B Kahl 1, M Hamadani 2, P Caimi 3, E Reid 4, K Havenith 5, S He 6, JM Feingold 6, O O Connor 7

Transcription

1 First Clinical Results of ADCT-42, a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate (ADC), in Relapsed/Refractory B-cell Lineage Non-Hodgkin Lymphoma B Kahl 1, M Hamadani 2, P Caimi 3, E Reid 4, K Havenith 5, S He 6, JM Feingold 6, O O Connor 7 1 Department of Medicine, Oncology Division, Washington University, St. Louis, MO, USA; 2 Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 3 University Hospitals Cleveland Medical Center/Case Western Reserve University, Cleveland, OH, USA; 4 Department of Hematology/Oncology, Moores Cancer Center, University of California, San Diego, CA, USA; 5 ADC Therapeutics, London, UK; 6 ADC Therapeutics, Murray Hill, NJ, USA; 7 Center for Lymphoid Malignancies, Columbia University Medical Center New York Presbyterian Hospital, New York, NY, USA Wednesday 14 June, th International Conference on Malignant Lymphoma (ICML)

2 Disclosures Drs. Kahl, Hamadani, Caimi, Reid, and O Connor have received research funding from ADC Therapeutics for their centers participation in this study. Drs. Havenith, He, and Feingold are employees of ADC Therapeutics. 2

3 CD19 as a Therapeutic Molecular Target Human CD19 is a 95 kilodalton (kda) type I transmembrane glycoprotein belonging to the immunoglobulin Ig super family 1 Once bound by an antibody, CD19 is rapidly internalized by the cell 2 The majority of B cell malignancies express CD19 at normal to high levels: 3 8% 88% 1% ALL B-cell lymphomas B-cell leukemias 1. Carter RH and Barrington RA. Curr Dir Autoimmun. 24;7:4 32; 2. Blanc V et al. Clin Cancer Res. 211;17(2): ; 3.Wang K et al. Exp Hematol Oncol. 212;1:36. 3

4 Pyrrolobenzodiazepine (PBD) Dimers as Anti-Tumor Agents PBD is DNA cross-linking agent Non-distortive of DNA Less visible to DNA repair mechanisms Effective in MDR (+) cell lines Non-tubulin approach Active in slowly proliferating cancers Measurable pharmacodynamic endpoints Demonstrable Therapeutic Index IC5 potency in picomolar range (1-12 ) 4

5 Pyrrolobenzodiazepine Comparison of Free Drug Potency Methotrexate Auristatin Doxyrubicin Calicheamicin Daunomycin PBD Maytansine Taxol/Taxotere Vinblastine Free drug potency (IC5, M) The PBD dimer in ADCT-31 is designated as SG3199 5

6 ADCT-42 PBD Molecular Structure 8-polyethylene glycol Proteasesensitive valine-alanine linker Para-aminobenzoic acid Humanized monoclonal antibody specific for human CD19 of the immunoglobulin G1 (IgG1) kappa isotype Maleimide Linker component SG3199 PBD dimer Self-immolative group CD19-specific IgG1 Tesirine/SG3249 PBD linker comprising the PBD dimer SG3199 and all linker components (stochastic conjugation) 6

7 ADCT-42 Mechanism of Action ADCT-42 ADCT-42 binds to the CD19 antigen on the tumor cell surface CD19 Following internalization of the ADC, the protease-sensitive linker is cleaved and the cytotoxic PBD dimer is released inside the cell The free PBD dimers bind in the minor groove of the cell DNA and forms potent cytotoxic DNA cross-links in a sequence-selective fashion. The cross-links result in a stalled DNA replication fork, blocking cell division and causing cancer cell death Cytotoxic cross-links Stalled DNA replication fork 1. Hartley JA. The development of pyrrolobenzodiazepines as antitumour agents. Expert Opin Investig Drugs 211;2(6):

8 ADCT Phase I Study (NCT266917) Part 1: Dose escalation R/R B-cell lineage non-hodgkin Lymphoma (B-NHL)* Failed, or intolerant to, any established therapy OR No other available treatment options (investigator opinion) No intra-patient dose escalation allowed 1 hour IV infusion (15 2 µg/kg) Day 1 every 3 weeks Dose Level ADCT-42 Dose (µg/kg) Part 2: Dose expansion using the recommended dose from Part 1 * Diffuse large B-cell lymphoma; Follicular lymphoma; Chronic lymphocytic leukemia; Mantle cell lymphoma; Marginal Zone B-cell lymphoma; Burkitt s lymphoma; Lymphoplasmacytic lymphoma (Waldenstrom macroglobulinemia) 8

9 ADCT Phase I Study (NCT266917) PRIMARY STUDY OBJECTIVES Evaluate the safety and tolerability and determine the maximum tolerated dose of ADCT-42 Determine the recommended dose of ADCT-42 for dose expansion (Part 2) Evaluate the safety and tolerability of ADCT-42 at the dose level recommended in Part 1 SECONDARY STUDY OBJECTIVES Evaluate the clinical activity of ADCT-42 as measured by overall response rate, duration of response, progression-free survival, and overall survival Characterize the pharmacokinetic profile of ADCT-42 Evaluate anti-drug antibodies in blood before, during, and after treatment with ADCT-42 9

10 Patient Enrollment By Dose Latest interim data cut off: 1 May 217 Interim study populations 15 (n=4) 3 (n=4) 6 (n=4) 9 (n=5) Dose (µg/kg) 12 (n=14) 15 (n=1) 2 (n=24) Total (N=65) Pts enrolled (n[%]) Safety analysis set 4 (1) 4 (1) 4 (1) 5 (1) 12 (85.7) 1 (1) 23 (95.8) 62 (95.4) DLT-evaluable analysis set 4 (1) 4 (1) 4 (1) 5 (1) 12 (85.7) 5 (5.) 2 (83.3) 54 (83.1) Efficacy analysis set 4 (1) 4 (1) 4 (1) 5 (1) 12 (85.7) 3 (3.) 16 (66.7) 48 (73.8) Enrollment for Phase 1a is ongoing 1

11 Patient Baseline Characteristics Sex* Race (n[%]) Age (years)* Patient Baseline Characteristic Female Male White Black or African American Asian Other Median (Min, Max) Total (N=62) 21 (33.9) 41 (66.1) 58 (93.5) 2 (3.2) 67. (24, 85) Number of previous chemotherapies Median (Min, Max) 3. (1., 1.) Prior chemotherapy response status (n[%])* Prior stem cell transplantation (n[%])* Relapsed Refractory Missing Yes No 23 (37.1) 38 (61.3) 15 (24.2) 47 (75.8) * Safety analysis set 11

12 Patient Diagnosis at Baseline Patient Diagnosis at Baseline Total (N=62) Non-Hodgkin Lymphoma Diffuse large B-cell lymphoma (DLBCL) Mantle cell lymphoma Follicular lymphoma (FL) Chronic lymphocytic leukemia (CLL) Marginal Zone B-cell lymphoma Transformed follicular lymphoma High-grade B-cell lymphoma Primary mediastinal B-cell lymphoma Mixed DLBCL-Burkitt s lymphoma Small lymphocytic lymphoma (SLL)/CLL CLL/SLL recurrence and simultaneous FL 41 (66.1) 9 (14.5) 4 (6.5) 12

13 Most Common TEAEs Listed by Grade (By Preferred Term) Treatment-emergent adverse events (TEAEs) Grade 1 (n) Grade 2 (n) Grade 3 (n) Grade 4 (n) Grade 5 (n) All Grades (n[%]) Non-hematologic* Nausea Vomiting Abdominal pain Fatigue Peripheral edema Increased γ-glutamyltransferase Decreased appetite Myalgia Dyspnea Pleural effusion Maculopapular rash Hematologic Decreased hemoglobin Decreased platelet count Decreased neutrophil count N/A N/A N/A 16 (25.8) 9 (14.5) 11 (17.7) 3 (48.4) 16 (25.8) 12 (19.4) 11 (17.7) 11 (17.7) 11 (17.7) 9 (14.5) 12 (19.4) 6 (98.4) 44 (72.1) 35 (62.5) * All-Grades total of n 9 All hematologic values are sourced from laboratory measurements. Missing values have been excluded from the All-Grades calculations. 13

14 Number of TEAEs by Grade and Dose TEAE Grade 15 (n=4) 3 (n=4) 6 (n=4) 9 (n=5) Dose (µg/kg) 12 (n=12) 15 (n=1) 2 (n=23) Total (N=62) 12 (n=45) Grade (14.5) 4 (8.9) Grade (19.4) 9 (2.) Grade (33.9) 17 (37.8) Grade (21.) 1 (22.2) Grade (4.8) 2 (4.4) All Grades (93.5) 42 (93.3) 14

15 Drug Exposure The median number of ADCT-42 cycles received to date is 2 (range 1 14) The median duration of treatment is 43 days (range 7 296) Dose (µg/kg) n Total number of cycles dosed (Median [Min, Max]) Duration of treatment (days) (Median [Min. Max]) (2, 7) 43. (34, 147) (2, 13) 43.5 (43, 274) (1, 14) 43. (22, 296) (3, 11) 87. (64, 231) (2, 9) 81. (43, 241) (1, 3) 21. (16, 72) (1, 3) 32. (7, 296) Total (1, 14) 43. (7, 296) 15

16 PK Exposure vs Time and Dose ADCT42 Total Antibody C avg vs. Dose Cycle 1 PBD-Conjugated Antibody Mean Concentration vs Time by Dose (µg/kg) Cycle 1 C avg (µg/l) Dose (µg/kg) Concentration (µg/l) Dose (µg/kg) Limit of quantitation Dose (µg/kg) Time (days) Exposure metrics (C avg shown), as well as C max, C trough, and AUC, based on total Ab concentration increase with dose Modest accumulation seen for 9, 12 and 2 µg/kg with multiple doses; variability increases proportionately with exposure PK profiles for PBD-antibody conjugate are comparable to total antibody Concentrations of unconjugated warhead (SG3199) were predominantly below quantifiable limit 16

17 Best Overall Responses* at Each ADCT-42 Dose All Patients Dose (µg/kg) Response (n[%]) Complete Response (CR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) Overall Response Rate (CR +PR) 15 (n=4) 3 (n=4) 6 (n=4) 9 (n=5) 12 (n=12) 15 (n=3) 2 (n=16) Total (N=48) 12 (n=31) (31.3) 13 (41.9) (18.8) 6 (19.4) (18.8) 5 (16.1) (31.3) 7 (22.6) (5.) 19 (61.3) * Best visit responses based on the 214 Lugano Classification Criteria. All efficacy assessments to date have been investigator-determined 17

18 Nodal Regression All Patients* (Best Percentage Change From Baseline) Best Percentage Change From Baseline (%) Subjects 15 µg/kg (n=3) 3 µg/kg (n=4) 6 µg/kg (n=3) 9 µg/kg (n=5) 12 µg/kg (n=12) 15 µg/kg (n=3) 2 µg/kg (n=14) * All efficacy assessments to date have been investigator-determined 18

19 Best Overall Responses* at Each ADCT-42 Dose DLBCL Patients Dose (µg/kg) Response (n[%]) Complete Response (CR) Partial Response (PR) Stable Disease (SD) Progressive Disease (PD) Overall Response Rate (CR + PR) 15 (n=2) 3 (n=3) 6 (n=3) 9 (n=2) 12 (n=1) 15 (n=1) 2 (n=1) Total (N=31) 12 (n=21) (32.3) 9 (42.9) (12.9) 3 (14.3) (22.6) 5 (23.8) (32.3) 4 (19.) (45.2) 12 (57.1) * Best visit responses based on the 214 Lugano Classification Criteria. All efficacy assessments to date have been investigator-determined 19

20 Nodal Regression DLBCL Patients* (Best Percentage Change From Baseline) Best Percentage Change From Baseline (%) Subjects 15 µg/kg (n=3) 3 µg/kg (n=4) 6 µg/kg (n=3) 9 µg/kg (n=5) 12 µg/kg (n=12) 15 µg/kg (n=3) 2 µg/kg (n=14) * All efficacy assessments to date have been investigator-determined 2

21 Summary In this first in-human study, ADCT-42 has demonstrated encouraging single-agent anti-tumor activity and manageable toxicity in patients with recurrent B-cell lineage NHL who had failed or were intolerant to established therapies, or who had no other treatment options available One DLT (worsening thrombocytopenia at 2 μg/kg) has been reported and the MTD has not yet been reached At doses 12 μg/kg, the overall response rate was: 61% in the total R/R B-NHL patient population (comprising 42% CR and 19% PR) 57% in patients with R/R DLBCL (comprising 43% CR and 14% PR) Further evaluation in specific NHL subtypes is now warranted A dose expansion in DLBCL is planned 21