Daratumumab: Mechanism of Action

Transcription

1 Phase 3 Randomized Controlled Study of Daratumumab, Bortezomib and Dexamethasone (D) vs Bortezomib and Dexamethasone () in Patients with Relapsed or Refractory Multiple Myeloma (RRMM): CASTOR* Antonio Palumbo, Asher Chanan-Khan, Katja Weisel, Ajay K. Nooka, Tamas Masszi, Meral Beksac, Ivan Spicka, Vania Hungria, Markus Munder, Maria Victoria Mateos, Tomer Mark, Ming Qi, Jordan Schecter, Himal Amin, Xiang Qin, William Deraedt, Tahamtan Ahmadi, Andrew Spencer, and Pieter Sonneveld on behalf of the CASTOR investigators *NCT213613

2 Daratumumab: Mechanism of Action Human CD38 IgGκ monoclonal antibody Direct and indirect anti-myeloma activity 1-5 Depletes CD38+ immunosuppressive regulatory cells 5 Promotes T-cell expansion and activation 5 1. Lammerts van Bueren J, et al. Blood. 21;12:Abstract Jansen JMH, et al. Blood. 212;12:Abstract de Weers M, et al. J Immunol. 211;186: Overdijk MB, et al. MAbs. 215;7: Krejcik J, et al. Blood Epub ahead of print. 2

3 Daratumumab: Single-agent Activity Daratumumab as a single agent Approved by FDA and conditionally approved by EMA in relapsed/refractory multiple myeloma 1,2 Patients received a median of 5 prior lines of therapy 86.5% of patients were double refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD) 3 Combined overall response rate (ORR): 31% 3 Median overall survival (OS): 2.1 months 3 2-year OS was ~75% in responders Median OS was 18.5 months in patients with MR/SD Patients Alive (%) No. at risk Responders MR/SD PD/NE Median OS=NE (95% CI, NE-NE) Responders MR/SD PD/NE Median OS=18.5 months (95% CI, ) Median OS=3.7 months (95% CI, ) Months MR, minimal response; SD, stable disease; PD, progressive disease; OS, overall survival; CI, confidence interval; NE, not evaluable Lokhorst HM, et al. N Engl J Med. 215;373: Lonial S, et al. Lancet. 216;387: Usmani SZ, et al. Blood Epub ahead of print. 3

4 CASTOR: Study Design Multicenter, randomized, open-label, active-controlled phase 3 study Key eligibility criteria RRMM 1 prior line of therapy Prior bortezomib exposure, but not refractory R A N D O M I Z E 1:1 D (n = 251) Daratumumab (16 mg/kg IV) Every week - cycles 1-3 Every 3 weeks - cycles -8 Every weeks - cycles 9+ Vel: 1.3 mg/m 2 SC, days 1,,8,11 - cycles 1-8 dex: 2 mg PO-IV, days 1,2,,5,8,9,11,12 - cycles 1-8 (n = 27) Vel: 1.3 mg/m 2 SC, days 1,,8,11 - cycles 1-8 dex: 2 mg PO-IV, days 1,2,,5,8,9,11,12 - cycles 1-8 Primary Endpoint PFS Secondary Endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Cycles 1-8: repeat every 21 days Cycles 9+: repeat every 28 days Statistical analyses 295 PFS events: 85% power for.3 month PFS improvement Interim analysis: ~177 PFS events Daratumumab IV administered in 1 ml to 5 ml; gradual escalation from 5 ml to 2 ml/hour permitted RRMM, relapsed or refractory multiple myeloma; D, daratumumab/bortezomib/dexamethasone; IV, intravenous; Vel, bortezomib; SC, subcutaneous; dex, dexamethasone; PO, oral;, bortezomib/dexamethasone; PFS, progression-free survival; TTP, time to progression; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease.

5 Baseline Demographics and Clinical Characteristics Characteristic Age, years Median (range) 75, n (%) ISS staging, n (%) a I II III D (n = 251) 6 (3-88) 23 (9) 98 (39) 9 (38) 59 (2) (n = 27) 6 (33-85) 35 (1) 96 (39) 1 (1) 51 (21) Characteristic Prior lines of therapy, n (%) >3 D (n = 251) 122 (9) 7 (28) 37 (15) 22 (9) (n = 27) 113 (6) 7 (3) 32 (13) 28 (11) Prior ASCT, n (%) 156 (62) 19 (6) Prior PI, n (%) 169 (67) 172 (7) Cytogenetic profile, n (%) b Del17p t(;1) Time from diagnosis, years Median (range) 28 (16) 1 (8) 3.87 (.7-2.7) 21 (12) 15 (9) 3.72 ( ) Prior IMiD, n (%) 179 (71) 198 (8) Prior PI + IMiD, n (%) 112 (5) 129 (52) Refractory to IMiD, n (%) 7 (3) 9 (36) Refractory to last line of therapy, n (%) 76 (3) 85 (3) ISS, international staging system; ASCT, autologous stem cell transplant; a ISS staging is derived based on the combination of serum β2-microglobulin and albumin; b Investigator-reported. 5

6 Patient Disposition Accrual: September 21 September 215 Clinical cut-off date: January 11, 216 Median follow-up: 7. (range, -1.9) months Patients D (n = 251) (n = 27) Randomized, n Treated, n (%) 23 (97) 237 (96) Discontinued treatment, n (%) Reasons for discontinuation Progressive disease Adverse event Non-compliance with study drug Withdrawal by patient Death 7 (31) 7 (19) 19 (8) 3(1) 1 (.) (2) 1 () 6 (25) 23 (1) 8 (3) 9() (2) 6

7 Progression-free Survival 1. Median: not reached 1-year PFS* Proportion surviving without progression Median: 7.2 months 6.7% 26.9% D No. at risk D Months HR:.39 (95% CI, ); P< % reduction in the risk of disease progression or death for D vs *KM estimate; HR, hazard ratio. 7

8 Time to Progression 1. Median: not reached 1-year TTP* Proportion surviving without progression Median: 7.3 months 65.% 28.8% D No. at risk D HR:.3 (95% CI,.21-.3); P< Months % reduction in the risk of disease progression for D vs *KM estimate 8

9 PFS: Subgroup Analysis HR (95% CI) HR (95% CI) Age <65 years 65 ISS staging I II III Prior lines of tx >3 Prior ASCT Yes No. (.28,.68).35 (.22,.57).25 (.13,.8).37 (.23,.61).55 (.31,.98).31 (.18,.52).5 (.28,.89).66 (.31, 1.1).8 (.2, 1.16).38 (.26,.57).3 (.19,.59) Prior bortezomib tx Yes No Prior IMiD Yes No Refractory to IMiD Yes No Refractory to last line of prior tx Yes No Renal function (baseline CrCl) >6 ml/min 6 ml/min.6 (.32,.66).25 (.13,.7).38 (.27,.55).5 (.2, 1.).5 (.31,.8).32 (.18,.59).2 (.25,.7).38 (.25,.59).3 (.2,.).55 (.3, 1.2) Favor D Favor Favor D Favor Tx, treatment; CrCl, creatinine clearance. 9

10 PFS: 1 Prior Line of Treatment 1. Median: not reached 1-year PFS* Proportion surviving without progression Median: 7.5 months 77.5% 29.% D No. at risk D Months HR:.31 (95% CI, ); P< % reduction in the risk of progression or death for D vs *KM estimate 1

11 Overall Response Rate a P <.1 Response rate, % P < P = % D ORR VGPR CR MRD-neg (1 - ) a Response-evaluable population. 11

12 Time to Response 1 D (PR or better) 8 (PR or better) Responders, % 6 D (CR or better) 2 (CR or better) No. at risk Months (PR or better) D (PR or better) (CR or better) D (CR or better)

13 Most Common ( 2%) Treatment-emergent Adverse Events (TEAE) Patients D Number treated Patients with TEAE, % Thrombocytopenia 59 Sensory peripheral neuropathy (PN) 7 38 Diarrhea Anemia Upper respiratory tract infection Cough 2 13 Fatigue Constipation

14 Most Common (>5%) Grade 3- TEAE Non-hematologic Hematologic Thrombocytopenia Anemia Neutropenia Lymphopenia Pneumonia Hypertension Sensory PN Grade 3 Grade D Grade 3 D Grade Patients, % Bleeding: All grades: 7% in D vs % in Grade 3-: 3 pts in D vs 2 pts in Infections: Grade 3- AEs: 21% in D vs 19% in Serious AEs: 2% in D vs 18% in Discontinued for sensory peripheral neuropathy: All grades:.% in D vs 3% in Discontinued for TEAE: 7% in D vs 9% in 1

15 Infusion-related Reactions (IRRs) Safety Analysis Set (n = 23) All grades Grade 3 Patients with IRRs, % 5 9 Most common (>5%) IRRs Dyspnea 11 2 Bronchospasm 9 3 Cough 7 No grade or 5 IRRs observed 98% of patients with IRRs experienced the event on the first infusion 2 patients discontinued due to IRRs Bronchospasm in the first patient Bronchospasm, laryngeal edema, and skin rash in the second patient Preinfusion: dexamethasone 2 mg, paracetamol 65-1 mg, diphenhydramine 25-5 mg Stop infusion immediately for mild symptoms; once resolved, resume at half the infusion rate 15

16 PI-based Studies Daratumumab D vs Carfilzomib Kd vs 1 Panobinostat P vs 2,3 Elotuzumab E vs PFS HR (95% CI).39 ( ) PFS, median mo NE VGPR 59% CR 19%.53 (.-.65).63 ( ).72 ( ) % 28% 36% 13% 11% % Duration of response, mo NE OS HR (95% CI).77 (.7, 1.26).79 ( ).9 ( ).61 ( ) 1. Dimopoulos MA, et al. Lancet Oncol. 216;17(1): San-Miguel JF, et al. Lancet Oncol. 21;15(11): San-Miguel JF, et al. Blood. 215;126(23):Abstract Jakubowiak A, et al. Blood Epub ahead of print. 16

17 Conclusions Daratumumab- significantly improved PFS, TTP, and ORR in comparison with alone D was associated with a 61% reduction in the risk of progression/death Treatment benefit of D vs was consistent across subgroups Earlier treatment with D may be the most beneficial Daratumumab- doubled VGPR and CR rates Daratumumab- was not associated with any cumulative toxicities 17

18 Conclusions Daratumumab- significantly improved PFS, TTP, and ORR in comparison with alone D was associated with a 61% reduction in the risk of progression/death Treatment benefit of D vs was consistent across subgroups Earlier treatment with D may be the most beneficial Daratumumab- doubled VGPR and CR rates Daratumumab- was not associated with any cumulative toxicities Daratumumab- can potentially be considered a new standard of care for RRMM currently receiving alone 18

19 Acknowledgments Patients who participated in this study Staff members at the study sites Data and safety monitoring committee Staff members involved in data collection and analyses 16 countries This study was funded by Janssen Research & Development, LLC Medical writing and editorial support was provided by Jason Jung, PhD (MedErgy) and was funded by Janssen Global Services, LLC 19