Preliminary results from a Phase I study of isatuximab in - - PowerPoint PPT Presentation

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-Lopez10

1University Hospital Marqués de Valdecilla (IDIVAL). University of Cantabria, Santander, Spain and University Hospital of Salamanca

(IBSAL) - Cancer Research Center (IBMCC-CSIC-USAL), Salamanca, Spain; 2University Clinic of Navarra, Center for Applied Medical Research (CIMA), IDISNA, Pamplona, Spain; 3Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy; 4Charité Berlin, Hematology/Oncology, Centrum 14, Berlin, Germany; 5Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse, France; 6University Hospital, Nantes, France; 7Sanofi, Vitry-Alfortville, France; 8Sanofi, Cambridge, MA, USA; 9Sanofi R&D, Beijing, China; 10Hematology, Hospital Universitario 12 de Octubre, CNIO, Complutense, Madrid, Spain

ISATUXIMAB + VRd

Targeting CD38 with Isatuximab

• 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;
• 3. Schwonzen M, et al. Br J Haematol 1993;83:232–9; 4. Keyhani A, et al. Leukemia Res 2000;24:153–9;
• 5. Domingo-Domènech E, et al. Haematologica 2002;87:1021–7; 6. Jiang H, et al. Leukemia 2016;30:399–408

Isatuximab is an IgG1 monoclonal antibody that targets a specific epitope on the CD38 transmembrane glycoprotein6

(c)ADPR, (cyclic) adenosine diphosphate–ribose; Ig, immunoglobulin; MAC, membrane attack complex; NAD, nicotinamide adenine dinucleotide

CD38 functions as a receptor and an ectoenzyme, and is highly and uniformly expressed on multiple myeloma cells1–5 Isatuximab has multiple modes of action:6

• ADCC, CDC and ADCP
• Inhibition of CD38 ectoenzyme activity
• Immunomodulation
• Direct apoptosis

2

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 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 VRd is current standard of care in NDMM based on the Ph III study of lenalidomide + bortezomib (SWOG S0777)2

• 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

3

ISATUXIMAB + VRd Phase I Study: Design and Eligibility

Key eligibility criteria:  Adults with NDMM  Patients non-eligible for transplantation  Adequate bone marrow reserve and organ function Primary Objective

• CR rate (according to IMWG criteria1)

Secondary Objectives

• Safety, ORR, DOR, PFS, PK

Exploratory Objective

• MRD negativity in patients achieving ≥VGPR
• PD
• Unacceptable

toxicity

• Any other

reasons

Maintenance phase (4-week cycles)

• 1. Palumbo A, et al. J Clin Oncol 2014;32:587–600

Target population N=27

4

Induction phase (4 x 6-week cycles)

Isatuximab QW C1, Q2W C2–4 10 mg/kg IV Lenalidomide D1-14 25 mg/d p.o. D22-35 Dexamethasone D1-2, 4-5, 8-9, 11-12, 15 20 mg/d IV/p.o D22-23, 25-26, 29-30, 32-33 Bortezomib D1, 4, 8, 11 1.3 mg/m² s.c D22, 25, 29, 32 Isatuximab D1, 15 10 mg/kg IV Lenalidomide D1-21 25 mg/d p.o. Dexamethasone D1, 8, 15, 22 40 mg/d IV/p.o*

Data cut-off: September 3, 2018; *20 mg/day in patients >75 years old

ISATUXIMAB + VRd

Patient Demographics and Clinical Characteristics

Data to be added when ready

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) IgG 21 (77.8) 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) High-risk cytogenetics*, n/N (%) 3/23† (13.0)

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

5

ISATUXIMAB + VRd

Preliminary Analysis: Patient Disposition and Drug Exposure

Drug exposure All patients (N=27) Median number of cycles, n (range) 6.0 (1, 15) Median duration of exposure, months (range) 7.2 (0.2, 16.1) Median relative dose intensity (%) Isatuximab 95.7 Bortezomib 95.6 Lenalidomide 92.8 Dexamethasone 100.8

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)

All treated population (N=27) Discontinued treatment (n=3)

AEs leading to discontinuation

• Grade 4 bacteremia at Cycle 4 with

fatal outcome, related to lenalidomide and dexamethasone

• Grade 3 infusion reaction at Cycle 1,

related to isatuximab AE (n=2) Consent withdrawn (n=1)

6

Ongoing treatment (n=24)

Induction: 4 cycles (n=19) Maintenance: ≤6 cycles (n=9)

ISATUXIMAB + VRd

Response Summary (IMWG Criteria): Efficacy-Evaluable Patients

• No patients experienced PD
• 92% of patients achieved ≥VGPR*

including the three patients with high-risk cytogenetics (among these

• ne patient achieved CR)
• 13 of 19 patients with VGPR had

IgG kappa disease at baseline

ORR (n=26): 100%

20 40 60 80 100 ORR (%) sCR/CR (n=5) VGPR (n=19) PR (n=2) 92% ≥VGPR

*Serum immunofixation electrophoresis interference has not been investigated and may underestimate quality of CR response

19% 73% 8%

7

ISATUXIMAB + VRd

Time to Response and Maximum Change in Paraprotein

Change in paraprotein The majority of patients achieved a 100% reduction in paraprotein

Time to response* All patients (N=27) Time to first response in months, median (range) 1.4 (1.1, 7.6) Time to best response in months, median (range) 2.8 (1.2, 13.2) sCR/CR VGPR PR Best overall response: * IgGκ patients Paraprotein, change from baseline (%) 100 75 50 25 –25 –50 –75 –100 25% reduction 50% reduction

* * * * * * * * * * * * * * * *

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) 8

Median duration of follow-up: 6.8 months (range 2.8–15.7 months)

ISATUXIMAB + VRd

Minimal Residual Disease Evaluation*

69% 50% 33% 75% 44% 18% 20 40 60 80 MRD Negativity Rate (%)

Next-generation sequencing (NGS)† Next-generation flow (NGF)

10-4 (n=11/16) 10-5 (n=8/16) 10-6 (n=4/12) 10-4 (n=12/16) 10-5 (n=7/16) 10-6 (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 (BMA) 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 9

ISATUXIMAB + VRd

Time to MRD negativity at 10-5

Time to first response VGPR sCR/CR MRD negative MRD positive

Pt, patient

18 16 14 12 10 8 6 4 2

Pt 007 (IgG λ)

Time on treatment (months)

Pt 006 (IgG κ) Pt 005 (IgA λ) Pt 004 (IgG κ) Pt 003 (IgG λ) Pt 002 (IgG κ) Pt 001 (IgA κ)

10

4/7 patients who achieved MRD negativity did so within 6 months

ISATUXIMAB + VRd

TEAEs All grades Grade ≥3 Any TEAE (%) 100 63.0 Peripheral sensory neuropathy† 70.3 3.7 Infusion-related reaction 63.0 3.7 Edema peripheral 63.0 3.7 Constipation 59.3 Diarrhea 51.9 7.4 Asthenia 44.4 3.7 Hypotension 40.7 3.7 Fatigue 40.7 3.7 Cough 25.9 Muscoskeletal pain 25.9 Dizziness 25.9 Back pain 22.2 7.4 Dyspnea 22.2 7.4

Treatment Emergent Adverse Events* and Hematologic Laboratory Abnormalities for all Patients (N=27)

Grade ≥3 infections were reported in 7 patients (25.9%)

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%

11

No new safety signals were observed

Hematologic laboratory abnormalities (%) All grades Grade 3 Grade 4 Thrombocytopenia 100 25.9 7.4 Anemia 96.3 7.4 Neutropenia 70.4 51.9 Lymphopenia 100 51.9 22.2 Discontinuations due to TEAEs: Bortezomib, 6 (22.2%) patients Lenalidomide, 2 (7.4%) patients

ISATUXIMAB + VRd

5 10 15 20 Infusion 1 Infusion 2+ Number of patients with IR Grade 1 Grade 2 Grade 3

1 14 2 1

Isatuximab Administration and IRs

1 2 3 4 All patients (N=27) Time (h) Infusion 1 Infusion 2+ 3.7 2.7

Isatuximab median infusion duration IRs in 17 patients (63%)

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)

12

ISATUXIMAB + VRd

• Encouraging clinical activity of isatuximab combined with VRd as induction, followed by isatuximab with Rd as

maintenance therapy in NDMM

• ORR confirmed as 100% in efficacy-evaluable patients: ≥VGPR was achieved in 92%
• Overall, 7/16 MRD-evaluable patients (44%) achieved MRD negativity by NGS and/or NGF at the 10-5

sensitivity level

• The isatuximab regimen was well tolerated with a manageable safety profile; AEs with this combination were

generally consistent with the known safety profiles of the individual agents

• IRs were generally Grade 1/2 in severity (one Grade 3 reaction), and predominantly occurred during the first

infusion

• Median infusion duration for isatuximab was 3.7 h for 1st infusion and 2.7 h for subsequent infusions

Conclusions

Two Phase III isatuximab plus VRd backbone studies are ongoing in NDMM GMMG HD-7 (NCT03617731): transplant eligible patients1 IMROZ (NCT03319667): transplant ineligible patients2

13

ISATUXIMAB + VRd

Acknowledgments

The authors would like to thank the participating patients and their families The authors would also like to acknowledge the work of all the study centers and investigators for their contributions to the study The authors would also like to thank Prof. Bruno Paiva (University of Navarra, Pamplona, Spain) and Sandrine Macé (Sanofi) for their contributions to MRD assessment This study was sponsored by Sanofi Lenalidomide was provided by Celgene Corporation Editorial assistance was provided by Joanna Chapman of Aspire Scientific and Louise Wright of Adelphi Communications Ltd, funded by Sanofi The authors were responsible for all content and received no honoraria related to the development/presentation of this publication

14

ISATUXIMAB + VRd

Disclosures

EM Ocio: Consultancy: AbbVie, Amgen, Celgene, Janssen, Novartis, Pharmamar, Seattle Genetics, Takeda; Honoraria: Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Takeda; Research funding: Amgen, Array Pharmaceuticals, Celgene, Mundipharma, Sanofi P Rodriguez-Otero: Consultancy: Celgene, Janssen, Takeda; Honoraria: Celgene, Janssen; Speakers’ bureau: Bristol- Myers Squibb, Celgene, Janssen; Research Funding: Bristol-Myers Squibb, Celgene S Bringhen: Consultancy: Takeda; Honoraria / Advisory role: Amgen, Johnson & Johnson; Honoraria: Bristol-Myers Squibb, Celgene S Oliva: Honoraria: Amgen, Celgene, Takeda; Advisory role: Janssen A Nogai: Consultancy: Takeda, Janssen, Celgene M Attal: None P Moreau: Consultancy / Honoraria: Amgen, Celgene, Janssen, Novartis, Takeda D Kanagavel: Employee and stock holder of Sanofi T Fitzmaurice: Employee of Sanofi J Wu: Employee of Sanofi J Martinez-Lopez: Speakers’ bureau / Research funding: Bristol-Myers Squibb, Celgene, Janssen, Novartis

15