ISATUXIMAB + VRd Preliminary results from a Phase I study of isatuximab in combination with bortezomib, lenalidomide, dexamethasone in patients with newly diagnosed multiple myeloma non-eligible for transplant Enrique M. Ocio, 1 Paula Rodriguez-Otero, 2 Sara Bringhen, 3 Stefania Oliva, 3 Axel Nogai, 4 Michel Attal, 5 Philippe Moreau, 6 Dheepak Kanagavel, 7 Thomas Fitzmaurice, 8 Junlong Wu, 9 Joaquin Martinez-Lopez 10 1 University Hospital Marqués de Valdecilla (IDIVAL). University of Cantabria, Santander, Spain and University Hospital of Salamanca (IBSAL) - Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain; 2 University Clinic of Navarra, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain; 3 Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy; 4 Charité Berlin, Hematology/Oncology, Centrum 14, Berlin, Germany; 5 Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France; 6 University Hospital, Nantes, France; 7 Sanofi, Vitry-Alfortville, France; 8 Sanofi, Cambridge, MA, USA; 9 Sanofi R&D, Beijing, China; 10 Hematology, Hospital Universitario 12 de Octubre, CNIO, Complutense, Madrid, Spain
2 ISATUXIMAB + VRd Targeting CD38 with Isatuximab CD38 functions as a receptor and an ectoenzyme, and is highly and uniformly expressed on multiple myeloma cells 1–5 Isatuximab is an IgG1 monoclonal antibody that targets a specific epitope on the CD38 transmembrane glycoprotein 6 Isatuximab has multiple modes of action: 6 • ADCC, CDC and ADCP • Inhibition of CD38 ectoenzyme activity • Immunomodulation • Direct apoptosis 1. Lin P, et al. Am J Clin Pathol 2004;121:482–8; 2. Angelopoulou MK, et al. Eur J Haematol 2002;68:12–21; (c)ADPR, (cyclic) adenosine diphosphate–ribose; Ig, immunoglobulin; MAC, 3. Schwonzen M, et al. Br J Haematol 1993;83:232–9; 4. Keyhani A, et al. Leukemia Res 2000;24:153–9; membrane attack complex; NAD, nicotinamide adenine dinucleotide 5. Domingo-Domènech E, et al. Haematologica 2002;87:1021–7; 6. Jiang H, et al. Leukemia 2016;30:399–408
3 ISATUXIMAB + VRd Background and Rationale Phase I study of isatuximab + VCd in NDMM (TCD13983) 1 N=15; 73% achieved ≥VGPR of which 40% were ≥CR VRd is current standard of care in NDMM based on the Ph III study of lenalidomide + bortezomib (SWOG S0777) 2 Based on data from SWOG S0777 and the encouraging results with isatuximab + VCd, the study was expanded to include an isatuximab + VRd arm in NDMM (NCT02513186) 1 1. Ocio EM, et al. Presented at the 59th Annual Meeting of the American Society of Hematology, December 2017. Abstract #3160; 2. Durie BG, et al. Lancet 2017;389:519–527
4 ISATUXIMAB + VRd Phase I Study: Design and Eligibility Primary Objective Key eligibility criteria: • CR rate (according to IMWG criteria 1 ) Adults with NDMM Secondary Objectives Patients non-eligible for transplantation • Safety, ORR, DOR, PFS, PK Adequate bone marrow reserve and organ Exploratory Objective function • MRD negativity in patients achieving ≥VGPR Induction phase (4 x 6 -week cycles) Maintenance phase (4 -week cycles) Bortezomib D1, 4, 8, 11 1.3 mg/m² s.c D22, 25, 29, 32 • PD Lenalidomide D1- 21 25 mg/d p.o. • Unacceptable Lenalidomide D1- 14 25 mg/d p.o. D22 -35 Dexamethasone D1, 8, 15, 22 toxicity 40 mg/d IV/p.o* • Any other Dexamethasone D1- 2, 4 - 5, 8 - 9, 11 - 12, 15 Isatuximab D1, 15 20 mg/d IV/p.o D22 - 23, 25 - 26, 29 - 30, 32 -33 reasons 10 mg/kg IV Isatuximab QW C1, Q2W C2 – 4 10 mg/kg IV Target population N=27 1. Palumbo A, et al. J Clin Oncol 2014;32:587–600 Data cut-off: September 3, 2018; *20 mg/day in patients >75 years old
5 ISATUXIMAB + VRd Patient Demographics and Clinical Characteristics All patients (N=27) Age in years, median (range) 71 (63, 77) Weeks since initial diagnosis, median (range) 7.9 (0.9, 640.1) Type of myeloma at diagnosis, n (%) Light chain only 1 (3.7) IgA 5 (18.5) Data to be added IgG 21 (77.8) when ready Light chain (kappa) 16 (59.3) Light chain (lambda) 5 (18.5) ISS stage at baseline, n (%) Stage I 14 (51.9) Stage II 11 (40.7) Stage III 2 (7.4) CrCl <60 mL/min, n (%) 6 (22.2) 3/23 † (13.0) High- risk cytogenetics*, n/N (%) Data cut-off: September 3, 2018; *Defined as t(4;14) and/or t(14;16) and/or del17p; † Cytogenetics results available for 23/27 patients
6 ISATUXIMAB + VRd Preliminary Analysis: Patient Disposition and Drug Exposure All treated population (N=27) All patients Discontinued treatment (n=3) Drug exposure (N=27) Median number of cycles, 6.0 (1, 15) n (range) Ongoing treatment (n=24) Median duration of 7.2 exposure, months (range) (0.2, 16.1) Consent withdrawn AE (n=2) (n=1) Median relative dose intensity (%) Induction: 4 cycles (n=19) Maintenance: ≤6 cycles (n=9) Isatuximab 95.7 AEs leading to discontinuation Bortezomib 95.6 • Grade 4 bacteremia at Cycle 4 with Lenalidomide 92.8 fatal outcome, related to lenalidomide and dexamethasone Dexamethasone 100.8 • Grade 3 infusion reaction at Cycle 1, related to isatuximab AE, adverse event; Data cut- off: September 3, 2018; Last patient in: 30 April 2018 Median duration of follow- up: 6.8 months (range 2.8 –15.7)
7 ISATUXIMAB + VRd Response Summary (IMWG Criteria): Efficacy -Evaluable Patients ORR (n=26): 100% 100 ● No patients experienced PD 19% 80 ● 92% of patients achieved ≥VGPR* including the three patients with ORR (%) 60 92% high-risk cytogenetics (among these ≥VGPR one patient achieved CR) 73% sCR/CR (n=5) 40 VGPR (n=19) ● 13 of 19 patients with VGPR had PR (n=2) 20 IgG kappa disease at baseline 8% 0 *Serum immunofixation electrophoresis interference has not been investigated and may underestimate quality of CR response
8 ISATUXIMAB + VRd Time to Response and Maximum Change in Paraprotein All patients Paraprotein, change from baseline (%) Change in paraprotein Time to response* (N=27) 100 Best overall response: Time to first response in sCR/CR 75 1.4 (1.1, 7.6) months, median (range) VGPR 50 PR Time to best response in 2.8 (1.2, 13.2) 25 months, median (range) * IgG κ patients 0 25% –25 Median duration of follow-up: 6.8 reduction months (range 2.8–15.7 months) 50% –50 reduction –75 –100 * * * * * * * * * * * * * * * * The majority of patients achieved a 100% reduction in paraprotein IFE, immunofixation electrophoresis; Median follow- up duration: 6.8 months (range 2.8, 15.7) *First disease assessment was performed at the end of Cycle 1 (Week 6)
9 ISATUXIMAB + VRd Minimal Residual Disease Evaluation* Next- generation sequencing (NGS) † Next- generation flow (NGF) 80 75% MRD Negativity Rate (%) 69% 60 50% 44% 40 33% 18% 20 0 10 - 4 10 -5 10 - 6 10 - 4 10 -5 10 - 6 (n=11/16) (n=8/16) (n=4/12) (n=12/16) (n=7/16) (n=2/11) The high MRD negativity rate achieved by NGS and NGF is concordant 7/16 evaluable patients (44%) achieved MRD negativity by NGS and/or NGF at 10 -5 sensitivity level *Of 18 efficacy-evaluable patients with BMA samples collected at MRD cut- off (all ≥VGPR), 2 patients had bone marrow aspirate (B MA) samples not evaluable by NGS or NGF at 10 -4 or 10 -5 sensitivity levels, and some patients had BMA samples that did not reach the standard limit of detection (10 -6 ) for NGS (4 patients) and NGF (5 patients) †Overestimation of MRD negativity rate by NGS may be due to hemodilution of BMA samples from 2 patients
10 ISATUXIMAB + VRd Time to MRD negativity at 10 -5 Pt 001 (IgA κ ) Time to first response Pt 002 (IgG κ ) sCR/CR Pt 003 (IgG λ ) VGPR Pt 004 (IgG κ ) Pt 005 (IgA λ ) MRD negative MRD positive Pt 006 (IgG κ ) Pt 007 (IgG λ ) 0 2 4 6 8 10 12 14 16 18 Time on treatment (months) 4/7 patients who achieved MRD negativity did so within 6 months Pt, patient
11 ISATUXIMAB + VRd Treatment Emergent Adverse Events* and Hematologic Laboratory Abnormalities for all Patients (N=27) TEAEs All grades Grade ≥3 Hematologic laboratory All grades Grade 3 Grade 4 Any TEAE (%) 100 63.0 abnormalities (%) Peripheral sensory 70.3 3.7 Thrombocytopenia neuropathy† 100 25.9 7.4 Infusion-related reaction 63.0 3.7 Anemia 96.3 7.4 0 Edema peripheral 63.0 3.7 Constipation 59.3 0 Neutropenia 70.4 51.9 0 Diarrhea 51.9 7.4 Lymphopenia Asthenia 44.4 3.7 100 51.9 22.2 Hypotension 40.7 3.7 Fatigue 40.7 3.7 Discontinuations due to TEAEs: Cough 25.9 0 Bortezomib, 6 (22.2%) patients Muscoskeletal pain 25.9 0 Lenalidomide, 2 (7.4%) patients Dizziness 25.9 0 Back pain 22.2 7.4 Dyspnea 22.2 7.4 Grade ≥3 infections were reported in 7 patients (25.9%) No new safety signals were observed TEAE, treatment emergent adverse event; *TEAEs in ≥25% of patients (all grades) or ≥5% (Grade 3/4) † Grade 1 = 29.6%; Grade 2 = 37.0%; Grade 3 = 3.7%
12 ISATUXIMAB + VRd Isatuximab Administration and IRs Isatuximab median infusion duration IRs in 17 patients (63%) Number of patients with IR Grade 1 Grade 2 Grade 3 Infusion 1 Infusion 2+ 4 20 1 3.7 3 15 Time (h) 2.7 2 10 14 1 5 1 2 0 0 Infusion 1 Infusion 2+ All patients (N=27) Mandatory pre-treatment prophylaxis* Discontinuation due to Grade 3 IR occurred in 1 patient Starting infusion rate was 175 mg/h IRs predominantly occurred during the first infusion † *Prophylaxis: Dexamethasone 40 mg (or 20 mg for patients ≥75 years old) IV/PO, diphenhydramine 25 –50 mg IV (or equivalent), ranitidine 50 mg IV (or equivalent), and acetaminophen 650–1000 mg PO 15– 30 minutes (but ≤60 minutes) prior to isatuximab infusion † One patient experienced two IRs (Grade 2)
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