Background: RO7283420 (RG6007) is a 2+1 TCR-like (TCR-L) T-cell bispecific (TCB) antibody targeting CD3 and the RMFPNAPYL peptide of Wilms Tumor 1 (WT1) protein presented by the major histocompatibility complex-I HLA-A*02 on acute myeloid leukemia (AML) blasts and other antigen presenting cells. The pre-clinical evaluation of RO7283420 in our in vivo humanized AML xenografts and ex vivo AML co-culture models showed strong T-cell mediated AML cell killing (Augsberger C, et al. Blood 2021). A Phase 1 dose-escalation (DE) study (NCT04580121) evaluated the safety, tolerability, pharmacokinetics, anti-drug antibodies (ADAs), and anti-leukemic activity of RO7283420 in patients with relapsed/refractory (R/R) AML.

Methods: In this open-label, multi-center study, DE was performed using a 3+3 design. Patients received RO7283420 every 3 weeks (Q3W, n=46), or every week (QW, n=4) as intravenous (IV) infusions. Preliminary anti-leukemic activity included response assessment according to European Leukemia Net (ELN) response categories (adapted from Döhner H, et al. Blood 2017).

Results: As of 13 April 2023, 50 HLA-A2+ R/R AML patients received at least one dose of RO7283420. Patients had a median age of 65.5 years (range 35-84), presented with ECOG of 0 (56%) or 1 (38%) or 2 (6%), and 58% were male. Median prior line of therapy was 2 (range 1-5). Overall, 58% of patients had relapsed and 42% had primary refractory disease. According to the ELN 2017 risk stratification, patients were of adverse (48%), intermediate (38%) or favorable (8%) risk category, for 6% of patients the risk category missing. The most common genetic abnormalities reported were RUNX1 (21%), ASXL1 (17%), TP53 (10.6%), FLT3-ITD (6.4%) and NPM1 (6.4%) of the 47 patients tested. Median bone marrow blast percentage at baseline was 35% (range 3-90%), while the median of circulating blast was 17% (range 0-88%). Study patients received RO7283420 IV at 13 different dose levels, ranging from a Minimum Anticipated Biological Effect Level (MABEL) of 0.15 mg (flat) to 18 mg Q3W (with a preceding weekly 1/3 mg ‘double step-up’ during Cycle 1) and one QW dose level with 9 mg preceded by a 1/3 mg step-up. Maximum tolerated dose was reached at 1/3/12 mg double step-up Q3W. Explored alternative QW schedule was not tolerable at 1/3/9 mg.

The most common (≥20%) adverse events (AEs) were cytokine release syndrome (CRS) occurring in 34 (68%), pneumonia 14 (28%), pyrexia 13 (26%), febrile neutropenia 13 (26%), hyperglycemia 12 (24%), hypokalemia 11 (22%), and nausea 10 (20%) of patients. Eight dose limiting toxicities (DLTs) were reported: five G3 CRS (at 1/3, 2/12, 1/6/12 mg dose levels), G3 stomatitis (at 1/3/12 mg), G3 myositis (at 1/3/18 mg), and G4 thrombocytopenia (at 1/3/18 mg). Eleven patients (22%) experienced Grade 5 AEs with pneumonia, sepsis, and hemophagocytic lymphohistiocytosis (HLH) reported in >1 patient; all Grade 5 events were considered unrelated to RO728342 except 1 (at 1/3/9 mg) of 2 HLH events.

IV PK has been overall dose-linear and characterized by a terminal half-life of 29 to 84 hours and a clearance of 58 to 92 mL/h. Preliminary ADA incidence within the study population was 19%. In the dose ranges tested, a trend for study drug exposure-dependent blast reduction was observed in blood, while a clear exposure-response relationship could not be established with BM blast reduction. Furthermore, our preliminary pharmacodynamic analysis identified expansion of naive and memory CD8 T cells in blood and activated CD8+ T cells in bone marrow, in line with the expected mode of action (MoA) of RO7283420. Preliminary efficacy signals were observed with 3 complete responses (CR), including 1 CR with incomplete blood count recovery.

Conclusions: RO7283420 is the first TCR-L TCB antibody evaluated in AML. We observed pharmacodynamic evidence of T-cell activation and expansion in the clinic, in line with the expected MoA of TCBs, however, at the explored doses, no clear exposure-response relationship and only a modest clinical activity were observed. The safety profile was shown to be consistent with the other TCBs and R/R AML population. Based on the totality of data, the study was discontinued.

Hutchings:AbbVie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Montesinos:Celgene: Consultancy; Janssen: Speakers Bureau; Kura oncology: Consultancy; OTSUKA: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; BMS: Consultancy, Other, Research Funding; Abbvie: Consultancy, Research Funding, Speakers Bureau; Ryvu: Consultancy; BEIGENE: Consultancy; INCYTE: Consultancy; GILEAD: Consultancy; Pfizer: Consultancy, Research Funding, Speakers Bureau; NERVIANO: Consultancy; Novartis: Consultancy, Research Funding; Menarini-Stemline: Consultancy, Research Funding; Jazz pharma: Consultancy, Research Funding, Speakers Bureau; Astellas: Consultancy, Speakers Bureau. Santoro:Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Lilly: Speakers Bureau; Arqule: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Speakers Bureau; Amgen: Speakers Bureau; AbbVie: Speakers Bureau; Roche: Speakers Bureau; BMS (Bristol Myers Squibb): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; Incyte: Consultancy; Sanofi: Consultancy; MSD (Merck Sharp & Dohme): Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hou:AbbVie: Consultancy, Honoraria, Other: investigator on AbbVie-sponsored clinical trials; travel, Research Funding; BMS: Consultancy, Honoraria, Other: travel, Research Funding; Celgene: Consultancy, Honoraria, Other: travel, Research Funding; Kirin: Consultancy, Honoraria, Other: travel, Research Funding; PharmaEssential: Consultancy, Honoraria, Other: travel, Research Funding; Astellas: Consultancy, Other: travel; BeiGene: Consultancy, Honoraria, Other: travel; Chugai: Consultancy, Honoraria, Other: travel; CSL Behring: Consultancy, Honoraria, Other: travel; Daiichi Sankyo: Consultancy, Honoraria, Other: travel; IQVIA: Consultancy, Honoraria, Other: travel; Johnson & Johnson: Consultancy, Honoraria, Other: travel; Lotus: Consultancy, Honoraria, Other: travel; Merck Sharp & Dohme: Consultancy, Honoraria, Other: travel; Novartis: Consultancy, Honoraria, Other: travel; Ono: Consultancy, Honoraria, Other: travel; Panco healthcare Co: Consultancy, Honoraria, Other: travel; Pfizer: Consultancy, Honoraria, Other: travel; Roche: Consultancy, Honoraria, Other: travel; Synmosa: Consultancy, Honoraria, Other: travel; Takeda: Consultancy, Honoraria, Other: travel; TSH Biopharm: Consultancy, Honoraria, Other: travel; TTY Biopharm Company: Consultancy, Honoraria, Other: travel; Zuellig Pharma: Consultancy, Honoraria, Other: travel. Galimberti:Abbvie, Janssen, Novartis, Roche, Jazz, Astra Zeneca, Pfizer, Incyte: Speakers Bureau. Frigeni:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceutical: Honoraria. Salamero:BMS: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Yee:AbbVie, Novartis, Taiho: Honoraria; Astex, Forma Therapeutics, F. Hoffmann-La Roche, Genentech, Geron, Gilead Sciences, Janssen, Jazz, Novartis, Treadwell Therapeutics: Research Funding; Bristol Myers Squibb/Celgene, F. Hoffmann-La Roche, GSK, Jazz, Novartis, Pfizer, Shattuck Labs, Taiho Oncology, Takeda: Membership on an entity's Board of Directors or advisory committees. Schnetzler:Roche: Current Employment, Current equity holder in publicly-traded company. Barata:Hoffman-LaRoche Ltd: Current Employment. Simon:Hoffman-LaRoche Ltd: Current Employment, Current equity holder in publicly-traded company. Hinton:ROCHE: Current Employment, Current equity holder in publicly-traded company. Korfi:Roche Glycart/Roche: Current Employment, Current equity holder in publicly-traded company. Richard:Roche: Current Employment, Current equity holder in publicly-traded company. Keshelava:Roche Glycart/Roche: Current Employment, Current equity holder in publicly-traded company; Jazz Pharmaceuticals: Current equity holder in publicly-traded company. Subklewe:Ichnos Sciences: Consultancy, Honoraria; Seagen: Research Funding; Roche: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding; AstraZeneca: Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel Support, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Gilead/Kite: Consultancy, Honoraria, Other: Travel Support, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; AvenCell: Consultancy, Honoraria; Incyte Biosciences: Consultancy, Honoraria; Molecular Partners: Consultancy, Honoraria, Research Funding; GSK: Speakers Bureau; LAWG: Speakers Bureau; Springer Healthcare: Speakers Bureau; AbbVie: Consultancy, Honoraria; Autolus: Consultancy, Honoraria; advesya (CanCell Therapeutics): Consultancy, Honoraria; Genmab US: Consultancy, Honoraria; Interius BioTherapeutics: Consultancy, Honoraria; Nektar Therapeutics: Consultancy, Honoraria; Orbital Therapeutics: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Scare: Consultancy, Honoraria.

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2023
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