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Daratumumab Michele Cavo Sergnoli Institute of Hematology Bologna - PowerPoint PPT Presentation

Jun 08, 2023 •1.08k likes •1.54k views

Three recent impressive stories: Daratumumab Michele Cavo Sergnoli Institute of Hematology Bologna University School of Medicine Bologna, Italy New Drugs in Hematology, October 1-3, 2018, Bologna, Italy Myeloma Drug Development 2

  1. Three recent “impressive” stories: Daratumumab Michele Cavo Seràgnoli Institute of Hematology Bologna University School of Medicine Bologna, Italy New Drugs in Hematology, October 1-3, 2018, Bologna, Italy

  2. Myeloma Drug Development 2

  3. Immunotherapy Targets in MM Borrello et al. Blood 2016.

  4. Targets for mAbs in MM a SLAMF7 Lonial et al, Leukemia 2015

  5. CD38 As an Ectoenzyme and Cell Surface Receptor • CD38 has several intracellular functions 1. Regulates signaling, homing and adhesion in close contact with BCR complex and CXCR4 2. Regulates activation and proliferation of human T lymphocytes 3. As an ectoenzyme, CD38 interacts with NAD+ and NADP+, which are converted to cADPR, ADPR, and NAADP in intracellular Ca2+-mobilization • Type II transmembrane protein (m.w. ≈45 kDa) • Highly and uniformly expressed on myeloma cells – CD38 present on CD4, CD8, NK cells and B lymphocytes at relatively low levels – Also some CD38 expression on tissues of non- hematopoietic origin 5 Malavasi F, et al. Blood 2011;118:3470-3478.

  6. mAb(s) Targenting CD38 Under Clinical Development Chimeric: Fully human: Daratumumab (IgG 1-k) Isatuximab (IgG 1-k) MOR202 (IgG 1- λ ) van de Donk et al. Blood 2016 ;127(6):681-695

  7. Daratumumab: Mechanism of Action  Direct anti-myeloma activity through Fc-dependent immune-effector mechanisms 1-4  Immunomodulatory effects through depletion of CD38 + immunosuppressive regulatory cells 5  Promotes T-cell expansion and activation 5 1. Lammerts van Bueren J, et al. Blood . 2014;124:Abstract 3474. 2. Jansen JMH, et al. Blood . 2012;120:Abstract 2974. 3. de Weers M, et al. J Immunol . 2011;186:1840-8. 4. Overdijk MB, et al. MAbs . 2015;7:311-21. 5. Krejcik J, et al. Blood . 2016. Epub ahead of print. 7

  8. GEN501: First-in-Human Phase 1/2 Study Part 1 – Open label, dose-escalation Pre-dosing Dosing Follow-up Dose cohorts 0.005* – 0.05* – 0.1** – 0.5** – 1** – 2** – 4** – 8** – 16** – 24** mg/kg Treatment scheme 0 1 2 3 4 5 6 7 8 10 12 16 20 24 48 52 Time since first daratumumab infusion (weeks) *: 1 (+3)(+3) patients *: 1 (+3) patients Part 2 – Open label, single-arm, dose-expansion , sequential cohorts Pre-dosing Dosing Schedule A † 8 mg/kg 16 patients Schedule B 8 mg/kg 8 patients Schedule C 8 mg/kg 6 patients Schedule D 16 mg/kg 20 patients Schedule E 16 mg/kg 22 patients 0 1 2 3 4 5 6 7 8 9 11 13 15 17 19 21 23 27 31 35 39 92 96 Time since first daratumumab infusion (weeks) †: Schedules A -E were conducted consecutively Lokhorst HM, et al. New Engl J Med . 2015 373(13):1207-19.

  9. Phase 2 SIRIUS Randomized Study: Design Randomization  Open-label, international, multicenter study of Simon-2-stage design  Initially, patients randomized 1:1 to receive DARA 16 mg/kg 8 mg/kg (n = 16) (n = 18) – 8 mg/kg every 4 weeks (Q4W) or – 16 mg/kg every week (QW) for 8 weeks, every 2 weeks (Q2W) for 16 weeks, then Q4W thereafter  16 mg/kg DARA was established as the recommended dose for Response evaluated further study  Results are reported for all patients who were treated with 16 Additional 90 patients mg/kg DARA (n = 106) enrolled at 16 mg/kg DARA 16 mg/kg (n = 106) Lonial S, et al. Presented at: 2015 American Society of Clinical Oncology (ASCO); May 29-June 2, 2015; Chicago, IL, USA.

  10. Phase 2 SIRIUS Study: Baseline Refractory Status • Patients were heavily pretreated, and most patients were Refractory to, n (%) n = 106 refractory to multiple lines of PI and IMiD treatment Last prior therapy 103 (97) – 97% were refractory to their last line of therapy PI and IMiD 101 (95) – 95% were double refractory BORT 95 (90) – 66% were refractory to 3 of 4 therapies (BORT, LEN, CARF, and POM) CARF 51 (48) – 63% were refractory to POM LEN 93 (88) – 48% were refractory to CARF POM 67 (63) Alkylating agent 82 (77) BORT+LEN 87 (82) BORT+LEN+CARF 42 (40) BORT+LEN+POM 57 (54) BORT+LEN+CARF+POM 33 (31) BORT+LEN+CARF+POM+THAL 12 (11) Lonial S, et al. Presented at: 2015 American Society of Clinical Oncology (ASCO); May 29-June 2, 2015; Chicago, IL, USA. 10/2/2018 Oncology Therapeutic Area 10

  11. Phase 2 SIRIUS Study: Overall Response Rate • ORR was 29% (95% CI, 21 – 39) in patients receiving 16 35 mg/kg DARA • ORR = 29% The clinical benefit rate (ORR + MR) was 34% (95% CI, 30 sCR 25 – 44) n = 3 (3%) Overall response rate, % • 25 VGPR or better was achieved in 12% (95% CI, 7 – 20) of VGPR patients, including stringent complete response (sCR) 20 n = 10 (9%) in 3% of patients (95% CI, 0.6 – 8.0) 15 PR 10 n = 18 (17%) 5 0 16 mg/kg Oncology Therapeutic Area 11 10/2/2018 Lonial S, et al. Presented at: 2015 American Society of Clinical Oncology (ASCO); May 29-June 2, 2015; Chicago, IL, USA.

  12. Phase 2 SIRIUS Study: PFS and OS OS PFS 100 100 Median PFS = 3.7 (95% CI, 2.8 – 4.6) months Median OS = NE (95% CI, 13.7 – NE) Patients progression-free and 80 80 Patients alive (%) alive (%) 60 60 40 40 20 20 0 0 14 0 2 4 6 8 10 12 14 16 0 2 4 6 8 10 12 16 Months from start of treatment Months from start of treatment Patients at risk 106 96 85 82 64 23 10 2 0 Patients at risk 106 63 38 32 17 5 4 1 0 • 29 of 31 responders are still alive • The 1-year survival rate was 65% (95% CI, 51.2 – 75.5) Oncology Therapeutic Area 12 10/2/2018 Lonial S, et al. Presented at: 2015 American Society of Clinical Oncology (ASCO); May 29-June 2, 2015; Chicago, IL, USA

  13. GEN501 and SIRIUS Studies: Clinical Safety Grade ≥3 Any grade TEAE, n (%) N = 148 N = 148 Fatigue 61 (41) 3 (2) Nausea 42 (28) 0 Anemia 41 (28) 26 (18) Back pain 36 (24) 3 (2) Cough 33 (22) 0 Neutropenia 30 (20) 15 (10) Thrombocytopenia 30 (20) 21 (14) Upper respiratory tract infection 30 (20) 1 (<1) • AEs were consistent with the individual GEN501 and SIRIUS studies; no new safety signals were identified • 48% of patients had IRRs – 46%, 4%, and 3% occurred during the first , second, and subsequent infusions , respectively Usmani S, et al. Oral presentation: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2015; Orlando, FL. Abstract 29. 14

  14. Anti-CD38 mAb Daratumumab  Daratumumab Daratumumab’s Mechanisms of Action – Human IgGκ monoclonal antibody CD38 receptor Daratumumab targeting CD38 with a direct DIRECT ON-TUMOR actions may contribute to IMMUNOMODULATORY actions on-tumor and immunomodulatory RAPID response 1-6 may contribute to mechanism of action DEEP & DURABLE response 1,7-9  Approved – As monotherapy for RRMM CD38 receptor CDC Modulation of tumor patients after ≥3 prior lines of microenvironment C1q complex therapy including a PI and an Clonal expansion of IMiD or who are double Myeloma ADCC cytotoxic T cells cell refractory to a PI and an IMiD Increase in – NK cell In combination with bortezomib, helper T cells melphalan, and prednisone in non- ADCP transplant NDMM (United States, Brazil, etc.) Macrophage Increase in CD8 +  granzyme B + cells Efficacy Apoptosis – Daratumumab-based combinations reduce risk of progression or death Depletion of CD38 + Daratumumab and induce rapid, deep, and durable immunosuppressive cells responses in RRMM and NDMM 10-12 MYELOMA CELL DEATH CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cellular cytotoxicity; NK, natural killer; ADCP, antibody-dependent cellular phagocytosis; RRMM, relapsed/refractory multiple myeloma. 1. DARZALEX US PI; 2018. 2. Liszewski MK, et al. Adv Immunol . 1996;61:201-283. 3. Debets JM, et al. J Immunol . 1988;141(4):1197-1201. 4. Overdijk MB, et al. mABs . 2015;7(2):311-321. 5. Lokhorst HM, et al. N Engl J Med . 2015;373(13):1207-1219. 6. Plesner T, et al. Blood . 2012;120:73. 7. Krejcik J, et al. Blood . 2016;128(3):384-394. 8. Adams H, et al. Poster presented at: ASH; December 3-6, 2016; San Diego, CA. 9. Chiu C, et al. Poster presented 15 at: ASH; December 3-6, 2016; San Diego, CA. 10. Palumbo A, et al. N Engl J Med . 2016;375(8):754-766. 11. Dimopoulos MA, et al. N Engl J Med . 2016;375(14):1319-1331. 12. Mateos MV, et al. N Engl J Med . 2018;378:518-528.

  15. Preclinical Rationale Supporting the Combination of IMiDs with Daratumumab  IMiDs increase NK-cell number and activity, thus enhancing NK-cell mediated ADCC  IMiDs promote tumoricidal activity of macrophages and enhance ADCP  Mechanistic rationale: IMiDs bind to cereblon which acquires the ability to ubiquitinate and degrade the transcriptional factors Ikaros and Aiolos which repress the activity of interferon stimulated genes, including CD38  IMiD-induced loss of Ikaros and Aiolos results in the upregulation of CD38 surface expression on MM cells, which are primed for Daratumumab induced NK-cell mediated ADCC These data have supported the exploratory use of Daratumumab combined with IMiDs in both RRMM and NDMM 16

  16. Fedele et al, Blood First Edition, September 18 2018

  17. POLLUX Phase 3 Study Design Dimopoulos et al. Presented at EHA 2016 (Abstract LB2238), oral presentation.

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