Dual CD20-Targeted Therapy With Concurrent CD20-TCB and Obinutuzumab Shows Highly Promising Clinical Activity and Manageable Safety in Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma: Preliminary Results From a Phase Ib Trial
Authors: Morschhauser Franck , Carlo-Stella Carmelo , Offner Fritz , Salles Gilles A. , Hutchings Martin , Iacoboni Gloria , Sureda Anna , Crump Michael , Martinez-Lopez Joaquin , Thomas Denise , Morcos Peter N , Ferlini Cristiano , Keelara Abiraj , Bröske Ann-Marie E , Bacac Marina , Dimier Natalie , Moore Tom , Weisser Martin , Dickinson Michael 
Published: November 2019

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.