CD20‐TCB (RG6026), A NOVEL “2:1” FORMAT T‐CELL‐ENGAGING BISPECIFIC ANTIBODY, INDUCES COMPLETE REMISSIONS IN RELAPSED/REFRACTORY B‐CELL NON‐HODGKIN'S LYMPHOMA (2019)

Introduction: CD20-TCB (RG6026) is a T-cell-engaging bispecific antibody with a novel “2:1” molecular format which preclinically showed greater avidity for CD20 antigen, combinability with other anti-CD20 antibodies, and greater efficacy as compared to other CD20-CD3 bispecific formats. NP30179 is an ongoing multicenter phase I dose escalation trial investigating the safety, tolerability, pharmacokinetics (PK), biomarkers and antitumor activity of CD20-TCB. Methods: Patients receive escalating doses of CD20-TCB as intravenous infusions guided by a model implementing a Bayesian CRM method with overdose control. To reduce the risk of cytokine release syndrome (CRS), a single dose of obinutuzumab as pretreatment (Gpt) is administered seven days prior to CD20-TCB to debulk B cells in peripheral blood and normal tissues (Bacac et al Clin Canc Res 2018). Updated data at clinically-relevant doses of 600 μg and above are reported. Results: As of February 13th 2019 a total of 87 pts with r/r aggressive (a)NHL (DLBCL/PMBCL/trFL/Richter's transformation; n=79) and r/r FL (n=8) received CD20-TCB doses ranging from 600 μg to 25mg in a Q2W or Q3W schedule. Median age was 61 years (range 22-84), median prior lines of therapy was 3 (range 1-13), and 86% pts were refractory to prior therapy. CRS (according to the criteria by Lee et al. Blood 2014) occurred in 45 patients (23% G1, 24% G2, 3% G3, 1% G4). At the highest dose cohort (25 mg) >G3 CRS occurred in 3/8 pts at cycle 1, thereby preventing further dose escalation. One patient in the 25 mg cohort died of upper GI bleeding after an episode of severe CRS. All other CRS events were manageable and resolved, and patients were retreated without delay at the same dose at cycle 2, where only one additional CRS event was seen (G1). In the efficacy evaluable pts (n=84) the ORR and CR rate by investigator assessment (Lugano 2014 criteria) in aNHL (n=76) was 46% and 29%, and in FL (n=8) 63% and 50%, respectively. In the highest dose cohorts (10-25 mg) the ORR and CR rate in aNHL (n=38) was 55% and 37% indicating a dose-response relationship. CR was usually achieved at the first or second response assessments (C3 or C6) although in 4 aNHL pts late conversion from PR or SD to CR was observed at cycle 12. A patient with FL initially dosed at 15 μg who had progressed was retreated at 10 mg, achieving CR. After a median follow up of 3.8 months all but 2 CRs are still ongoing. Responses were seen across NHL subtypes and across prognostic factors such as disease burden, prior lines of therapy, and refractoriness to prior therapy. CD20-TCB exposure and receptor occupancy increased dose-dependently across the investigated dose range. No anti-drug-antibodies have been found. Mode of action was demonstrated by rapid and sustained T cell activation in peripheral blood and tumor biopsies. Conclusions: CD20-TCB is a novel 2:1 format T-cell-engaging bispecific antibody which displays highly promising clinical activity in heavily-pretreated NHL. Keywords: B-cell lymphoma; CD20; immune system. Disclosures: Dickinson, M: Consultant Advisory Role: Roche; Honoraria: Roche. Morschhauser, F: Consultant Advisory Role: Advisory role for Celgene, Roche, BMS, Gilead, Epizyme, Verasteem; Honoraria: Novartis, Janssen, Abbvie. Iacoboni, G: Honoraria: Celgene, Novartis, Roche. Carlo-Stella, C: Consultant Advisory Role: Sanofi, ADC Therapeutics, Servier France, Roche; Honoraria: BMS, MSD, Novartis, Janssen. Sureda, A: Other Remuneration: Travel Grants from Roche. Salles, G: Consultant Advisory Role: Abbvie, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, Takeda; Honoraria: Abbvie, Amgen, BMS, Celgene, Gilead, Epizyme, Janssen, Karyopharm, Kite, Merck, Morphosys, Novartis, Roche, Servier, Takeda. Martinez, J: Honoraria: Novartis, Celgene, BMS, Jansen; Research Funding: Novartis, Celgene, BMS, Jansen. Crump, M: Consultant Advisory Role: Roche Canada, Servier, Kyte/Gilead. Thomas, D: Employment Leadership Position: Roche; Stock Ownership: Roche. Morcos, P: Employment Leadership Position: Roche; Stock Ownership: Roche. Ferlini, C: Employment Leadership Position: Roche; Stock Ownership: Roche. Broeske, A: Employment Leadership Position: Roche. Bacac, M: Employment Leadership Position: Roche; Stock Ownership: Roche. Dimier, N: Employment Leadership Position: Roche; Stock Ownership: Roche. Umaña, P: Employment Leadership Position: Roche; Stock Ownership: Roche. Moore, T: Employment Leadership Position: Yes; Stock Ownership: Yes. Weisser, M: Employment Leadership Position: Roche; Stock Ownership: Yes. Hutchings, M: Consultant Advisory Role: Takeda, Roche, Celgene; Honoraria: Takeda, Roche, Celgene, Janssen; Research Funding: Takeda, Roche, Novartis, Celgene.