CD20 × CD3 bispecific antibodies for lymphoma therapy: latest updates from ASCO 2023 annual meeting

Abstract

Multiple bispecific antibodies (bsAbs) have been approved for cancer immunotherapy. Several CD20 × CD3 bsAbs have demonstrated significant anti-B-cell non-Hodgkin lymphoma (NHL) activity by engaging T cells to target CD20⁺ NHL cells in clinical trials. Mosunetuzumab, epcoritamab and glofitamab have been approved recently for B-cell NHL therapy. In this study, we summarized several latest reports on CD20 × CD3 bsAbs for the therapy of B-cell NHL from the ASCO 2023 annual meeting (ASCO2023).

To the editor

Several CD20 × CD3 bispecific antibodies (bsAbs) have demonstrated significant anti-B-cell non-Hodgkin lymphoma (NHL) activity by engaging T cells to target CD20⁺ NHL cells in clinical trials. Mosunetuzumab (Mosun), epcoritamab (Epcor) and glofitamab (Glofit) have been approved recently for refractory/relapsed (R/R) B-cell NHL therapy. We summarized several latest reports on CD20 × CD3 bsAbs from the ASCO 2023 annual meeting.

Properties of CD20 × CD3 bsAbs

Glofit is a full-length IgG1 bsAb with a 2:1 molecular configuration of anti-CD20 and anti-CD3 (Table 1). The Fc of Glofit has a PG LALA mutation, resulting in the loss of the Fc-FcγRs interaction while retaining its binding ability to FcRn [1]. This particular structure possesses a longer half-life of 10 days when compared to earlier generation of bsAbs. Glofit is currently being investigated as a single agent and in combination regimens [2,3,4].

Table 1 Properties of CD20 × CD3 bispecific antibodies

Mosun is a fully humanized IgG1 bsAb (Table 1). Mosun was administered as a fixed-duration regimen with step-up dosing to minimize cytokine release syndrome (CRS). The intravenous (IV) formulation has been approved, while subcutaneous (SC) Mosun is still in trials [5]. Mosun has been evaluated in clinical trials as a monotherapy or in combination regimens for the treatment of B-cell NHL [6,7,8].

Epcor is another IgG1 bsAb. It was designed to bind to a unique epitope on CD20 antigen, allowing co-binding of other anti-CD20 agents (Table 1) [5]. Compared with IV administration, SC Epcor (also known as GEN3013) demonstrated comparable bioavailability and B-cell depletion in cynomolgus monkeys [9].

Efficacies of CD20 × CD3 bsAbs as a single agent

In a phase II clinical trial for patients (pts) with R/R large B cell lymphoma (LBCL), obinutuzumab was administered prior to Glofit monotherapy to first reduce the tumor load [2, 4]. Glofit was given at a step-up dosing regimen. In the latest update, the complete response (CR) and overall response rates (ORR) were 38% and 59%, respectively, with a median follow-up (mFU) of 20.1 months (m) (Table 2). Notably, prior CAR T cell therapy did not adversely affect ORR. The median duration of CR was 24.1 m [95% CI: 19.8–not reached (NR)]. Among pts who received doses lower than recommended but ≥ 10 mg, the CR duration was extended to 30.1 m. The 18-m overall survival (OS) rate was 41%. CRS was the most frequently reported adverse event (AE). Glofit was recently approved for R/R LBCL.

Table 2 2023 ASCO updates from clinical trials of CD20 × CD3 bispecific antibodies for lymphoma therapy

In the EPCORE NHL-1 trial for R/R LBCL, single-agent Epcor was administered with a step-wise dosing regimen [10]. The CR and ORR were 39.5% and 63.1%, respectively (Table 2). Median OS was 18.5 m. CRS occurred in 51% of pts, and immune effector cell‐associated neurotoxicity syndrome (ICANS) occurred in 6% of pts. Epcor was recently approved for R/R LBCL.

Efficacies of CD20 × CD3 bsAbs in combination regimens

In the EPCORE NHL-2 trial, Epcor was combined with R-CHOP in adults with untreated high-risk DLBCL [11]. In the latest report, 47 pts had received Epcor 48 mg + R-CHOP with a mFU of 11.5 m (Table 2). All pts achieved a response (100%), and 76% achieved a complete metabolic response (CMR). The CMR occurred in 82% double/triple-hit pts. CRS occurred in 60% of pts, and 1 pt experienced ICANS.

In the EPCORE NHL-2 trial, SC Epcor was combined with R + lenalidomide in treating R/R follicular lymphoma (FL) [12]. One hundred and nine pts were treated with a mFU of 8.8 m. The CMR and ORR were 86% and 97%, respectively (n = 101) (Table 2). CRS occurred in 48% of pts, while 2 pts developed ICANS.

Glofit was employed in combination with polatuzumab vedotin (Pola) plus R-CHP for untreated DLBCL pts, with Pola-R-CHP given on Day 1 of each cycle (C) and Glofit administered in C2–C6 at a step-up dosing [3]. The CMR and ORR occurred in 76.5% and 100% of the 24 enrolled pts after a mFU of 5.1 m (Table 2). CRS and neurological AEs occurred in 13% and 46% pts, respectively.

In addition to the above trials, several clinical trials on CD20 × CD3 bsAbs in combination regimens are enrolling now. These include SC Mosun + IV Pola in pts with R/R NHL [8], SC Mosun with lenalidomide augmentation in pts with untreated FL and marginal zone lymphoma [7], and SC Epcor + R-CHOP in pts with newly diagnosed DLBCL [13].

In summary, Mosun, Epcor and Glofit have been approved recently for R/R B-cell NHL therapy. SC administration of Epcor offers convenience. CD20 × CD3 bsAbs in combination regimens are in clinical trials.