Glofitamab Step-up Dosing Induces High Response Rates in Patients (pts) with Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL), Most of Whom Had Failed Prior Bruton's Tyrosine Kinase Inhibitor (BTKi) Therapy
Authors: Phillips Tycel , Dickinson Michael , Morschhauser Franck , Bachy Emmanuel , Crump Michael , Trněný Marek , Bartlett Nancy L. , Zaucha Jan , Humphrey Kathryn , Perez-Callejo David , Lundberg Linda , Relf James , Filézac de L'Étang Audrey , Carlile David , Clark Emma , Carlo-Stella Carmelo 
Published: November 2021

Abstract
Background: MCL is an aggressive non-Hodgkin lymphoma (NHL) subtype and pts with progressive disease (PD) after BTKi therapy have a poor prognosis (Martin et al. Blood 2016).
Glofitamab is a T-cell-engaging, CD20xCD3 bispecific antibody with a novel 2:1 molecular configuration with bivalency for CD20 on B cells and monovalency for CD3 on T cells. Glofitamab with obinutuzumab pretreatment (Gpt) has shown promising efficacy with frequent, durable complete responses (CR) and manageable tolerability with fixed dosing (NCT03075696; Dickinson et al. EHA 2020) and step-up dosing (SUD; Hutchings et al. J Clin Oncol 2021) in NHL.
Glofitamab and obinutuzumab compete for binding to CD20 receptors; as a result, Gpt reduces the receptor occupancy (RO) of glofitamab. Pts with MCL have a 2-fold higher clearance of obinutuzumab vs other NHL histologies (Gibiansky et al. CPT Pharmacometrics Syst Pharmacol 2014), leading to lower obinutuzumab concentrations and higher glofitamab RO at the start of glofitamab treatment (Djebli et al . Blood 2020). A higher dose of Gpt prior to glofitamab SUD may therefore further reduce the risk of cytokine release syndrome (CRS) in MCL. We report preliminary data from the NP30179 Phase I/II trial in pts with R/R MCL who received a 1000mg or 2000mg dose of Gpt prior to glofitamab monotherapy.
Methods: All pts received Gpt 7 days prior to the first glofitamab dose. Intravenous glofitamab SUD was given on days 1 and 8 of Cycle (C)1, then at the target dose from C2 day (D)1 (from C3D1 for SUD starting at 0.5mg), every 3 weeks for up to 12 cycles (0.5/2.5/10/30, 2.5/10/16 or 2.5/10/30mg after 1000mg Gpt, or 2.5/10/30mg after 2000mg Gpt). Pts on fixed dosing received glofitamab (0.6, 16 or 25mg) after 1000mg Gpt from C1 for up to 12 cycles. Response rates are based on the Lugano criteria (Cheson et al. J Clin Oncol 2014).
Results: As of May 18, 2021, 29 pts had received glofitamab: fixed dosing after 1000mg Gpt (n=3); SUD after 1000mg Gpt (n=7; 1 pt received SUD starting at 0.5mg) or 2000mg Gpt (n=19). Median age was 69 years (range, 41-84; 69% male), 83% of pts had Ann Arbor Stage III-IV disease and 62.1% had MCL international prognostic index score ≥6 at study entry. Median prior lines of therapy was 3 (range, 1-6), 69% (n=20) had prior BTKi therapy and 14% (n=4) had prior lenalidomide therapy. Many pts were refractory to their first line of therapy (52%; n=15) and/or their last prior therapy (69%; n=20). Median time since last therapy was 1.7 months (range, 0.1-107.5).
In efficacy-evaluable pts (n=21), the overall response rate was 81.0% (n=17) and complete metabolic response rate was 66.7% (n=14; Table 1). Similar response rates were observed in pts who had received prior BTKi therapy vs pts who had not (Table 2). Median duration of CR follow-up was 2.4 months (range, 0.0-25); 85.7% (12/14) pts with a CR remained in remission at the data cut-off (median duration of response and median duration of CR were not reached).
In safety-evaluable pts (n=29), the most common adverse events (AEs) were CRS (58.6%) and infusion-related reactions (24.1%). All CRS events were Grade (Gr) 1-2 (by ASTCT criteria), except for 1 Gr 4 CRS in the 1000mg Gpt + SUD cohort (3.4%; pt died due to cardiopulmonary insufficiency as a result of rapid PD; at time of death CRS was persisting).
CRS rates were lower in the 2000mg Gpt + SUD cohort (9/19; 47.4%) vs the 1000mg Gpt + SUD (5/7; 71.4%) and 1000mg Gpt + fixed dosing (3/3; 100%) cohorts. Overall, median time to first CRS event and duration of CRS event were 16.8 hrs and 38.8 hrs, respectively. All CRS events were manageable (tocilizumab used in 4 pts, low-flow oxygen in 2 pts) and most resolved at data cut-off. Neurologic AEs occurred in 6 pts (20.7%, all Gr 1 [n=5] or Gr 2 [n=1]). Immune effector cell-associated neurotoxicity syndrome (ICANS)-like AEs occurred in 1 pt (3.4%): Gr 1 confusional state and Gr 2 ataxia, both resolving in 1 day. Tumor flare events occurred in 3 pts (10.3%, all Gr 1 [n=2] or Gr 2 [n=1]). No pts discontinued treatment due to AEs. Three deaths were reported and considered unrelated to study treatment: PD (n=2); cardiac arrest (n=1).
Conclusions: Glofitamab SUD as monotherapy after Gpt induced high response rates in pts with MCL, most of whom had failed prior BTKi therapy. CRS rates were manageable and mostly low grade. ICANS-like AEs were infrequent, low grade and resolved within 1 day. No treatment discontinuations due to AEs were observed. Further analyses will be presented.
Figure 1 Figure 1.

Disclosures
Phillips: Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; ADCT, BeiGene, Bristol Myers Squibb, Cardinal Health, Incyte, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics: Consultancy; AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; BMS: Consultancy, Research Funding; Incyte: Consultancy, Other: received travel expenses from Incyte, Research Funding. Dickinson: Celgene: Research Funding; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Takeda: Research Funding; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Morschhauser: Epizyme: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Genentech, Inc.: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Crump: Kyte/Gilead: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Epizyme: Research Funding. Trněný: MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Celgene: Consultancy; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Bartlett: Washington University School of Medicine: Current Employment; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Research Funding; Autolus: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Kite Pharma: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zaucha: Takeda: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Roche: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Humphrey: Roche: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Perez-Callejo: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lundberg: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Relf: Roche Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company; F-Star Therapeutics: Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months; Harpoon Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months. Filézac de L'Étang: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Carlile: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Clark: Roche Products Ltd: Current Employment. Carlo-Stella: Sanofi: Consultancy, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure:
Glofitamab is a full-length, humanized, immunoglobulin G1 bispecific antibody with a 2:1 molecular format that facilitates bivalent binding to CD20 on B-cells, and monovalent binding to CD3 on T-cells. Glofitamab redirects T cells to engage and eliminate malignant B cells. Glofitamab is an investigational agent.