First-in-Human Phase 1 Study of SAR442257 in Patients with Relapsed/Refractory Multiple Myeloma and Non-Hodgkin Lymphoma

Background: SAR442257 (SAR'257) is a trispecific antibody that targets CD38, CD3 and CD28. Simultaneous CD3 and CD28 binding triggers T cell co-signaling, and additional CD38 recognition directs the T cells to CD38+ cancer cells such as multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). This is a first-in-human phase 1 study investigating the safety, efficacy, pharmacokinetic (PK) and pharmacodynamic (PD) profile of SAR'257 in patients (pts) with refractory and relapsed (rr) MM and rrNHL.

Methods: This is a multicenter, international, open-label, dose-escalation study (NCT04401020) of SAR'257 in pts with rrMM refractory to standard-of-care (SOC) options, including anti-CD38 monoclonal antibodies, and in pts rrNHL without any SOC options. SAR'257 was administered intravenously with lead-in doses (Day 1−5) in the first week, followed by twice weekly (BIW) or once weekly (QW) dosing; 11 target dose levels (TDLs) in pts with rrMM (9 TDLs: 0.06-11 µg/kg BIW; 2 TDLs: 18-27 µg/kg QW), and 2 TDLs in pts with rrNHL (2 µg/kg BIW and 4 µg/kg QW).

Results: As of February 19, 2024, 47 pts (rrMM, n=40; rrNHL, n=7) received SAR'257. The median ages (years) were 64 (rrMM; range: 40−84) and 70 (rrNHL; range: 18−75). The median number of prior lines was 5 (range: 3−12) for rrMM and 5 (range: 2−7) for rrNHL cohort. In rrMM cohort, all (100%) pts had prior exposure to an anti-CD38 monoclonal antibody (MAb) and were refractory to anti-CD38 and in rrNHL cohort all were anti-CD38 naïve. The median time from last anti-CD38 dose was 2.7 (range: 1−65) months for rrMM cohort. Safety analysis revealed that 68% (n=32) pts had treatment-emergent adverse events (TEAEs; 26 pts in rrMM and 6 pts in rrNHL); 21.3% pts (n=10) Grade (G) ≥3 TEAEs (7 in rrMM and 3 in rrNHL). Cytokine release syndrome (CRS) was the most common TEAE, occurring in 52.5% of rrMM pts across all TDLs (n=21; G≥3 in 1 pt from 11 µg/kg BIW TDL) and in 57.1% of rrNHL pts (n=4; no G≥3) at the two TDLs tested. Repetitive CRS episodes (>1 episode) were more frequent at higher TDLs. Infusion-related reactions (IRRs; any G) were observed in 22.5% pts with rrMM (n=9; no G≥3) and in 28.5% pts with rrNHL (n=2; G≥3 in 1 pt). Epstein-Barr virus (EBV) infection/reactivation was reported in 17.5% (n=7; G≥3 in 4 pts) and 28.6% (n=2; no G≥3) pts with rrMM and rrNHL respectively. Further, 15% (n=6, G≥3 in 2 pts) from rrMM and 14.3% (n=1; G2 CMV reactivation) pts from rrNHL cohort reported cytomegalovirus (CMV) infection/reactivation. One case of immune effector cell-associated neurotoxicity syndrome (ICANS) was reported (G4) in the rrNHL cohort. Four dose-limiting toxicities (DLTs) were observed in the rrMM cohort [1 at 4 µg/kg BIW (G3 hepatotoxicity); 1 at 11 µg/kg BIW (G5 CRS−EBV reactivation; and 2 at 27 µg/kg QW (G3 CMV infection reactivation and G3 febrile neutropenia in same pt)]. Three DLTs were observed in the rrNHL cohort (2 at 2 µg/kg BIW [G4 neutropenia and G4 thrombocytopenia; same pt] and 1 at 4 µg/kg QW [ICANS G4]). For pts with rrMM, the maximum plasma concentration of SAR'257 reached within or above the theoretical efficacious range (0.1−1nM; extrapolated from ex vivo models), starting at 8 µg/kg BIW and 18 µg/kg QW in the first treatment cycle. As of July 08, 2024, the overall response rate (ORR), defined as partial response (PR) or better, was 5% (n=2) in the rrMM cohort: 1 pt exhibited stringent complete response (duration of response [DOR]=8.1 months, on-going) and 1 showed a complete response (CR) at 27 µg/kg QW TDL. In rrNHL cohort, the ORR was 14.3%, 1 pt achieved PR (DOR=7.1 months) at 2 µg/kg BIW TDL. The disease control rate (stable disease or better for >8 weeks) was 60% (n=24) and 28.6% (n=2) in the rrMM and rrNHL cohorts respectively. For both cohorts exploratory biomarker analysis revealed that: (1) SAR'257 treatment activated peripheral blood T cells and reduced regulatory T cell numbers and CD4/CD8 ratio; (2) CD38 expression on plasma cells positively corelated with time since the last anti-CD38 MAb dose; (3) Among the pts experiencing CRS, the peak values of cytokines (Interleukin (IL)-6, IL-8, and C-reactive protein) were significantly higher during the first cycle in comparison to subsequent cycles.

Conclusion: This Phase 1 study of SAR'257 showed an anti-tumor response in a small number of pts from the rrMM and rrNHL cohorts. Due to safety concerns, in particular high rates of EBV and CMV reactivation and recurrent episodes of CRS in the higher dose levels, the study was terminated during dose escalation.

Schjesvold:Daiichi Sankyo: Other: Honoraria for lectures and educational material; Amgen: Other: Honoraria for lectures and educational material; Bristol Myers Squibb: Consultancy, Other: Honoraria for lectures and educational material; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; Oncopeptides: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; Sanofi: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; SkylineDx: Other: Honoraria for lectures and educational material; Novartis: Other: Honoraria for lectures and educational material; Targovax: Research Funding; Celgene: Consultancy, Other: Honoraria for lectures and educational material, Research Funding; AbbVie: Consultancy, Other: Honoraria for lectures and educational material; Pfizer: Other: Honoraria for lectures and educational material; Takeda: Consultancy, Other: Honoraria for lectures and educational material; Schain: Other: Honoraria for lectures and educational material; Skylite: Other: Honoraria for lectures and educational material. Jelinek:Amgen: Research Funding; Janssen: Consultancy, Other: Honoraria for lectures, Research Funding; Sanofi: Other: Honoraria for lectures, Research Funding; Pfizer: Consultancy, Other: Honoraria for lectures; Bristol Myers Squibb: Other: Honoraria for lectures; GlaxoSmithKline: Consultancy, Other: Honoraria for lectures. Polgarova:Kyowa Kirin: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Roche: Honoraria. Yoon:Janssen, Novartis, F. Hoffmann-La Roche Ltd, Genentech, Inc.: Consultancy; F. Hoffmann-La Roche Ltd, Genentech, Inc.: Research Funding; Janssen: Honoraria. Kim:BeiGene: Research Funding; Boryong: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Sanofi: Research Funding. Fosså:Merck Sharp and Dohme: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria; Roche: Honoraria, Research Funding; Johnson and Johnson: Honoraria; SOBI: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Eusapharma: Research Funding; Kite Gilead: Consultancy, Honoraria. San-Miguel:Takeda: Other: Advisory board; MSD: Other: Advisory board; Haemalogix: Other: Advisory board; Janssen-Cilag: Other: Advisory board; Abbvie: Consultancy, Other: Advisory Board; Regeneron: Other: Advisory board; GlaxoSmithKline: Other: Advisory board; Celgene: Other: Advisory board; Novartis: Other; Roche: Other: Advisory board; Sanofi: Other: Advisory board; Amgen: Consultancy, Other: Advisory Board ; Karyopharm: Other: Advisory board; Bristol Myers Squibb: Other: Advisory board; SecuraBio: Other: Advisory board. Canales:Kite: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Lilly: Membership on an entity's Board of Directors or advisory committees; MSD: Other: Honoraria for lectures; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Genmab: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures. Rodríguez-Otero:Johnson & Johnson - Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; GSK: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Amgen: Other: Honoraria for lectures; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Roche: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Regeneron: Other: Honoraria for lectures; Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: Honoraria for lectures; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Oriol:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Sanofi: Speakers Bureau; Menarini: Honoraria; Pfizer: Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria; Takeda: Research Funding; GlaxoSmithKline: Honoraria, Research Funding, Speakers Bureau; Oncopharm: Honoraria. Martínez-Lopez:Amgen: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Incity: Research Funding. Kapoor:Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Loxo Pharmaceuticals: Research Funding; Mustang Bio: Membership on an entity's Board of Directors or advisory committees; Angitia Bio: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ichnos: Research Funding; Karyopharm: Research Funding; Regeneron: Research Funding; Amgen: Research Funding; CVS Caremark: Consultancy; Keosys: Consultancy. Landgren:Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees.; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Adaptive: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Membership on independent data monitoring committees. Raje:Caribou Biosciences Inc: Membership on an entity's Board of Directors or advisory committees; Amgen Inc: Other: Steering Committee; Takeda Pharmaceuticals USA Inc: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Immuneel Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; bluebird bio: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Biotech Inc: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Roche Laboratories Inc: Other: Steering Committee. Wang:Sanofi: Current Employment. Jhunjhunwala:Sanofi: Current Employment. Zhao:Sanofi: Current Employment. Wang:Sanofi: Current Employment. Morisse:Sanofi: Current Employment. Van de Velde:Sanofi: Current Employment.