Combining cd19‐4‐1bbl (ro7227166) with glofitamab is safe and shows early efficacy in patients suffering from relapsed or refractory b‐cell non‐hodgkin lymphoma

Introduction: The antibody-like fusion protein RO7227166 simultaneously targets CD19 on B-cells and 4-1BB (CD137) on T cells. RO7227166 activity is strictly dependent on CD19 crosslinking and exhibits no single-agent activity. RO7227166 plus glofitamab shows strong synergy in preclinical models and is being developed for patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (R/R B-NHL). Methods: This first-in-human trial BP41072 (NCT04077723) evaluated the safety, tolerability, pharmacokinetics/dynamics and preliminary activity of RO7227166 in combination with glofitamab. After a single obinutuzumab dose (1000 mg), pts started glofitamab step up dosing receiving the first target dose of 30 mg on C2D1. On C2D8 RO7227166 dose was given intravenously. From C3D1 both drugs were administered Q3W for a maximum of 12 cycles. Dose escalation was conducted using an mCRM EWOC model with overdose control. Response rates were assessed using Lugano criteria. Results: As of 15 December, 57 pts with aggressive (aNHL) and 23 pts with indolent NHL (iNHL) out of a total of 104 enrolled (all histologies) were evaluable. Aggressive NHL include 42 DLBCL (diffuse large B-cell lymphoma) and 15 trFL (transformed follicular lymphoma). RO7227166 doses ranging from 360 ug up to 75 mg were assessed and the maximum tolerated dose was not reached. Pts (aNHL/iNHL) had median age of 63/62, 39% female, ECOG 0 (56%/74%) or 1 (44%/26%), and stage IV (54%/56%). Patients were heavily pre-treated (median 3 for both [1–8]; 46%/4% had prior CAR-T and 19.7%/9% were primary refractory. Across the 84 safety evaluable pts (all histologies) who received both glofitamab and RO7227166 at least once, the most common adverse events (>15% of pts) were cytokine release syndrome (CRS, 58.3%), neutropenia (28.6%), COVID-19 (25.0%), anemia (22.6%), diarrhea and rash (19.0% each), fatigue (17.9%) and pyrexia (16.7%). Grade 5 events were reported in 5 pts (6%), related to study treatment in 2 pts. A Grade 5 pneumocystis jiroveci pneumonia, related to glofitamab qualified as dose-limiting toxicity (n = 1). CRS was grade 1 in 50.0%, grade 2 in 16.7% and grade 3 in a single patient, mostly confined to the first two cycles of glofitamab. CRS was considered related to only RO7227166 in 6 pts and were all grade 1. Across all doses investigated, best ORR (aNHL/iNHL) was 70%/ 95.7% with CRR of 53%/74%. The aNHL pts with prior CAR-T had 68% BORR and 42% CRR. RO7227166 exposure increased in an almost dose proportional manner for doses ≥22 mg. Furthermore, pharmacodynamic analysis showed expansion of primed and activated CD8, and effector memory T-cells, with a reduction of exhausted T cell phenotypes. Conclusions: Glofitamab can be safely combined with a costimulatory bispecific antibody (RO7227166) in R/R B-NHL. The safety profile of the combination was mainly driven by glofitamab and we did not detect an additive safety signal from RO7227166. Keywords: aggressive B-cell non-Hodgkin lymphoma, immunotherapy, ongoing trials Conflicts of interests pertinent to the abstract M. Hutchings Consultant or advisory role: Genmab, Roche, Takeda Honoraria: Genmab, Roche, Takeda Research funding: Celgene, Daiichi-Sankyo, Genmab, Janssen, Novartis, Roche, Sanofi, Takeda M. Dickinson Consultant or advisory role: Roche, Abbvie Honoraria: Roche, Abbvie Research funding: Roche Educational grants: Roche C. Carlo-Stella Employment or leadership position: Humanitas University, Milano (Italy) Consultant or advisory role: Sanofi, ADC Therapeutics, Bristol-Myers Squibb, Celgene, Karyopharm Therapeutics, Roche Honoraria: AstraZeneca, Bristol-Myers Squibb, Incyte, Janssen Oncology, Takeda, ADC Therapeutics Research funding: ADC Therapeutics, Roche, Sanofi Educational grants: Roche, Janssen Oncology, Takeda F. Morschhauser Consultant or advisory role: Roche, Gilead, Genmab, Novartis, Abbvie Honoraria: Chugai (scientific lectures) F. Bosch Research funding: Roche G. Gritti Consultant or advisory role: Roche, Takeda, Kite-Gilead, Ideogen, Genmab Educational grants: Janssen, Beigene, Sandoz W. Townsend Consultant or advisory role: Roche, Takeda, Gilead, Incyte Honoraria: Roche, Takeda, Gilead, Incyte Educational grants: Roche and Takeda N. L. Bartlett Consultant or advisory role: tbd Honoraria: tbd Research funding: tbd G. Cartron Consultant or advisory role: ROCHE, BMS, Abbvie, MedXcell, MabQi, Ownards Therapeutics Honoraria: GILEAD, BMS, Roche, Abbvie, Jansen, Novartis Educational grants: Roche H. Ghesquieres Consultant or advisory role: tbd Honoraria: tbd Research funding: tbd R. Houot Consultant or advisory role: Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, ADC Therapeutics, Incyte, Miltenyi Honoraria: Kite/Gilead, Novartis, Incyte, Janssen, MSD, Takeda, Roche A. Christiansen Consultant or advisory role: Roche N. Dimier Employment or leadership position: Roche Stock ownership: Roche C. Jamois Employment or leadership position: Roche Stock ownership: Roche E. Harrop Employment or leadership position: Roche Stock ownership: Roche S. Herter Employment or leadership position: Roche Stock ownership: Roche G. Hölzlwimmer Employment or leadership position: Roche Stock ownership: Roche A. Keelara Employment or leadership position: Roche Stock ownership: Roche K. Korfi Employment or leadership position: Roche Stock ownership: Roche J. Luong Employment or leadership position: Roche Stock ownership: Roche C. Mueller Employment or leadership position: Roche Stock ownership: Roche S. Mycroft Employment or leadership position: Roche Stock ownership: Roche M. Whayman Employment or leadership position: Roche Stock ownership: Roche I. Prieto Employment or leadership position: Roche Stock ownership: Roche D. Rukina Consultant or advisory role: Roche K. Lechner Employment or leadership position: Roche Stock ownership: Roche