Glofitamab Monotherapy Induces High Complete Response Rates in Patients with Heavily Pretreated Relapsed or Refractory Mantle Cell Lymphoma

Background: New treatment options are needed for patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL), especially those with progressive disease (PD) after Bruton's tyrosine kinase inhibitor (BTKi) therapy. In a retrospective cohort study of 114 patients with MCL who had PD while receiving ibrutinib, median OS upon ending ibrutinib treatment was 2.9 months (95% CI: 1.6-4.9; Martin et al. Blood 2016).

The CD20xCD3 T-cell-engaging bispecific monoclonal antibody, glofitamab, has a novel 2:1 (CD20:CD3) configuration with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Obinutuzumab pretreatment (Gpt) is given 7 days prior to the first dose of glofitamab to mitigate the risk of cytokine release syndrome (CRS).

Phase I/II (NCT03075696) data for glofitamab monotherapy with step-up dosing (SUD) and Gpt (1000mg or 2000mg) have shown high response rates and manageable, mostly low-grade CRS in patients with R/R MCL, most of whom had prior BTKi therapy (Phillips et al. ASH 2021). Here, we report on the durability of response with glofitamab SUD in a larger cohort with additional follow up.

Methods: All patients received Gpt 7 days before the first dose of glofitamab. Intravenous glofitamab SUD was given on Days (D) 8 (2.5mg) and 15 (10mg) of Cycle (C) 1, then at the target dose (16mg or 30mg after 1000mg Gpt; 30mg after 2000mg Gpt) from C2D1, every 3 weeks for up to 12 cycles. Response rates were assessed by Lugano criteria (Cheson et al. JCO 2014).

Results: As of March 14, 2022, 37 patients had received glofitamab SUD after Gpt (1000mg Gpt, n=16; 2000mg Gpt, n=21). Median age was 72.0 years (range: 41-84), 73.0% of patients were male, 91.9% had Ann Arbor Stage III/IV disease and 32.4% had MCL IPI score ≥6 at study entry. Median prior lines of therapy was three (range: 1-5); 24 (64.9%) patients had prior BTKi therapy and seven (18.9%) had prior lenalidomide therapy. The majority of patients were refractory to their first line of therapy (62.2%; n=23) and/or their last prior therapy (73.0%; n=27). Median time since last therapy was 1.9 months (range: 0.1-107.5).

After a median follow up of 8 months (range: 0-19), overall response rate (ORR) and complete response (CR) rates were 83.8% (31/37) and 73.0% (27/37), respectively, across both Gpt cohorts. In the 2000mg Gpt cohort, ORR and CR rates were 90.5% (19/21) and 81.0% (17/21), respectively. In the 1000mg Gpt cohort, ORR and CR rates were 75.0% (12/16) and 62.5% (10/16), respectively. Across both Gpt cohorts, median time to CR was 51 days. The majority of CRs (20/27; 74.1%) were ongoing at the data cut-off and an estimated 71.6% of patients with a CR remained in response at 9 months. Median duration of response was 12.6 months (95% CI: 10.0-NE) and median duration of CR was 10.0 months (95% CI: 4.9-NE). The two deaths that occurred after 10 months were due to COVID-19 (Figure).

In safety-evaluable patients (n=37), the most common adverse events (AEs) were CRS (75.7%; by ASTCT criteria) and neutropenia (40.5%). CRS rates were lower in the 2000mg Gpt (14/21; 66.7%) vs the 1000mg Gpt (14/16; 87.5%) cohort. CRS events in the 2000mg Gpt cohort were all Grade (Gr) 1-3 (Gr 1, 33.3%; Gr 2, 23.8%; Gr 3, 9.5%), whereas there were two Gr 4 CRS events in the 1000mg Gpt cohort (Gr 1, 25.0%; Gr 2, 37.5%; Gr 3, 12.5%; Gr 4, 12.5%). All CRS events were manageable (17 patients received tocilizumab to manage CRS) and most resolved by data cut-off (one patient had ongoing CRS at the time of analysis).

Neurologic AEs (NAEs) occurred in 19 patients (51.4%); all were Gr 1/2 except for one Gr 3 subdural hematoma in the 2000mg Gpt cohort. NAEs consistent with immune effector cell-associated neurotoxicity syndrome following glofitamab administration occurred in five patients (13.5%, all Gr 1/2 and nonserious). Tumor flare events occurred in five patients (13.5%, all Gr 1/2). No patients discontinued treatment due to AEs. Ten deaths were reported and considered unrelated to study treatment: PD, n=5; AEs, n=5 (COVID-19/pneumonia, n=4; cardiac arrest, n=1).

Conclusions: Fixed-duration glofitamab monotherapy after Gpt (1000mg or 2000mg) induced high and durable CR rates, the majority of which were achieved early, in heavily pretreated patients with MCL, most of whom had prior BTKi therapy and thus a particularly poor prognosis. CRS events were manageable and mostly low grade. This is one of the largest datasets and longest follow-ups reported with a CD20xCD3 bispecific monoclonal antibody for patients with R/R MCL.

Phillips:Pharmacyclics: Consultancy; Genmab: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; Bayer: Consultancy; Xencor: Consultancy; Epizyme: Consultancy; Genentech: Consultancy, Research Funding; Incyte: Consultancy, Other: Travel Expenses ; Eli Lilly: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding. Dickinson:Roche, Novartis, Kite, Gilead, MSD, Takeda, Celgene: Research Funding; Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD, Amgen: Honoraria; Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD: Consultancy. Morschhauser:Genentech: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Membership on an entity's Board of Directors or advisory committees; Allogene therapeutics: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees. Bachy:Kite, Gilead, Novartis, Roche, Incyte, Miltenyi Biotech, Takeda, Sanofi: Honoraria; Roche, Gilead, ADC Therapeutics, Takeda, Novartis, Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, BMS: Research Funding; Hospices Civils de Lyon: Current Employment. Crump:Roche: Research Funding; Kyte-Gilead, Novartis: Honoraria. Bartlett:Autolus, Bristol-Meyers Squibb, Celgene, Forty Seven, Janssen, Kite Pharma, Merck, Millennium, Pharmacyclics: Research Funding; Washington University School of Medicine: Current Employment; ADC Therapeutics, Roche/Genentech, Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zaucha:Takeda, Roche, Abbvie, Amgen: Consultancy; BMS: Research Funding; Takeda, Roche, Abbvie, Amgen: Honoraria. Wrobel:Roche, Novartis, Janssen-Cilag, BMS/Celgene, Takeda, Amgen, Sanofi, Pfizer, Gilead, Abbvie: Consultancy; Roche, Celgene, Janssen-Cilag: Research Funding; Roche, Novartis, Janssen-Cilag, BMS/Celgene, Takeda, Amgen, Sanofi, Pfizer, Gilead, Abbvie: Honoraria. Humphrey:Roche Products Ltd: Current Employment; Roche: Current equity holder in private company, Current holder of stock options in a privately-held company. Lundberg:F-Hoffmann La Roche: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties. Relf:Roche, F-Star Therapeutics and Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Roche, F-Star Therapeutics: Current equity holder in publicly-traded company; Roche Products Limited: Current Employment. Filézac de L'Étang:F. Hoffmann-La Roche AG: Current Employment, Current equity holder in publicly-traded company. Carlile:Roche Products Ltd: Current Employment; AstraZeneca, Roche: Current equity holder in publicly-traded company; Roche: Patents & Royalties: Patent. Byrne:Roche Products Ltd, Welwyn Garden City, United Kingdom: Current Employment, Current equity holder in private company, Current equity holder in publicly-traded company. Qayum:Roche: Current Employment, Current equity holder in publicly-traded company. Carlo-Stella:Roche: Other: Consultancy/Advisory, Research Funding; Celgene/Bristol Myers Squibb: Other: Consultancy/Advisory; Bristol Myers Squibb: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Incyte: Honoraria; AstraZeneca: Honoraria; Janssen Oncology: Honoraria; ADC Therapeutics: Honoraria, Other: Consultancy/Advisory, Research Funding; Sanofi: Other: Consultancy/Advisory, Research Funding; Karyopharm Therapeutics: Other: Consultancy/Advisory; Scenic Biotech: Other: Consultancy/Advisory.

Glofitamab is a full-length, humanized immunoglobulin G1 bispecific monoclonal antibody with a 2:1 (CD20:CD3) configuration that facilitates bivalent binding to CD20 on B cells, and monovalent binding to CD3 on T cells. Glofitamab redirects T cells to eliminate normal and malignant B cells. Glofitamab is an investigational agent. Obinutuzumab (Gazyva) is a CD20-directed cytolytic antibody indicated: in combination with chlorambucil, for the treatment of patients (pts) with previously untreated CLL; in combination with bendamustine followed by obinutuzumab monotherapy, for the treatment of pts with FL who relapsed after, or are refractory to, a rituximab-containing regimen; in combination with chemo followed by obinutuzumab monotherapy in pts achieving at least a PR, for the treatment of adult pts with previously untreated stage II bulky, III or IV FL.