Dose-Dependent Efficacy of Daratumumab as Monotherapy in Patients with Relapsed or Refractory Multiple Myeloma

Transcription

1 Dose-Dependent Efficacy of Daratumumab as Monotherapy in Patients with Relapsed or Refractory Multiple Myeloma Henk Lokhorst, Jacob Laubach, Hareth Nahi, Torben Plesner, Peter Gimsing, Markus Hansson, Monique Minnema, Ulrik Lassen, Jakub Krejcik, Tahamtan Ahmadi, Steen Lisby, Linda Basse, Nikolai Brun, Paul Richardson University Medical Center Utrecht, Netherlands; Dana-Farber Cancer Institute, Boston, MA, USA; Karolinska Institutet, Stockholm, Sweden; Vejle Hospital, Denmark; Rigshospitalet, Copenhagen, Denmark; Lund University Hospital, Lund, Sweden; Janssen Research & Development, Raritan, NJ, USA; Genmab A/S, Copenhagen, Denmark;

2 Disclosures Genmab: Advisory Board, research support Johnson & Johnson: Advisory Board, research support

3 Daratumumab Daratumumab (HuMax -CD38) is a fully human IgG1k monoclonal antibody with a broad spectrum of mechanisms of action including CDC, ADCC, ADCP, apoptosis induction and inhibition of enzymatic activity In development for treatment of patients with multiple myeloma Ongoing trials as monotherapy as well as in combination with Lenalidomide & Dexamethasone

4 GEN501 - Monotherapy Part 1 (N=32): First-in-Human, dose escalation Results from part 1 a : Daratumumab well-tolerated Twelve patients dosed 4 24 mg/kg 5/12 (42%) achieved a PR as best response Part 2: Ongoing, cohort expansion Here we present preliminary data b from the first 50 patients. a Lokhorst et al. EHA 2013 abstract S576 b Data cut-off: May 02, 2014

5 Objectives Primary: Establish the safety profile of daratumumab as monotherapy in relapsed or relapsed and refractory multiple myeloma Secondary: Evaluate the efficacy of daratumumab Optimize premedication and infusion parameters for daratumumab Establish the optimal daratumumab dose Establish the PK profile for daratumumab

6 Trial Design Part 2 8 weekly doses, followed by 8 doses twice monthly and monthly dosing up to 24 months Cohort A Cohort B Cohort C Cohort D Dose (mg/kg) Pre-dose (10% of full dose, max 10 mg) Yes Yes No No Wash out (3 weeks between 1st and 2nd full infusion) No No No Yes Infusion time, 1 st full 4h 6h 6.5h 6.5h planned 2 nd full 3h15min 4h 4h 4h 3 rd full 3h15min 3h15min 3h15min 3h15min Infusion volume, ml 1 st full nd full rd full

7 Patient Characteristics Cohort A (N=16) Cohort B (N=8) Cohort C (N=6) Cohorts A+B+C Cohort D (N=20) (N=30) Dose (mg/kg) Age, years A 60 (41-77) 56 (38-74) 60 (45-73) 59 (38-77) 62 (51-76) Sex F/M% B 25/75 38/63 33/67 30/70 25/75 ECOG PS 1 (0-2) 1 (0-2) 1 (0-1) 1 (0-2) 1 (0-1) Prior therapy lines (numbers) 4 (3-8) 6.5 (3-10) 5 (3-11) 5 (3-11) 4 (2-12) Refractoriness, BORT C 19 (63) 8 (50) D n (%) LEN C 24 (80) 12(75) D C 18 (60) 6 (38) D BORT & LEN A: median (range) B: F/M = female/male, percent C: two patients have not been treated with Bortezomib or Lenalidomide D: one patient has not received Bortezomib or Lenalidomide and one patient is not evaluable.

8 Infusion Times Cohort A Cohort B Cohort C Cohort Cohort D A+B+C Dose, mg/kg Pre-dose Yes Yes No Yes/No No Number of full infusions 10 (1-20) 10.5 (1-21) 11.5 (3-18) 10.5 (1-21) 11.5 (1-15) Duration of full 1 st full 6.5 ( ) 7.6 ( ) 6.5 ( ) 6.6 ( ) 7.4 ( ) infusions, 2 nd full hours ( ) ( ) ( ) ( ) ( ) 3 rd full 3.5 ( ) 3.3 ( ) 3.3 ( ) 3.4 ( ) 3.4 ( ) : median (range)

9 All AEs Grade 3/4 and SAEs per Dose Group 8mg/kg (N=30) 16mg/kg (N=20) Adverse event Grades 3/4 SAE Grades 3/4 SAE Total # of pts with AEs N (%) E 18 (60%) (40%) 17 6 (30%) 11 5 (25%) 6 Hematological Thrombocytopenia Anemia Neutropenia Lymphopenia 4 (13%) 6 1(3%)1 1 (3%) 2 1(5%)1 2(10%)4 2 (10%) 2 Non-hematological Hyperglycaemia Hypercalcaemia Hypokalemia Hypomagnesaemia Back Pain Muskuloskeletal Pain Osteoporotic fracture Pneumonia Bacteriemia Influenza RSV infection Pyrexia Chest Pain Face oedema Fatigue INR increased CPK increased Eye Swelling Limb Amputation 6th Nerve paralysis Renal Impairment Hypertension 2 (7%) 2 1 (3%) 2 1 (3%) 2 3 (10%) 4 1 (3%)1 1 (3%)1 1(3%)1 3 (10%) 4 1(3%) 1 1(3%)1 1(3%)1 1(3%)1 1 (5%) 2 1 (5%) 2 1 (5%) 1 1 (5%) 1 1 (5%) 1 1 (5%) 1 1 (5%) 2

10 Infusion Related Reactions (IRR) Dilution of the drug in 1000mL reduced the number of IRRs (cohorts C and D)

11 Best Change in Response Paraprotein (%) 100 IMWG Criteria (for measurable disease at baseline) Cohort A 8mg/kg Cohort B 8mg/kg Cohort C 8mg/kg Cohort D 16mg/kg mg/kg: in the 4 of 7 responders who had >=5% BM PCs at study entry, the BM PCs were cleared following treatment. 16 mg/kg: in the SSS 4 of 7 SSUS responders S F Swho SSSSSUSFSSSUUS had >=5% BM PCs at study SUFSUSU entry, the BM F UUUUUU 0 PCs were cleared following US treatment. S S S SSSS S Serum, U Urine, F FLC

12 Response Response rate (%) N=29 N=20 RR=10% RR=35% PR n=4 (20%) VGPR n=1 (5%) PR n=3 (10%) CR n=2 (10%) 8 mg/kg 16 mg/kg IMWG Criteria

13 Reduction in Bone Marrow Plasma Cells BM PCs (%) mg/kg: in the 4 of 7 responders who had >=5% BM PCs at study entry, the BM PCs were cleared following treatment. 16 mg/kg: in the 4 of 7 responders who had >=5% BM PCs at study entry, the BM PCs were cleared 30 following treatment Weeks 8mg/kg 16mg/kg All patients who achieved a PR or better at 16 mg/kg and who had bone marrow involvement cleared BMPC after daratumumab treatment (4/4 patients)

14 Progression-Free Survival 8 mg/kg 16 mg/kg Median PFS (weeks) Observed events 22 9 Censored observations 7 11 Follow up Median (range) (weeks) 13.4 (0 47) 14.7 ( ) The median PFS estimate in the 16 mg/kg is rather immature. The current median PFS in the 16 mg/kg group is 23 weeks which is also the longest follow-up of any patient in this cohort.

15 Conclusions 1/2 Safety Daratumumab was well-tolerated No severe infusion-related reactions (IRRs) were seen All IRRs were grade 1 and 2 across all cohorts A,B,C (8mg/kg) and D (16mg/kg) Infusion times could be reduced to ~3.4 hours as of the 3 rd infusion

16 Conclusions 2/2 Efficacy The preliminary ORR (PR and better) showed a higher response of 35% in the 16 mg/kg cohort compared to 10% in the 8 mg/kg cohorts The response was deeper in the 16 mg/kg cohort in part 2 compared to the 8 mg/kg cohort and the higher dose cohorts. All patients who achieved a PR or better at 16 mg/kg and who had bone marrow involvement cleared BMPC after daratumumab treatment (4/4 patients)

17 Acknowledgments Special thanks to investigators, sub-investigators, research staff and patients and their families at the collaborating centers: Karolinska Institutet, Stockholm, Sweden Lund University Hospital, Lund, Sweden Rigshospitalet, Copenhagen, Denmark University Medical Center Utrecht, Utrecht, Netherlands Vejle Hospital, Vejle, Denmark Dana-Farber Cancer Institute, Boston MA, USA