ALBERT

Description: Introduction: CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. An ongoing Phase I dose-escalation study (NP30179; NCT03075696) has shown promising antitumor activity and acceptable safety in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) patients (pts) (Dickinson et al. ICML 2019). We investigated population pharmacokinetics (popPK) and exposure-response (E-R) relationships for CD20-TCB in NP30179. Methods: Indolent (i) and aggressive (a) R/R NHL pts received CD20-TCB doses of 0.005 to 25mg every 2 or 3 weeks following single 1000mg obinutuzumab (G) pre-treatment (Gpt) on Cycle 1 Day −7 to mitigate for cytokine release syndrome (CRS). Serial and spare PK data collected from pts were used to develop a popPK model in NONMEM v7.4. Physiologically relevant covariates were investigated for their potential influence on CD20-TCB PK variability. Using the previously established G popPK model (Gibiansky et al. CPT Pharmacometrics Syst Pharmacol 2014;3:e144), full G concentration-time profiles were constructed in order to estimate CD20-TCB receptor occupancy (RO%) in the presence of G concentrations competing for CD20 receptors over time. E-R relationships between CD20-TCB time-averaged RO% (AvgRO%) up to Cycle 3 Day 1 and objective response rate (ORR) and complete response rate (CRR) were investigated in aNHL pts who reached Cycle 3 Day 1, and the relationship between CD20-TCB AvgRO% over the first 24 hours (as the majority of events occurred within the first 24 hours) and CRS, the most common safety event, as defined by Lee et al. (Blood 2014;124:188-95), was investigated in iNHL and aNHL pts combined using logistic regression. Results: The popPK analysis included 139 iNHL and aNHL pts with at least one PK sample. The E-R analysis for efficacy included 76 aNHL pts with PK and efficacy data at Cycle 3 Day 1. The E-R analysis for safety included 121 iNHL and aNHL pts with PK and safety data. CD20-TCB PK was best described using a two-compartment PK model with linear clearance. Body weight had a statistically significant influence on PK and was retained using theory-based allometric scaling. There were no obvious differences in PK between iNHL and aNHL pts. In aNHL pts, logistic regression analyses demonstrated a significant positive E-R relationship between AvgRO% up to Cycle 3 Day 1 and efficacy (ORR and CRR, p=0.007; Figure 1 for CRR). In the highest tertile of AvgRO% (≥0.48%), the observed ORR was 76% versus 38.5% (

Description: CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. CD20-TCB has demonstrated highly promising single-agent activity in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) patients (pts) (Dickinson et al. ICML 2019). Preclinical data demonstrate CD20-TCB-induced programmed cell death protein 1 (PD-1) and programmed cell death-ligand-1 (PD-L1) upregulation on T cells and tumor cells. We hypothesized that the combination of T-cell engagement by CD20-TCB and PD-L1 inhibition by atezolizumab could lead to additive anti-tumor activity in B-NHL. We report preliminary data from NP39488 (NCT03533283), an ongoing Phase Ib study evaluating the safety, tolerability, pharmacokinetics, and preliminary efficacy (objective response rate [ORR] and complete response [CR] rate per modified Lugano 2014 criteria) of CD20-TCB in combination with atezolizumab in R/R B-NHL pts. A single dose of 1000mg obinutuzumab (G) is administered on Day −7 of Cycle 1 as pretreatment (Gpt) to mitigate for potential cytokine release syndrome (CRS). CD20-TCB is initiated on Day 1 of Cycle 1 and given in a q3w schedule. From Cycle 2 onwards, atezolizumab (1200mg) is added and given on the same day as CD20-TCB. CD20-TCB dose-escalation is ongoing and is guided by the modified continual reassessment method-escalation with overdose control (mCRM-EWOC). As of June 25, 2019, 38 pts with aggressive B-NHL (n=33; diffuse large B-cell lymphoma [DLBCL], transformed [tr] follicular lymphoma [FL], primary mediastinal large B-cell lymphoma, mantle cell lymphoma, tr lymphoplasmacytic lymphoma, tr Waldenstrom`s macroglobulinemia) or indolent B-NHL (n=5; FL) had received CD20-TCB doses from 0.07mg to currently 6mg. Pts (52.6% male) had a median age of 67 years (range: 38-82) and a median of three prior treatment lines (range: 1−10); 84% had refractory B-NHL. Two dose-limiting toxicities (Grade [Gr] 3 tumor flare at 6mg during Cycle 1 and Gr 3 myopathy at 1.8mg during Cycle 2) were transient and resolved completely. The most frequent adverse event (AE) was CRS (42%; 16/38 pts), with 24% Gr 1 (n=9), 18% Gr 2 (n=7), and no Gr ≥3 (according to Lee criteria, Lee et al. Blood 2014;124:188-95). The most common AEs (〉20%) were pyrexia (37%), anemia (29%), fatigue (24%), neutropenia (21%), diarrhea (21%), and decreased appetite (21%). The most common Gr ≥3 AEs (〉10%) were neutropenia (18%) and anemia (13%), with a single Gr 5 unrelated pneumonia. Three pts experienced a transient Gr ≥3 neurotoxicity (Gr 4 polyneuropathy, Gr 3 trigeminal nerve herpes zoster infection, and Gr 3 post-infection encephalopathy), all of which resolved. Thirty-six pts reached their first response assessment or withdrew early and were eligible for efficacy analysis. Across all doses, ORR and CR rates by investigator assessment were 36% (13/36 pts) and 17% (6/36), respectively (indolent NHL: 4/5 and 3/5 pts; aggressive NHL: 9/31 and 3/31 pts). All CRs are ongoing at the time of abstract submission. CD20-TCB exposure and receptor occupancy (RO%) increased dose-dependently across the dose-range evaluated, and are expected to be further optimized (Djebli et al. ASH 2019). At the higher CD20-TCB doses investigated, a trend towards increased clinical activity was observed (ORR of 60% [9/15 pts] in the 4mg and 6mg cohorts combined). The combination of CD20-TCB and atezolizumab has manageable safety in R/R B-NHL pts. No new safety signals or signs of increased immune-related AEs were detected, and the overall safety profile was consistent with that reported with single-agent CD20-TCB (Dickinson et al. ICML 2019). Dose escalation is ongoing and aims to optimize the dose and schedule of CD20-TCB when combined with atezolizumab using the established exposure-response model for CD20-TCB (Djebli et al. ASH 2019). Updated safety, efficacy, and biomarker data will be presented. Disclosures Hutchings: Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Celgene: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Janssen: Research Funding; Incyte: Research Funding. Gritti:Roche: Other: Not stated; Abbvie: Other: Not stated; Becton Dickinson: Other: Not stated; Autolus Ltd: Honoraria. Sureda:Sanofi: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria; BMS: Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support. Terol:Roche: Consultancy; Abbvie: Consultancy; Astra Zeneca: Consultancy; Janssen: Consultancy, Research Funding; Gilead: Research Funding. Dyer:Roche: Research Funding. Iacoboni:Novartis: Consultancy, Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Honoraria; Celgene: Honoraria. Townsend:Roche: Consultancy, Honoraria. Bacac:Roche: Employment, Equity Ownership, Patents & Royalties: Patents, including the one on CD20-TCB. Bröske:Roche: Employment, Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Keelara:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Lahr:Roche: Employment, Honoraria. Lechner:Roche: Employment, Other: Roche shareholder. Moore:Roche: Employment, Equity Ownership. Morcos:Roche: Employment, Equity Ownership. Panchal:Roche: Employment. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding (Fab) regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.

Description: Despite advancements in outcomes with the introduction of anti-CD20 monoclonal antibody therapy, a substantial proportion of B-cell Non-Hodgkin's Lymphoma (B-NHL) patients do not sustain a durable response to standard of care treatment. T-cell bispecific antibodies (TCBs) represent a new class of disease-targeting agents shown to activate T-cells to kill cancer cells, offering this exciting mechanism of action with 'off the shelf' availability. CD20-TCB (RG6026) is a novel T-cell-engaging bispecific antibody whose "2:1" format possesses two CD20 binders in addition to a CD3 binder, enabling increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing. NP30179 is a multicenter phase I dose escalation trial investigating the safety, tolerability, pharmacokinetics (PK), biomarker responses, and antitumor activity (assessed by overall response rate [ORR] and complete response rate [CR] per Lugano 2014 criteria) of single agent CD20-TCB. Patients receive escalating doses of CD20-TCB as intravenous infusions with dose escalation guided by a model implementing the Bayesian continuous reassessment method with overdose control. In order to reduce the potential risk of cytokine release syndrome (CRS) induced by CD20-TCB mediated systemic T-cell activation, a single dose of 1000 mg obinutuzumab (G) pretreatment (Gpt) is administered seven days prior to start of CD20-TCB and has preclinically been shown to debulk peripheral B cells and reduce systemic cytokine release (Bacac et al. Clin Canc Res 2018). As of July 29th 2018 a total of 64 patients (pts) with aggressive r/r B-NHL (DLBCL/PMBCL/trFL/Richter´s transformation (n=47)) and indolent r/r B-NHL (FL(n=17)) received CD20-TCB doses ranging from 5 µg to 1800 µg in a Q2W schedule. Median age was 64 years (range 28-82), 61% were male, median prior lines of therapy was 3 (range 1-10). A single DLT (myocardial infarction) was observed at 220 µg and until the maximum tested dose CD20-TCB was well tolerated. The most reported AEs were pyrexia (n=14, all Gr 1 and 2), neutropenia (all grades n=17, Gr 3 and 4 n=14) and cytokine release syndrome (CRS, n=14, all Grade 1-2 according to the criteria by Lee et al. Blood 2014). Two patients received tocilizumab for CRS management all CRS events were manageable and resolved, without leading to dose reduction or study withdrawal. No CNS toxicity was reported so far in this study. Fifty-five pts had at least one post-baseline response assessment and were eligible for efficacy analysis. Responses were observed from 15 µg onwards, and complete responses (CR) occurred from 300 µg onwards following two cycles of treatment. At doses of 300 µg or above (n=29) the ORR and CR rate by investigator assessment was 38% and 24%, respectively (FL: 3/5 pts and 2/5 pts respectively, aggressive B-NHL: 8/24 pts and 5/24 pts respectively). All CRs are sustained thus far with a median follow up 96 days (range 26-152). Responses were seen across various NHL subtypes and across prognostic factors such as prior lines of therapy, refractoriness to the most recent line of therapy, tumor burden, and IPI or FLIPI. CD20-TCB exposure and receptor occupancy increased dose-dependently across the investigated dose range; dose-escalation is continuing to optimize these factors. No anti-drug-antibodies have occurred. CD20-TCB is a novel 2:1 format T-cell-engaging bispecific antibody which already at suboptimal doses displays promising clinical activity in heavily-pretreated B-NHL. In addition, Gpt has shown clinical proof of principle as an approach to efficiently mitigate CRS. An update on safety and efficacy as well as biomarker data will be presented. Disclosures Hutchings: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Iacoboni:Celgene: Other: Travel funding; Roche: Honoraria. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sureda:Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Salles:Janssen: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Carlo-Stella:Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim: Consultancy; Sanofi: Consultancy; MSD: Other: Advisory Board; Genenta Science: Other: Advisory Board; BMS: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; AstraZeneca: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board. Martinez Lopez:Celgene: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Thomas:Roche: Employment, Equity Ownership. Morcos:Roche: Employment, Equity Ownership. Quackenbush:Roche: Employment. Ferlini:Roche: Employment. Bacac:F. Hoffmann-La Roche Ltd.: Employment, Other: stock, Patents & Royalties. Broeske:Roche: Employment, Equity Ownership. Dimier:Roche: Employment, Equity Ownership. Moore:Roche: Employment. Weisser:Roche: Employment, Equity Ownership, Patents & Royalties. Dickinson:GSK: Consultancy.

Description: Introduction: CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format that comprises two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats. The safety, tolerability, pharmacokinetics, biomarkers, and antitumor activity of CD20-TCB are currently being investigated in a multicenter Phase I dose-escalation trial (NP30179; NCT03075696). We recently presented preliminary clinical data demonstrating promising clinical activity in relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) patients with indolent or aggressive disease (Dickinson et al. ICML 2019). Here, we present preliminary blood and tissue biomarker analyses to explore modes of action, support optimal biological dose selection, and identify potential outcome predictors. Methods: For biomarker analyses, we performed immune profiling of peripheral blood by flow cytometry, analyzed plasma cytokine levels by ELISA, and characterized baseline and on-treatment tumor biopsies by immunohistochemistry/immunofluorescence assays and RNA sequencing. Biomarker data were obtained from 122 patients dosed with 0.005-25mg CD20-TCB. Results: CD20-TCB infusion led to a rapid and transient reduction in T cells in the peripheral circulation (T-cell margination) in all patients. T-cell margination reached nadir 6 hours after the first CD20-TCB infusion, and showed a strong association with CD20-TCB dose and receptor occupancy (RO%; as determined by Djebli et al. ASH 2019). Interestingly, rebound of T cells 160 hours after the first CD20-TCB infusion was associated with response to treatment. Responding patients showed long-term T-cell activation after the first infusion of CD20-TCB at doses from 0.6mg and above. T-cell activation was demonstrated by 2-4-fold elevation of T-cell activation markers such as Ki67, HLA-DR, PD-1, ICOS, OX40, and 4-1BB, which was sustained up to Cycle 5 (105 days). Analysis of paired pre- and on-treatment tumor biopsies (n=6) obtained before and 2-3 weeks after the first dose of CD20-TCB showed evidence of T-cell-mediated tumor cell killing. Analysis of archival and pre-treatment tumor biopsies (n=80) revealed that clinical responses were achieved irrespective of the amount of tumor T-cell infiltration at baseline. In contrast, preliminary baseline bulk tumor RNA sequencing data (n=46) showed upregulation of gene signatures associated with cell proliferation/Myc and T-cell subsets (effector vs exhausted-like) in non-responding patients. Conclusions: In this study, we demonstrated the mode of action of CD20-TCB, a novel bispecific antibody with promising clinical activity in R/R NHL. We also demonstrated that biomarker data on T-cell activation can support dose finding in conjunction with pharmacokinetics. Additional analysis is ongoing to evaluate response predictors and better characterize the population that will benefit most from T-cell mediated therapies. Disclosures Bröske: Roche: Employment, Equity Ownership. James:A4P Consulting Ltd: Consultancy. Belousov:Roche: Employment. Gomez:F. Hoffmann-La Roche Ltd: Employment. Canamero:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Ooi:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Grabole:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Wilson:F. Hoffmann-La Roche Ltd: Employment. Korfi:F. Hoffmann-La Roche Ltd: Consultancy. Kratochwil:F. Hoffmann-La Roche Ltd: Employment. Morcos:Roche: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Thomas:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Moore:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bacac:Roche: Employment, Equity Ownership, Patents & Royalties: Patents, including the one on CD20-TCB. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. Dickinson:Merck Sharpe and Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding (Fab) regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.

Description: CD20-TCB (RG6026) is a novel T-cell-engaging bispecific (TCB) antibody with a '2:1' molecular format comprising two fragment antigen binding regions that bind CD20 (on the surface of B cells) and one that binds CD3 (on the surface of T cells). CD20-TCB offers the potential for increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing versus other bispecific formats, and the ability to combine with another CD20-targeted agent. Preclinical studies of concurrent therapy with CD20-TCB plus obinutuzumab (G) in diffuse large B-cell lymphoma (DLBCL) models demonstrate strong and sustained tumor regression driven by multiple mechanisms of action. These include induction of direct tumor cell death and antibody-dependent cellular cytotoxicity/cellular phagocytosis mediated by G, as well as recruitment of T-cells into the tumor and T-cell cytotoxicity mediated by CD20-TCB. NP30179 (NCT03075696) is a multicenter Phase I/Ib dose-escalation trial investigating the safety, tolerability, pharmacokinetics, biomarker responses, and anti-tumor activity (assessed by objective response rate [ORR] and complete response [CR] rate per modified Lugano 2014 criteria) of CD20-TCB in relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) patients (pts). For the first time, we report preliminary data from Arm B, evaluating dual CD20-targeted therapy with concurrent CD20-TCB and G. All pts receive a single dose of 1000mg G as pre-treatment (Gpt) 7 days before the start of CD20-TCB therapy (Cycle 1) to mitigate cytokine release syndrome (CRS). From Cycle 2 onwards, 1000mg G is administered on the same day as CD20-TCB, which constitutes the start of an initial 28-day dose-limiting toxicity (DLT) window, in 3-weekly cycles. Pts receive escalating doses of CD20-TCB, guided by a model implementing the Bayesian continuous reassessment method with overdose control. As of May 22, 2019, a total of 28 pts with R/R aggressive (a) NHL (DLBCL/primary mediastinal large B-cell lymphoma/transformed follicular lymphoma [FL]/mantle cell lymphoma/Richter´s transformation; n=22) or FL (n=6) had received concurrent G in combination with CD20-TCB doses ranging from 0.6 to 16mg for 8-12 cycles. Median age was 65 years (range, 34-81), 15 (54%) were male, 19 (68%) were refractory to prior therapy, and median prior lines of therapy was 2 (range, 1-6). Twenty-three CRS events (according to Lee criteria, Lee et al. Blood 2014) occurred in 16 (57%) pts (maximum Grade [Gr]: Gr 1, 5 [18%]; Gr 2, 9 [32%]; Gr 3, 1 [4%]; Gr 4, 1 [4%]). CRS events were confined to Cycle 1 in all but two pts. Neurotoxicity was rare (Gr 1, 4 [14%]; Gr 2, 2 [7%]; Gr 3, 1 [4%]) and all events resolved. Apart from CRS, the most frequent adverse events were anemia (all Gr, 6 [21%]; Gr 3, 3 [11%]), thrombocytopenia (all Gr, 6 [21%]; Gr ≥3, 3 [11%]; no hemorrhages reported), neutropenia (all Gr, 4 [14%]; Gr ≥3, 3 [11%]), pyrexia (all Gr, 4 [14%], all Gr 1-2), and hypokalemia (all Gr, 4 [14%]; Gr ≥3, 1 [4%]). No DLTs were reported and no new safety signals were observed. The overall safety profile overlapped with that reported in the single arm of the same study. Twenty-one pts reached their first response assessment or withdrew early and were eligible for efficacy analysis. Overall, the ORR and CR rate by investigator assessment was 48% [10/21 pts] and 43% [9/21], respectively (aNHL: ORR, 38% [6/16]; CR, 31% [5/16]; FL: ORR and CR, 80% [4/5]). CD20-TCB exposure and receptor occupancy (RO%) increased dose-dependently across the investigated dose range, and consistent with the RO%-efficacy model (Djebli et al. ASH 2019), clinically relevant CD20-TCB RO% and increased clinical activity was observed at a dose of 16mg when combined with concurrent G. In the 16mg cohort that included 10 R/R pts, 70% of whom were refractory to prior therapy and median prior lines of therapy was 4, the ORR and CR rate were 90% (9/10 pts) and 80% (8/10), respectively (aNHL: CR, 71% [5/7]; FL: CR, 100% [3/3]), and all CRs were ongoing at the time of abstract submission. This is the first study to demonstrate that CD20-TCB can be safely combined with an anti-CD20 monoclonal antibody and further supports the promise of the '2:1' format for allowing combination therapy with therapeutic levels of other anti-CD20 antibodies, such as G. CD20-TCB plus G provides highly promising clinical activity in heavily pre-treated R/R B-cell NHL. Updated clinical and biomarker data will be presented. Disclosures Morschhauser: Janssen: Honoraria; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, 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. Carlo-Stella:AstraZeneca: Honoraria; ADC Therapeutics: Consultancy, Other: Travel, accommodations, Research Funding; Servier: Consultancy, Honoraria, Other: Travel, accommodations; Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim: Consultancy; Novartis: Consultancy, Research Funding; Janssen Oncology: Honoraria; Takeda: Other: Travel, accommodations; Sanofi: Consultancy, Research Funding; Genenta Science srl: Consultancy; F. Hoffmann-La Roche Ltd: Honoraria, Other: Travel, accommodations, Research Funding; Amgen: Honoraria; MSD: Honoraria; Janssen: Other: Travel, accommodations; Celgene: Research Funding; BMS: Honoraria. Salles:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Autolus: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria; Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; BMS: Honoraria; Novartis, Servier, AbbVie, Karyopharm, Kite, MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Other: Educational events. Hutchings:Janssen: Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Iacoboni:Celgene: Honoraria; Janssen: Honoraria; Novartis: Consultancy, Honoraria; Abbvie: Honoraria; Roche: Honoraria. Sureda:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Sanofi: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support; Gilead: Honoraria; Novartis: Honoraria. Crump:Servier: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Kite/Gilead: Consultancy. Martinez-Lopez:Novartis: Honoraria, Other: Advisory boards; Janssen: Honoraria, Other: Advisory boards and Non-Financial Support ; Incyte: Honoraria, Other: Advisory boards; VIVIA Biotech: Honoraria; Celgene: Honoraria, Other: Advisory boards and Non-Financial Support ; Amgen: Honoraria, Other: Non-Financial Support ; F. Hoffmann-La Roche Ltd: Honoraria; BMS: Honoraria, Other: Advisory boards. Thomas:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Morcos:Roche: Employment, Equity Ownership. Ferlini:Roche: Employment, Equity Ownership. Keelara:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Bröske:Roche: Employment, Equity Ownership. Bacac:Roche: Employment, Equity Ownership, Patents & Royalties: Patents, including the one on CD20-TCB. Dimier:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Moore:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Weisser:Pharma Research and Early Development Roche Innovation Center Munich: Employment, Equity Ownership, Patents & Royalties. Dickinson:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Merck Sharpe and Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. OffLabel Disclosure: CD20-TCB (also known as RG6026, RO7082859) is a full-length, fully humanized, immunoglobulin G1 (IgG1), T-cell-engaging bispecific antibody with two fragment antigen binding ('Fab') regions that bind to CD20 (on the surface of B cells) and one that binds to CD3 (on the surface of T cells) (2:1 format). The 2:1 molecular format of CD20-TCB, which incorporates bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells, redirects endogenous non-specific T cells to engage and eliminate malignant B cells. CD20-TCB is an investigational agent.