Background: Glofitamab, a CD20xCD3 T-cell engaging bispecific antibody with a novel 2:1 (CD20:CD3) format, induced frequent and durable complete responses (CRs) with a manageable safety profile in pivotal expansion cohorts of an ongoing Phase I/II study (NCT03075696) in patients (pts) with R/R LBCL (Dickinson et al. NEJM 2022, Falchi et al. ASCO 2023). Cytokine release syndrome (CRS) is a potentially life-threatening toxicity caused by immune activation that can be triggered non-specifically by T-cell engaging therapies. As previously reported, corticosteroid (steroid) premedication was required to prevent or mitigate CRS in pts treated with glofitamab. Dexamethasone (Dex) was mandated in one expansion cohort to assess if this could reduce the rate and severity of CRS versus other steroids. Here, we report data from the dose-escalation and expansion cohorts in pts with R/R LBCL who received Dex only versus non-Dex premedication.

Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [DLBCL NOS], high-grade B-cell lymphoma [HGBCL], primary mediastinal LBCL [PMBCL], or LBCL arising from follicular lymphoma [trFL]) and ≥2 prior therapies received 1000mg obinutuzumab pretreatment (Gpt) 7 days prior to the first glofitamab dose. IV glofitamab was administered with step-up dosing during Cycle (C) 1 (Day 8, 2.5mg; Day 15, 10mg) followed by the target dose (30mg) on Day 1 of C2-12 (21-day cycles; 8.4 months). Steroid premedication (80mg IV methylprednisolone, or equivalent dose of prednisone [100mg] or prednisolone [100mg], or 20mg IV Dex) was given at least 60 minutes prior to Gpt and each glofitamab dose. Responses were assessed using Lugano criteria (Cheson et al. JCO 2014). CRS events were graded by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019).

Results: As of May 1, 2023, 145 pts with R/R LBCL had received glofitamab, including 33 (22.8%) pts (DLBCL NOS, n=24 [72.7%]; HGBCL, n=2 [6.1%]; trFL, n=7 [21.2%]) who received Dex premedication before each glofitamab dose (Dex only cohort) and 112 (77.2%) pts (DLBCL NOS, n=81 [72.3%]; HGBCL, n=5 [4.5%]; PMBCL, n=6 [5.4%]; trFL, n=20 [17.9%]) who had not received Dex premedication before each glofitamab dose (non-Dex cohort). In the Dex only and non-Dex cohorts, median age was 73.0 years (range: 27-86) and 66.0 years (range: 21-90), and 26/33 (78.8%) pts and 83/112 (74.1%) pts had Ann Arbor stage III/IV disease, respectively. Median number of prior therapies was 3.0 for both cohorts. Ten (30.3%) and 37 (33.0%) pts had previously received chimeric antigen receptor T-cell therapy, and 6 (18.3%) and 22 (19.6%) pts had received autologous stem cell transplant in the Dex only and non-Dex cohorts, respectively. Median number of glofitamab cycles was 5.0 in both cohorts.

CRS of any grade occurred in 48.5% of pts in the Dex only cohort and 73.2% of pts in the non-Dex cohort, and CRS leading to serious adverse events occurred in 5 (15.2%) and 27 (24.1%) pts, respectively. In both cohorts, CRS events were mostly low grade and primarily occurred during C1 (Table; Figure). Recurring Grade (Gr) ≥2 CRS was not observed in the Dex only cohort and 6 (5.4%) pts had recurring Gr ≥2 CRS in the non-Dex cohort. Median time to CRS onset and median time to resolution were similar in the two cohorts. Treatment discontinuation rate was lower in the Dex only cohort (n=21, 63.6%) versus the non-Dex cohort (n=80, 71.4%), mainly due to progressive disease (Dex only cohort, n=12 [36.4%]; non-Dex cohort, n=52 [46.4%]).

In the DLBCL NOS and trFL population, the best overall response assessed by Independent Review Committee was similar between the Dex only (n=31) and non-Dex (n=101) cohorts, with CR reported in 14 (45.2%) and 44 (43.6%) pts, and 12 (38.7%) and 34 (33.7%) pts remaining in CR at data cutoff, respectively. The estimated event-free rate among complete responders at 12 months after the first CR was 83.1% (95% CI: 61.5-100.0) in the Dex only cohort and 77% (95% CI: 63.8-90.2) in the non-Dex cohort.

Conclusions: The incidence, severity, and seriousness of CRS after glofitamab administration in pts with R/R LBCL were numerically lower with Dex premedication versus premedication with other steroid regimens. Response rates in the Dex only cohort were similar to those reported in the non-Dex cohort. We therefore propose Dex as the steroid of choice for premedication to prevent or mitigate CRS in pts with LBCL treated with glofitamab monotherapy, considering its half-life and potency.

Falchi:Genmab: Consultancy, Research Funding; ADC Therapeutics: Other: Advisory Board; Roche: Consultancy, Research Funding; AstraZeneca: Consultancy; Seagen: Other: Advisory Board; Abbvie: Consultancy, Other: Advisory Board, Research Funding; Genentech: Consultancy, Other: Advisory Board, Research Funding. Carlo-Stella:Incyte: Honoraria; Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; SOBI: Honoraria, Membership on an entity's Board of Directors or advisory committees. Morschhauser:F. Hoffmann-La Roche Ltd, AbbVie, BMS, Genmab, Gilead, Novartis: Consultancy; F. Hoffmann-La Roche Ltd, Gilead, AbbVie: Membership on an entity's Board of Directors or advisory committees. Dickinson:F. Hoffmann-La Roche Ltd: Other: travel, accommodation, expenses; F. Hoffmann-La Roche Ltd, Amgen, MSD, Janssen, Bristol-Myers Squibb, Novartis, Gilead Sciences, Abbvie: Honoraria; Novartis, F. Hoffmann-La Roche Ltd, Takeda, Celgene, MSD, Abbvie, Lilly: Research Funding; Novartis, F. Hoffmann-La Roche Ltd, Bristol-Myers Squibb, Gilead Sciences, Janssen, Abbvie, Genmab: Consultancy. Bachy:Novartis: Honoraria, Other: Personal Fees; Incyte: Honoraria; Takeda: Honoraria; Pfizer: Honoraria, Other: Personal Fees; Hospices Civils de Lyon Claude Bernard Lyon 1 University: Current Employment; Bristol Myers Squibb: Honoraria, Other: Personal Fees, Research Funding; Amgen: Research Funding; Kite, a Gilead Company: Honoraria, Other: Personal Fees; Roche: Consultancy, Honoraria. Cartron:Ownards Therapeutics: Consultancy; MabQi: Consultancy; MedxCell: Consultancy; Janssen: Honoraria; Gilead: Honoraria; Emercell: Consultancy; BMS: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Jansen, Gilead, Novartis, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Honoraria; MedxCell, Ownards Therapeutics, MabQi, Emercell, F. Hoffmann-La Roche Ltd, BMS, Abbvie: Consultancy; MabQi, Ownards Therapeutics, Abbvie, Roche, Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Consultancy, Honoraria. Khan:Allegheny Health Network: Current Employment; Astrazeneca: Consultancy; Kite Pharma, ADC Therapeutics, Genentech, Inc., Astrazeneca, Abbvie, Janssen, BMS, Karyopharm, Pharmacyclics, Seagen: Speakers Bureau. Tani:Abbvie, Jansen-Cilag, Incyte: Membership on an entity's Board of Directors or advisory committees. Bartlett:ADC Therapeutics, Foresight Diagnostics, Kite, F. Hoffmann-La Roche Ltd / Genentech, Inc., Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics, Autolus, BMS/Celgene, Forty Seven, Gilead/Kite Pharma, Janssen, Merck, Millennium, Pharmacyclics, F. Hoffmann-La Roche Ltd / Genentech, Inc., Seattle Genetics: Research Funding; Washington University School of Medicine: Current Employment. Salar:Incyte, Beigene, F. Hoffmann-La Roche Ltd: Speakers Bureau; Ipsen: Membership on an entity's Board of Directors or advisory committees. Brody:Kite Pharma: Research Funding; Merck: Research Funding; Kite-Gilead: Research Funding; SeaGen, Merck, BMS, Pharmacyclics, ADC Therapeutics, Epizyme, Genentech, Inc., Kite: Consultancy; SeaGen, Merck, BMS, Pharmacyclics, ADC Therapeutics, Epizyme, Genentech, Inc., Kite: Research Funding; Genentech: Research Funding. Leppä:Gilead, F. Hoffmann-La Roche Ltd, Novartis, Incyte: Honoraria; Bayer, Celgene, Genmab, Hutchmed, Novartis, Nordic Nanovector, F. Hoffmann-La Roche Ltd, (Research Funding to the Institute): Research Funding; Abbvie, Beigene, Gilead, Incyte, Novartis, Orion, Pfizer, F. Hoffmann-La Roche Ltd, Sobi: Consultancy. Berthier:F. Hoffmann La Roche Ltd: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months. Kallemeijn:F. Hoffmann La Roche Ltd: Current Employment. Relf:F. Hoffmann La Roche Ltd.: Current equity holder in publicly-traded company; F-Star Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Roche Products Ltd: Current Employment. Chohan:F. Hoffmann La Roche Ltd: Current Employment. Lundberg:F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company; F. Hoffmann-La Roche Ltd: Current Employment; F. Hoffmann La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Hutchings:AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, F. Hoffmann-La Roche Ltd, Takeda: Consultancy; Martin Hutchings has a Consulting or Advisory Role at Takeda, Roche and Genmab and has received Research Funding from Celgene, Genmab, Roche, Takeda and Novartis.: Consultancy; AbbVie, AstraZeneca, Bristol Myers-Squibb, Celgene, Genentech, Genmab, Incyte, Janssen, Merck, Novartis, F. Hoffmann-La Roche Ltd, Takeda: Research Funding; AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, F. Hoffmann-La Roche Ltd, Takeda: Honoraria; AbbVie, AstraZeneca, Celgene, Genmab, Janssen, Merck, F. Hoffmann-La Roche Ltd, Takeda: Membership on an entity's Board of Directors or advisory committees.

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