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.

Trial registration: ClinicalTrials.gov NCT03075696.

Conflict of interest statement

Martin HutchingsConsulting or Advisory Role: Takeda, Roche, GenmabResearch Funding: Celgene, Genmab, Roche, Takeda, Novartis Franck MorschhauserConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Celgene, Bristol Myers Squibb, AbbVie, Epizyme, ServierSpeakers' Bureau: RocheExpert Testimony: Roche/Genentech Gloria IacoboniHonoraria: Gilead Sciences, Novartis, Roche/Genentech, Celgene/Bristol Myers Squibb, JanssenConsulting or Advisory Role: Novartis, Celgene/Bristol Myers Squibb, Gilead SciencesTravel, Accommodations, Expenses: Gilead Sciences, Novartis, Celgene/Bristol Myers Squibb Carmelo Carlo-StellaHonoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Janssen Oncology, AstraZeneca, Celgene, Takeda, Incyte, Gilead SciencesConsulting or Advisory Role: Sanofi, ADC Therapeutics, Roche, Karyopharm Therapeutics, Celgene/Bristol Myers Squibb, IncyteResearch Funding: ADC Therapeutics, Sanofi, RocheTravel, Accommodations, Expenses: Roche, Janssen, Takeda, ADC Therapeutics Anna SuredaHonoraria: Takeda, Bristol Myers Squibb, Merck Sharp & Dohme, Celgene, Janssen, Sanofi, Roche, Novartis, Gilead Sciences, Janssen-CilagConsulting or Advisory Role: Takeda, Bristol Myers Squibb, Gilead Sciences, Celgene, Janssen, NovartisSpeakers' Bureau: TakedaOther Relationship: Sanofi, Takeda, Roche, Celgene, Gilead Sciences Gilles SallesHonoraria: Roche/Genentech, Janssen, Celgene, Gilead Sciences, Novartis, AbbVie, MorphoSysConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Janssen, Celgene, Novartis, MorphoSys, Epizyme, Alimera Sciences, Genmab, Debiopharm Group, Velosbio, Bristol Myers Squibb, BeiGene, Incyte, Miltenyi Biotec Joaquín Martínez-LopezSpeakers' Bureau: Roche, Janssen-Cilag, BMSiResearch Funding: Astellas Pharma, Bristol Myers Squibb Michael CrumpHonoraria: Gilead Sciences, Servier/PfizerConsulting or Advisory Role: Servier, Gilead Sciences, Novartis Canada Pharmaceuticals IncResearch Funding: Roche Canada Denise N. ThomasEmployment: Roche TCRC, Genmab, Cellectis Peter N. MorcosEmployment: Roche/Genentech, BayerStock and Other Ownership Interests: Roche/Genentech, Bayer Cristiano FerliniEmployment: Roche/Genentech, AstraZenecaStock and Other Ownership Interests: AstraZeneca, Roche Ann-Marie E. BröskeEmployment: RocheStock and Other Ownership Interests: Roche, BioNTech AG Anton BelousovEmployment: Roche Marina BacacEmployment: RocheStock and Other Ownership Interests: RocheResearch Funding: RochePatents, Royalties, Other Intellectual Property: Coinventor in Roche patentsTravel, Accommodations, Expenses: Roche Natalie DimierEmployment: RocheStock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Roche David J. CarlileEmployment: Roche, AstraZenecaStock and Other Ownership Interests: AstraZeneca, Roche Linda LundbergEmployment: F. Hoffmann LaRocheStock and Other Ownership Interests: F. Hoffmann LaRoche David Perez-CallejoEmployment: RocheStock and Other Ownership Interests: Roche Pablo UmañaEmployment: RocheLeadership: RocheStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: Co-inventor in Roche-owned patents on glofitamab and obinutuzumabTravel, Accommodations, Expenses: Roche Tom MooreEmployment: RocheStock and Other Ownership Interests: RocheTravel, Accommodations, Expenses: Roche Martin WeisserEmployment: RocheStock and Other Ownership Interests: RochePatents, Royalties, Other Intellectual Property: I hold patents for biomarkers and drug combinations. These are not related to the present study. I do not receive royalties Michael J. DickinsonHonoraria: Roche, Amgen, MSD, Janssen, Bristol Myers Squibb, NovartisConsulting or Advisory Role: Novartis, Bristol Myers Squibb, Gilead Sciences, Roche, JanssenSpeakers' Bureau: NovartisResearch Funding: Novartis, Roche, Takeda, Celgene, MSDTravel, Accommodations, Expenses: RocheNo other potential conflicts of interest were reported.

Figures

FIG 1.

(A) Shows adverse events with an incidence of ≥ 10% or an NCI-CTCAE grade of 5 as of August 3, 2020. (B) Shows the incidence of CRS by cycle and dose (Lee grade). CRS events were predominantly confined to cycles 1 and 2. Step-up dosing of glofitamab allowed the administration of a high target dose (30 mg). AE, adverse event; C, cycle; CRS, cytokine release syndrome; NCI-CTCAE, National Cancer Institute-Common Terminology Criteria for Adverse Events.

FIG 2.

(A) Waterfall plot of the best overall change in the size of tumor target lesions. The percentage changes in the sum of the products of diameters of target lesions are shown. The columns represent the results from individual patients, color-coded according to the doses of glofitamab received. The dashed lines indicate 50% increase or decrease from baseline sum of the products of diameters. (B) PET scans of a 64-year-old patient with primary refractory transformed lymphoma who achieved complete response after two cycles of 10 mg glofitamab. The patient remains treatment-free and in complete response as of September 2020, 18 months after completion of glofitamab treatment. aNHL, aggressive non-Hodgkin lymphoma; CMR, complete metabolic response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; ICE, ifosfamide, carboplatin, and etoposide; iNHL, indolent non-Hodgkin lymphoma; MCL, mantle cell lymphoma; ND, not determined; NMR, no metabolic response; PET, positron emission tomography; PFS, progression-free survival; PMBCL, primary mediastinal B-cell lymphoma; PMD, progressive metabolic disease; PMR, partial metabolic response; R-CHOP, rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone; RS, Richter's transformation; trFL, transformed follicular lymphoma; trOth, transformed other.

FIG 3.

(A) Represents the cumulative incidence of time to CR. Kaplan-Meier curves for (B) DOR (PR and CR), (C) duration of CR, and (D) PFS. aNHL, aggressive non-Hodgkin lymphoma; CR, complete response; DOR, duration of response; iNHL, indolent non-Hodgkin lymphoma; NE, not estimable; PFS, progression-free survival; PR, partial response.