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737 Glofitamab Plus R-CHOP Induces High Response Rates and a Favorable Safety Profile in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma (DLBCL): Results from a Phase Ib Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 626. Aggressive Lymphomas: Prospective Therapeutic Trials: Frontline Treatment of Large B-cell Lymphoma
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Lymphomas, non-Hodgkin lymphoma, Bispecific Antibody Therapy, Clinical Research, Diseases, aggressive lymphoma, Therapies, Lymphoid Malignancies
Monday, December 12, 2022: 11:30 AM

Max S. Topp1, Monica Tani, MD2*, Michael Dickinson, MD3, Nilanjan Ghosh, MD, PhD4, Armando Santoro, MD5*, Antonio Pinto, MD6*, Francesc Bosch, MD, PhD7, Christopher P. Fox8*, Armando López-Guillermo, MD, PhD9*, Claudia Carlucci10*, Chun Wu11*, Kathryn Humphrey10*, Pauline Baumlin12*, Martin Barrett10*, Naseer Qayum10* and Franck Morschhauser, MD, PhD13*

1Universitätsklinikum Würzburg, Würzburg, Germany
2Ospedale Santa Maria delle Croci, Ravenna, Italy
3Peter MacCallum Cancer Centre, Royal Melbourne Hospital and The University of Melbourne, Melbourne, Australia
4Levine Cancer Institute/Atrium Health, Charlotte, NC
5Humanitas University and IRCCS Humanitas Research Hospital, Humanitas Cancer Center, Milan, Italy
6Istituto Nazionale Tumori, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
7Hospital Universitari Vall d’Hebron, Barcelona, Spain
8Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
9Hospital Clínic de Barcelona, Barcelona, Spain
10Roche Products Ltd, Welwyn Garden City, United Kingdom
11Roche (China) Holding Ltd., Shanghai, China
12F. Hoffmann-La Roche Ltd, Basel, Switzerland
13Hôpital Claude Huriez Univ. Lille, CHU Lille, ULR 7365 - GRITA - Groupe de Recherche sur les formes Injectables et les Technologies Associées and Centre Hospitalier Régional Universitaire de Lille, Lille, France

Background: R-CHOP is a standard treatment for previously untreated DLBCL, however, more than one-third of patients are not cured by R-CHOP and there is a clear need for more effective novel first-line treatment combinations. Glofitamab is a CD20xCD3 T-cell-engaging bispecific monoclonal antibody with a novel 2:1 (CD20:CD3) configuration that confers high-avidity bivalent binding to CD20 on B cells (unlike the 1:1 format of conventional bispecific antibodies, which confers monovalent binding to CD20); this bivalency for CD20 enables combination with anti-CD20 antibodies, including rituximab. Glofitamab has shown high activity as a single agent in patients with heavily pretreated and/or highly refractory DLBCL (Dickinson et al. ASCO 2022).

Preliminary findings from the safety run-in phase of the ongoing NP40126 study (NCT03467373) demonstrated tolerable safety with glofitamab (Glofit) + R‑CHOP as first-line therapy for patients with DLBCL (Ghosh et al. ASH 2021); here, we present efficacy and safety data from both the safety run-in portion and the expansion stage of this study.

Methods: Patients received R-CHOP in Cycle (C)1 with the aim of tumor debulking to mitigate cytokine release syndrome (CRS) risk. In total, 6–8 21-day cycles of R-CHOP were administered. Intravenous glofitamab was given during C2 (Day [D]8, 2.5mg; D15, 10mg) and at the target dose (30mg) from C3D8 onwards (21-day cycles). Hospitalization was at the discretion of the investigator for those patients enrolled in the expansion stage.

Response was assessed by PET-CT using Lugano criteria (Cheson et al. J Clin Oncol 2014). Patients who were scheduled to reach end of treatment (EOT) by the data cut-off were considered efficacy-evaluable (EOT population). CRS events were graded using ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Other adverse events (AEs) were graded using CTCAE.

Results: At data cut-off (May 25, 2022), 56 patients were enrolled (safety population); of these, 46 had reached their scheduled EOT assessment (EOT population). Two patients in the EOT population were withdrawn from the study prior to receiving glofitamab (Grade [Gr] 5 infusion-related reaction [IRR] related to rituximab at C1D1; Gr 4 thrombosis following R-CHOP); the total number of patients exposed to glofitamab 30mg + R-CHOP was 44. Median age was 68 years (range: 21–84) and 54 pts (96.4%) had Ann Arbor Stage III/IV disease. In the EOT population, median IPI score was 3 (IPI 1: 2.2% [1/46], IPI 2: 30.4% [14/46], IPI 3: 34.8% [16/46], IPI 4: n= 28.3 [13/46], IPI 5: n= 4.3% [2/46]).

After a median 5.6 (range: 5.1—10.3) months follow up, the complete metabolic response rate was 76.1% (35/46) and the overall response rate was 93.5% (43/46) in the EOT population (BOR).

Of 56 patients in the safety population, Gr ≥3 AEs occurred in 40 (71.4%) patients and Gr ≥3 AEs related to glofitamab in 13 (23.2%) patients. Serious AEs (SAEs) were reported in 18 (32.1%) patients and SAEs related to glofitamab in five (8.9%) patients. Gr 5 AEs were reported in three (5.4%) patients (COVID-19 pneumonia, n=2; IRR to rituximab, n=1). AEs leading to dose modification/interruption of glofitamab occurred in 11 (19.6%) patients, including COVID-19 pneumonia (n=3) and COVID-19 (n=2). Median dose intensity was 100% for all R-CHOP components. One AE leading to discontinuation of glofitamab was reported (cerebrovascular accident, considered unrelated to glofitamab).

There were no severe Gr 3–5 CRS events and Gr 1–2 CRS was reported in six (10.7%) patients: Gr 1, n=4; Gr 2, n=2. All CRS events occurred during C2–3 and were resolved. Neurologic AEs (NAEs) occurred in 22 (39.3%) patients (of which the majority were Gr ≤2 [20/22]); Gr 3 NAEs included cerebrovascular accident (n=1) and herpes zoster (n=1). No glofitamab-related NAEs potentially consistent with immune effector cell-associated neurotoxicity syndrome were reported. Neutropenia was reported in 27 (48.2%) patients (Gr ≥3 neutropenia: Gr 3, n=6; Gr 4, n=19) and serious infection in nine (16.1%) patients.

Conclusions: The low incidence and severity of CRS, minimal toxicity and promising efficacy reported in this analysis suggest that glofitamab can be safely combined with R-CHOP as a fixed-duration treatment for patients with first-line DLBCL. The dose intensity of R‑CHOP was maintained in all patients. Glofit + R-CHOP may be suitable for the outpatient setting.

Disclosures: Topp: KITE, BMS, Janssen, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche, Regeneron, KITE, BMS: Research Funding; Universitätsklinikum Würzburg: Ended employment in the past 24 months; Universitätsklinikum Würzburg: Current Employment. Dickinson: Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD: Consultancy; Roche, BMS, Novartis, Kite, Gilead, NKARTA, AdiCet Bio, Interius, Janssen, MSD, Amgen: Honoraria; Roche, Novartis, Kite, Gilead, MSD, Takeda, Celgene: Research Funding. Ghosh: Gilead/Kite: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Loxo/Lilly: Consultancy, Honoraria; Incyte/Morphosys: Consultancy, Research Funding; TH Therapeutics: Consultancy, Honoraria, Research Funding; Epizyme: Speakers Bureau; AbbVie: Research Funding; Roche/Genentech: Consultancy, Honoraria, Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen/Pharmacyclics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Seagen, TG Therapeutics, AstraZeneca, Phamacyclics, Janssen, Bristol Myers Squibb, Gilead Sciences, Beigene, Incyte, Karyopharm, Roche/Genentech, Novartis, Loxo Oncology, Genmab, Adaptive Biotech, ADC Therapeutics: Consultancy; TG Therapeutics, Genentech/Roche, Bristol Myers Squibb, Gilead, Morphosys, AbbVie: Research Funding; Gilead, AstraZeneca, Bristol Myers Squibb, Phamacyclics, Janssen, Epizyme: Speakers Bureau. Santoro: Abb-vie: Speakers Bureau; Amgen: Speakers Bureau; Celgene: Speakers Bureau; Sanofi: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eli-Lilly: Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Incyte: Consultancy; Roche: Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pinto: Servier Affaires Medicales: Honoraria; F. Hoffmann-La Roche AG, Incyte (Italy), Merck Sharp and Dohme, Servier Affaires Medicales: Honoraria; F. Hoffmann-La Roche AG, Merck Sharp and Dohme, Incyte (Italy): Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp and Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche AG: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bosch: Karyospharm: Honoraria; Astra Zeneca: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Beigene: Consultancy, Honoraria. Fox: Roche: Other: Travel to scientific congress; Celgene/BMS, Gilead/Kite, Incyte, Janssen, Roche, Takeda: Speakers Bureau; BeiGene: Research Funding; Abbvie, AstraZeneca, Atarabio, Celgene/BMS, GenMab, Gilead/Kite, Incyte, Janssen, Morphosys, Ono, Roche, Takeda: Consultancy. López-Guillermo: Hospital Clinic de Barcelona: Current Employment; Roche, Kite/Gilead, Celgene, Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Carlucci: Roche Holding AG: Current Employment, Current equity holder in publicly-traded company. Wu: Roche (China) Holding Ltd.: Current Employment; Roche: Current equity holder in publicly-traded company. Humphrey: Roche: Current equity holder in private company, Current holder of stock options in a privately-held company; Roche Products Ltd: Current Employment. Baumlin: Hoffmann La Roche: Current Employment. Barrett: Roche Products Ltd. UK: Current Employment, Current equity holder in private company. Qayum: Roche: Current Employment, Current equity holder in publicly-traded company. Morschhauser: Genentech: Consultancy; Genmab: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; Epizyme: Consultancy, 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: 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; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: 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. Rituximab (Rituxan) is a CD20-directed cytolytic antibody indicated for the treatment of adult patients (pts) with: relapsed or refractory, low grade or follicular, CD20-positive, B-cell NHL as a single agent; previously untreated follicular, CD20-positive, B-cell NHL in combination with first-line chemotherapy (chemo) and, in pts achieving a CR or PR to a rituximab product in combination with chemo, as single-agent maintenance therapy; non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line CVP chemo; previously untreated diffuse large B-cell, CD20-positive, NHL in combination with CHOP or other anthracycline-based chemo regimens; previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide.

*signifies non-member of ASH