The safety profiles and the high response rates observed with bispecific antibodies in patients with B-cell lymphoma suggest that these agents possess the potential to revolutionize the management of these diseases, particularly follicular lymphoma.

These agents, such as mosunetuzumab-axgb (Lunsumio), odronextamab (CD20xCD3) and epcoritamab-bysp (Epkinly), have demonstrated the ability to engage both B and T cells and offer clinicians a targeted and potent immune-mediated approach to treating the disease. Factors such as patient age, comorbidities, and safety profile may lead to earlier use of bispecific antibodies.

They offer high efficacy, milder toxicities, and their use as a potential off-the-shelf approach without the logistical and financial constraints of chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (R/R) FL. However, it is crucial to assess the long-term efficacy of these treatments to determine their appropriate sequencing and compare their cost-effectiveness. The role of bispecific antibodies will be explored in “Integrating Bispecifics into the Clinical Care of Patients With Follicular Lymphoma,” on Wednesday, September 6, 2023, at 7 am.

BsAbs that target lymphoma B cells, specifically CD20, exhibit high response rates in R/R FL patients, with an overall response rate (ORR) of around 80% and complete response (CR) rates ranging from 60% to 75% after at least 2 lines of therapy, and even higher when combined with rituximab (Rituxan) and lenalidomide (Revlimid).

In addition to their efficacy, bispecific antibodies have shown a relatively manageable safety profile. Although cytokine release syndrome (CRS) can occur, it is typically of low to moderate grade and resolves within a few days. Neurological events, similar to those observed with CAR T-cell therapy, have been infrequent. Other adverse events associated with bispecific antibodies, such as neutropenia and hypophosphatemia, can be managed with appropriate monitoring and supportive care. Furthermore, ongoing research aims to optimize the dosing strategies and formulations to further minimize adverse events.

The first FDA-approved bispecific antibody for third line R/R FL is CD3×CD20, mosunetuzumab-axgb, evaluated in an open-label, multicenter, phase 2 study.

 The efficacy population consisted of 90 patients with R/R FL who had received at least 2 prior lines of systemic therapy, including an anti-CD20 monoclonal antibody and an alkylating agent.

The primary efficacy outcome measure was ORR assessed by an independent review facility according to standard criteria for non-Hodgkin lymphoma. The ORR was 80%, with 60% achieving CR; specifically, patients with early progression had an ORR of 75%.

With a median follow-up of 28.6 months3 among responders, the estimated median duration of CR was not reached. The median progression-free survival (PFS) was not reached, with a PFS rate of 77% at 2 years.

Adverse events associated with mosunetuzumab included CRS (44% of patients, mostly grade 1 or 2), neurological events (5% of patients), neutropenia (26% grade 3 or 4), hypophosphatemia (17%), and serious infections (20% of patients). 

Odronextamab, another anti-CD3xCD20 agent, showed promising results in phase 2 trial in patients with R/R FL, with an ORR of 82% and a CR rate of 75%, consistent in all high-risk groups.

Notably, 92% of responders were complete responders. With a median follow-up of 22.4 months, responses were deep and durable, with a median PFS of 20 months.

Moreover, odronextamab exhibited a generally manageable safety profile, mainly when administered with the optimized step-up dosing regimen. CRS was primarily of grade 1 severity and mainly occurred during the step-up dosing in cycle 1. No cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were reported.

Recently, epcoritamab-bysp, another anti-CD3×CD20 agent was studied in combination with rituximab and lenalidomide for R/R patients. Early results of this study demonstrate a high antitumor activity and a manageable safety profile, although the median follow-up remains short (11 months).

CRS events were mainly low-grade and mostly occurred following the first full dose on cycle 1, day 15; all resolved, and none led to discontinuation. ICANS occurred in 2 patients and resolved. In 101 efficacy-evaluable patients, ORR was 97%, with complete metabolic response in 86%; high response rate was also demonstrated in high-risk groups with no difference between patients with early progression vs late progression. Estimated 6-month PFS was 93%.

Epcoritamab combined with rituximab and lenalidomide is also studied in the frontline setting. Glofitamab-gxbm (Columvi), focused on other B-cell lymphomas, also demonstrated activity in patients with FL.

Key focus areas that require further exploration include determining the optimal use and positioning of bispecific antibodies as single agents and in combination with other therapies. Efforts are also directed toward enhancing and improving the bispecific antibody; new formats are being developed, targeting other B-cell antigens (CD19, CD22, CD79b), and different formats (pentameric immunoglobulins), exhibiting 3 or 4 site specificities to engage multiple antigens on tumor cells or deliver additional co-stimulatory signals on T cells.

Studies also evaluate the potential of bispecific antibodies as a first-line therapy. A significant part of ongoing research aims to understand and overcome resistance mechanisms, focusing on factors like CD20 antigen loss and activation of immune-evasive gene expression programs, T-cell exhaustion, and changes in the tumor microenvironment. Furthermore, the possibility of a synergistic effect when combining bispecific antibodies with other immunotherapies is a subject of continuous exploration. All these efforts signify the dynamic evolution in this field, offering hope for improved treatment options for FL.

Ongoing research aims to optimize their use in combination with other agents, determine optimal sequencing strategies, and explore their efficacy in the first-line setting. As we gain further insights and refine the use of bispecific antibodies, they can potentially transform the treatment landscape for patients with FL, providing new hope and improved outcomes.

Falchi L, Vardhana SA, Salles GA. Bispecific antibodies for the treatment of B-cell lymphoma: promises, unknowns, and opportunities. 

. 2023;141(5):467-480. doi:10.1182/blood.2021011994

Sehn LH, Bartlett NL, Matasar M, et al. Mosunetuzumab demonstrates durable responses in patients with relapsed/refractory follicular lymphoma and ≥2 prior therapies: updated analysis of a pivotal phase II study. 

. 2023;41(S2):122-125. doi:10.1002/hon.3163_83

Novelli S, Luminari S, Taszner M, et al. Odronextamab in patients with relapsed/refractory follicular lymphoma (FL) grade 1–3A: results from a prespecified analysis of the pivotal phase II study ELM-2. 

. 2023;41(S2):121-122. doi:10.1002/hon.3163_82

Belada D, Falchi L, Leppä S, et al. Epcoritamab with rituximab + lenalidomide (

R2) provides durable responses in high-risk follicular lymphoma, regardless of POD24 status.

2023;41(S2):125-127. doi:10.1002/hon.3163_84

Efrat Luttwak, MD, MPH

Articles

Bispecific Antibodies May Revolutionize the Management of B-Cell Lymphoma