Glofitamab, a Novel, Bivalent CD20-Targeting T-Cell–Engaging Bispecific Antibody, Induces Durable Complete Remissions in Relapsed or Refractory B-Cell Lymphoma: A Phase I Trial

Abstract

PURPOSE Glofitamab is a T-cell–engaging bispecific antibody possessing a novel 2:1 structure with bivalency for CD20 on B cells and monovalency for CD3 on T cells. This phase I study evaluated glofitamab in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). Data for single-agent glofitamab, with obinutuzumab pretreatment ( Gpt) to reduce toxicity, are presented. METHODS Seven days before the first dose of glofitamab (0.005-30 mg), all patients received 1,000 mg Gpt. Dose-escalation steps were determined using a Bayesian continuous reassessment method with overdose control. Primary end points were safety, pharmacokinetics, and the maximum tolerated dose of glofitamab. RESULTS Following initial single-patient cohorts, 171 patients were treated within conventional multipatient cohorts and received at least one dose of glofitamab. This trial included heavily pretreated patients with R/R B-NHL; most were refractory to prior therapy (155; 90.6%) and had received a median of three prior therapies. One hundred and twenty-seven patients (74.3%) had diffuse large B-cell lymphoma, transformed follicular lymphoma, or other aggressive histology, and the remainder had indolent lymphoma subtypes. Five (2.9%) patients withdrew from treatment because of adverse events. Cytokine release syndrome occurred in 86 of 171 (50.3%) patients (grade 3 or 4: 3.5%); two (1.2%) patients experienced grade 3, transient immune effector cell–associated neurotoxicity syndrome-like symptoms. The overall response rate was 53.8% (complete response [CR], 36.8%) among all doses and 65.7% (CR, 57.1%) in those dosed at the recommended phase II dose. Of 63 patients with CR, 53 (84.1%) have ongoing CR with a maximum of 27.4 months observation. CONCLUSION In patients with predominantly refractory, aggressive B-NHL, glofitamab showed favorable activity with frequent and durable CRs and a predictable and manageable safety profile.

Recent Advances in the Management of Patients with Relapsed/Refractory Follicular Lymphoma

“…In a phase I study among 171 patients with R/R B-NHL, glofitamab achieved 70.5% ORR in 44 patients with FL, with 47.7% CR. 63 While the mDoR among the 31 responders was 10.8 months, 90.5% of patients with CR remained in CR up to 22.9 months, demonstrating that the CR can be long-lived. Notably the CRS was manageable, with low rates of grade ≥3 and no treatment withdrawals.…”

Principles and Current Clinical Landscape of Multispecific Antibodies against Cancer

“…The clinically most advanced CrossMab 2:1 ( Figure 2 and Table 1 ) is the anti-CD20/CD3 Glofitamab, where a CrossFab is inserted between the Fc region and one of the Fab fragments [ 122 ]. It is currently entering phase 2, based on a half-life of 6–11 days, similar to Mosunetuzumab, and an overall response rate (ORR) of 66%, with 57% complete response in r/r B-NHL patients who received the recommended phase 2 dose (NCT03075696, NCT04703686) [ 123 , 124 ]. Another CrossMab 2:1 is Cibisatamab, an anti-CEA/CD3 antibody for treatment of solid tumors (see Supplementary Table S1 ).…”

Immunomodulatory Drugs for the Treatment of B Cell Malignancies

“…Similarly, preclinical and preliminary clinical studies of CD19-CD3 BsAbs or novel BiTEs that target CD20 and CD3, such as glofitamab CD20-TCB (RG6026), odronextamab (REGN1979) and mosunetuzumab, have exhibited high potency and a significantly long half-life enabling a safer administration approach, as well as demonstrated clinical efficacy in R/R NHL [133][134][135][136][137]. Mosunetuzumab and CD20-TCB are currently being investigated in combination with lenalidomide in early-phase I clinical trials in R/R FL patients (NCT04246086) [138,139].…”