some of these challenges.

“The main advantage of bsAbs over [autologous] CAR T cells is that they’re off-the-shelf,” Ravandi-Kashani said. “You don’t have to engineer [bsAbs] for the patient.” As an off-the-shelf option, bsAbs can be used immediately and do not require a lengthy production process. On the other hand, CAR T cells are customized to each patient, and manufacturing time is typically greater than 3 to 4 weeks. Consequently, bsAb therapy may be a better option for individuals with rapidly progressive disease.⁸

In addition, although bsAbs are linked to adverse effects (AEs) comparable to those seen with CAR T cells (FIGURE 1⁹), such as cytokine release syndrome (CRS) and central nervous system toxicities, these AEs seem less frequent and severe.⁸“ [BsAbs] have some of the same toxicities as CAR [T-cell
therapy] in terms of CRS. Still, in general, it’s confined to the first cycle and is pretty manageable,” Loretta J. Nastoupil, MD, an associate professor and deputy chair in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center, said in an interview with Targeted
Therapies in Oncology™.

Additionally, despite the persistence of CAR T cells, disease relapse can occur.⁸ Immunosuppression from the tumor microenvironment, host
systemic inflammation, and intrinsic T-cell dysfunction may explain this occurrence.^9,10 BsAbs also rely on host T-cell function, therefore T-cell exhaustion and dysfunction could also underlie resistance to these therapies.⁸

BsAbs that are specific to CD3 show striking kinship with the adoptive cell transfer of T cells expressing CAR transgenes. CD3-BsAbs and CAR T cells are similar in many ways: Both target a surface tumor-associated antigen, exploit T-cell effector functions, and both are successfully used in the clinic for hematological malignancies and show a similar type of toxicity profile.¹¹ Also, resistance to anti-CD20 monoclonal antibodies (mAbs) can occur through loss of CD20 protein expression.¹² Whether this is a relevant mechanism of resistance to CD20/CD3 bsAbs is unclear.

Ultimately, the efficacy of bsAbs compared with CAR T cells is unknown. For FDA-approved anti-CD19 CAR T-cell treatment of R/R large B-cell lymphoma (LBCL), response rates are between 52% and 82%, with complete response (CR) rates between 40% and 54%.^13-15 Long-term follow-up data indicate that responses are durable, particularly for patients with CRs.⁸ Rates of response to bsAbs in aggressive lymphomas vary from 33% to 71%, with CRs of 19% to 64%, though these results may be influenced by previous CAR T-cell exposure. However, the experience with bsAbs is relatively limited, long-term follow-up is scant, and information on the durability of response is still lacking.⁸ Similarly, it is unclear how these agents compare with CAR
T-cell therapies in terms of survival. However, evidence shows that bsAbs are efficacious in individuals who have disease recurrence following CAR T-cell therapy.⁸

BsAbs in Multiple Myeloma

There have been significant therapeutic advancements in multiple myeloma (MM). Regardless, it remains primarily incurable, and novel therapeutic options are needed.¹⁶ The October 2022 approval of teclistamab
(Tecvayli), a bsAb that binds B-cell maturation antigen (BCMA) and CD3, expressed on T cells, to direct T cells to kill MM cells, provides one such option.¹⁷ In the Majes-TEC-1 trial (NCT04557098), 165 patients with R/R MM received teclistamab monotherapy at the recommended phase 2 dose. Results showed that 58.8% of patients had a very good partial response (VGPR) or better, and nearly 40% showed a CR (FIGURE 2¹⁸). In phase 2 of the MajesTEC-1 trial, patients with R/R MM who had received 3 or more prior lines of therapy were given teclistamab. At a median follow-up of 14.1 months, investigators reported the objective response rate(ORR) was 63.0%
and the duration of response (DOR) was 18.4 months. The median progressive-free survival (mPFS) was 11.3 months, and the median overall survival was 18.3 months.¹⁹

In the TRIMM-2 trial (NCT04108195), talquetamab was given with CD38 mAb
daratumumab (Darzalex) to patients with R/R MM who had received 3 or more prior lines of therapy. Study results showed that the combination therapy at the recommended phase 2 doses of talquetamab achieved high response rates; specifically, an ORR of 76.5%, a very good partial response or better of 64.7%, and a CR or better of 29.4%.^20,21 The ongoing TRIMM-3 trial (NCT05338775) is assessing the safety and tolerability of a PD-1 inhibitor in combination with talquetamab or teclistamab for treating R/R MM.

Recently, elranatamab, a BCMA/CD3-targeted bsAb, was granted breakthrough therapy designation for the treatment of patients with R/R MM.²² The basis for this designation was 6-month follow-up data from the
MagnetisMM-3 trial (NCT04649359), which showed an overall response rate of 61.0% among patients with no previous exposure to BCMA-targeted treatments. In addition, 90.4% of responders sustained the response
for at least 6 months. Lastly, elranatamab had a manageable safety profile, and most AEs were grade 1 or 2 in severity.²²

Another bsAb in the pipeline for MM treatment is ABBV-383, an anti–BCMA/
CD3 bsAb. Preclinical studies have shown that ABBV-383 maximizes MM target cell destruction while minimizing off-target toxicity and CRS.²³ D’Souza et al demonstrated that in 79 patients with R/R MM with 3 or more prior lines of therapy, ABBV-383 monotherapy generated an ORR of 57% and a 43% rate of VGPR or better. The most common treatment-emergent AE (TEAE) was CRS, and most TEAEs were grade 1 or 2 in severity.²⁴

Zonder et al recently published data from the LINKER-MM1 study (NCT03761108) regarding REGN5458, which is another BCMA/CD3 bsAb.²⁴ Previously, investigators demonstrated that REGN5458 induced early, deep, and durable responses in heavily pre-treated patients with R/R MM refractory to at least 3 lines of therapy. Monotherapy with REGN5458 was also well tolerated and had an acceptable safety profile. The updated analysis determined that REGN5458 maintained an acceptable safety and tolerability profile after dose escalation in patients with triple- to penta-refractory R/R MM. In addition, the response rate for the combined 96- and 200-mg dose levels was 73.3%.²⁴

Lastly, monotherapy with cevostamab, an Fc receptor-homolog 5 (FcRH5)/CD3 bsAb, demonstrated clinically meaningful activity in heavily pretreated patients with R/R MM in a phase 1 trial (NCT03275103).25The type I membrane protein FcRH5 is expressed exclusively in the B-cell lineage, with higher expression on myeloma cells than on healthy B cells. Thus, cevostamab-enhanced T cell–mediated cytotoxicity is specific to malignant cells. The median duration of response was 15.6 months, and the ORRs in patients with prior exposure to CAR T cells, bsAbs, and antibody drug conjugates were 44.4% (4 of 9 patients), 33.3% (3 of 9), and 50.0%
(7 of 14), respectively.²⁵

BsAbs in Lymphoma

Although CAR T cells have transformed the B-cell lymphoma therapeutic landscape, many individuals are refractory to therapy or experience a relapse of their illness. BsAb therapy provides an alternate option that may be more suitable for many patients. All bsAbs for lymphoma treatment target
CD20 and CD3; CD20 is widely expressed on malignant B cells. One such therapeutic is epcoritamab, a CD20/CD3 bsAb that is given subcutaneously. This administration route “leads to more delayed absorption, which may be a strategy to address CRS,” Nastoupil said.

In the EPCORE NHL-1 trial (NCT03625037), epcoritamab was given to patients with relapsed, progressive, or refractory CD20-positivematureB-cell non-Hodgkin lymphoma (B-NHL), including LBCL and diffuse large B-cell lymphoma (DLBCL). Epcoritamab elicited an ORR of 63% and a CR rate
of 39%. The median duration of response was 12 months.²⁶

In the dose-escalation phase of EPCORE NHL-1, epcoritamab demonstrated an ORR of 68% in patients with DLBCL with a CR rate of 45%. In patients with follicular lymphoma (FL), the ORR was 90% with a CR rate of 50%. Moreover, the safety profile was manageable and similar to previous findings.²⁶ A follow-up trial, EPCORE NHL-2 (NCT04663347), evaluated the safety and efficacy of epcoritamab plus rituximab (Rituxan) and lenalidomide (Revlimid) in 27 patients with R/R FL. The combination treatment achieved an ORR of 100% and a 93% complete metabolic response rate among all patients.^7,27,28

As far as epcoritamab receiving FDA authorization, Nastoupil is confident it will happen by spring 2023. “[Epcoritamab] may be an attractive option for community sites, given its subcutaneous route...the chair time might be reduced, so patients are in and out a little faster,” she said.

Another CD20/CD3 bsAb, mosunetuzumab (Lunsumio), induced deep and durable remissions and had a manageable safety profile in patients with R/R FL in a pivotal phase 2 study (NCT02500407).²⁹ Matasar et al discovered that mosunetuzumab induced an ORR of 87% and a CR rate of 70% in patients aged 65 years or older with R/R FL and at least 2 previous treatments. Results in patients younger than 65 were less impressive, with an ORR of 77% and a CR rate of 55%. Moreover, the rate of serious AEs was numerically lower in older individuals than in younger ones (37% vs 52%).³⁰

In the CELESTIMO trial (NCT04712097), investigators are assessing the efficacy and safety of mosunetuzumab in combination with lenalidomide vs rituximab plus lenalidomide in patients with treatment-refractory R/R FL.³¹ Lenalidomide is an immunomodulatory agent that improved the efficacy of rituximabin the trial.³¹ A previous phase 1b study (NCT4246086) showed that the mosunetuzumab/lenalidomide combination induced favorable safety and promising activity in patients with treatment-refractory R/R FL, providing the rationale for the CELESTIMO trial.³¹ Results from this trial are not yet complete.

Budde et al assessed the safety and anti-tumor activity of fixed-duration mosunetuzumab in patients with R/R FL who had received 2 or more previous therapies.³² “Because mosunetuzumab has a very favorable safety profile and promising efficacy across B-cell lymphomas, a phase 2 expansion was launched in R/R FL,” Nastoupil said. Patients in the study had at least 2 prior lines of therapy, including an anti-CD20 antibody and an alkylating agent.

“In this phase 2 single-arm study, mosunetuzumab as a single agent resulted
in quite impressive efficacy,” Nastoupil said. “The ORR was [approximately] 80%, the CR rate was 60%, and the [mPFS] was [approximately] 17 months. That compares quite favorably to the other options in the third line or later settings. And because most patients had grade 1 CRS, [and] few had grade 2 or higher, [mosunetuzumab] can likely be safely administered in an outpatient setting.”

Mosunetuzumab was also effective in treating R/RB-NHL. A dose-escalation
study of single-agent mosunetuzumab demonstrated that the best ORRs across all doses investigated were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively.³²

In comparison, the CR rates were 19.4% and 48.5%. Furthermore, the median DOR for individuals with a CR was 22.8 months for aggressive B-NHL and 20.4 months for indolentB-NHL. The most common AEs were neutropenia, low-grade CRS, and hypophosphatemia.³³

The ELM-1 trial (NCT02290951) assessed the safety and tolerability of odronextamab, a CD20/CD3 bsAb, in patients with CD20-positive B-cell malignancies who had previously received CD20-directed antibody treatment.³² A total of 145 heavily pretreated individuals were included in the study; 94 were enrolled in the dose-escalation portion of the study and 51 were enrolled in the dose-expansion portion. Results showed 72 of 142 trial participants achieved a response, for an ORR of 51%. Moreover, the
ORR was 91% (29 of 32) among patients with FL whose odronextamab dose was 5 mg or higher. Of these 32 responders, 23 (72%) had a CR. The safety profile was manageable, with most cases of CRS and neurological AEs being mild in severity.³

Pivotal phase 2 data presented at the 2022 American Society of Clinical Oncology Annual Meeting showed that glofitamab, another CD20/CD3 bsAb, induced durable CRs in patients with R/R DLBCL who had received a median of 3 prior therapies (NCT03075696).³⁵ Because of its unique configuration, glofitamab may have certain benefits over other bsAbs, according to Nastoupil. “Glofitamab has a 2:1 targeting of CD20 to CD3,” she said. “As a result, it might have even greater potency than what we see with mosunetuzumab.”

Among study participants, 59% were refractory to their initial therapy, and
approximately 35% had received prior CAR T-cell therapy. Most CRs were durable and ongoing at 12 months. CRS was the most common AE and was generally low grade, associated with initial doses, and caused only a single discontinuation.³⁵

“[Glofitamab’s] efficacy looks potentially even more promising than mosunetuzumab, particularly in the aggressive lymphoma subtypes,” Nastoupil said. “I expect it will be FDA approved this spring for the treatment of DLBCL in the third line or later stages.”

Moreover, glofitamab therapy was effective in R/R mantle cell lymphoma (MCL).³⁶ In a cohort of 29 patients with R/R MCL, glofitamab induced an ORR of 81%. Heini et al administered glofitamab to 2 patients with MCL who had relapsed after CAR T-cell therapy.³⁷ Glofitamab treatment resulted in a considerable increase in circulating CAR T cells and objective responses in both patients. However, the study authors asserted that because of the small sample size, any correlation between CAR T-cell levels and clinical response remains speculative, and the relative contributions of the bsAb and CAR
T-cell therapy cannot be determined.³⁷

The Future of BsAbs

Regarding the future of bsAbs, Nastoupil noted that research is ongoing. “There are other [bsAb] targets being explored,” she said, highlighting CD22 and ROR1 as 2 such targets of interest.

Wei et al demonstrated that REGN5837, a CD22/CD28 bsAb, enhanced the
antitumor activity of odronextamab in preclinical DLBCL models. Moreover, the combination of these 2 bsAbs may provide an alternative to chemotherapy for treating DLBCL.³⁸ Another bsAb, NVG-111, is a first-in-class, humanized, tandem scFv ROR1xCD3 bispecific T-cell engager. This therapy showed efficacy in a first-in-human phase 1/2 clinical trial for the treatment of chronic lymphocytic leukemia and MCL in patients who had received 2 or more prior systemic therapies (NCT04763083).³⁹

“There are other targets...that are also being explored with bsAbs and
even trispecifics [FIGURE2⁴⁰], where you may have a CD19/CD20/CD3 agent that’sbeingexplored,” Nastoupil said. Through in vitro, ex vivo, and in vivo
research, Wang et al demonstrated that A-319 (a CD3/CD19 bsAb) and A-2019 (a novel CD3/CD19/CD20 trispecific mAb) are effective antitumor agents that can recruit CD3-positive T cells and enhance their function, mediate B-cell depletion, and ultimately inhibit tumor growth in Raji xenograft models.⁴¹

“The other strategy being looked at is enhancing the activation of these
endogenous T cells,” Nastoupil said. “Combining these bsAbs with cytokines, or costimulatory molecules such as 4-1BB, are strategies that are also being explored.”

For Ravandi-Kashani, broadening the function of bsAbs is essential. “I am quite happy that bsAbs are being approved [in certain cancers],” he said.“ Hopefully, we will have a similar situation in [acute myelogenous leukemia] as well.”

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