Daratumumab: Mechanism of Action

Transcription

1 An Open-label, Randomised, Phase 3 Study of Daratumumab, Lenalidomide, and Dexamethasone (D) Versus Lenalidomide and Dexamethasone () in Relapsed or Refractory Multiple Myeloma (RRMM): POLLUX* Meletios A. Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San Miguel, Nizar J. Bahlis, Neil Rabin, Robert Z. Orlowski, Mieczyslaw Komarnicki, Kenshi Suzuki, Torben Plesner, Olga S. Samoilova, Sung-Soo Yoon, Dina Ben Yehuda, Paul G. Richardson, Hartmut Goldschmidt, Donna Reece, Nushmia Khokhar, Lisa O Rourke, Christopher Chiu, Xiang Qin, Mary Guckert, Tahamtan Ahmadi, Philippe Moreau, on behalf of the POLLUX investigators *NCT2769

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. 214;124: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 1,2 Approved by FDA and conditionally approved by EMA in relapsed/refractory multiple myeloma 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 Patients Alive (%) 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, ) Median overall survival (OS) of 2.1 months 3 2-year OS was ~75% in responders Median OS was 18.5 months in MR/SD patients No. at risk Responders MR/SD PD/NE 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 Daratumumab (D) With Lenalidomide and Dexamethasone () 1 In a phase 1/2 study, 32 patients with relapsed or refractory multiple myeloma were treated with daratumumab 16 mg/kg and lenalidomide/dexamethasone D induced rapid, deep, and durable responses Safety profile was manageable Neutropenia, the most common adverse event (AE), was managed with treatment interruptions, lenalidomide dose reduction, and growth factor administrations Patients progression-free and alive, % month PFS rate = 72% (95% CI, ) ORR, % % CR or better scr CR VGPR PR ORR = 81% 25% 9% 28% 63% VGPR or better Patients at risk Time from first dose, months % 16 mg/kg PFS, progression-free survival; scr, stringent complete response; CR, complete response; VGPR, very good partial response; PR, partial response. 1. Plesner T, et al. Presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 215; Orlando, FL. Abstract 57. 4

5 POLLUX: Study Design Multicenter, randomized (1:1), open-label, active-controlled phase 3 study D (n = 286) Key eligibility criteria RRMM 1 prior line of therapy Prior lenalidomide exposure, but not refractory Patients with creatinine clearance 3 ml/min Stratification factors R A N D O M I Z E 1:1 Daratumumab 16 mg/kg IV Qw in Cycles 1-2, q2w in Cycles 3-6, then q4w until PD R 25 mg PO Days 1-21 of each cycle until PD d 4 mg PO 4 mg weekly until PD (n = 283) R 25 mg PO Days 1-21 of each cycle until PD d 4 mg PO 4 mg weekly until PD Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Time to response Duration of response Statistical analyses No. prior lines of therapy ISS stage at study entry Cycles: 28 days 295 PFS events: 85% power for 7.7 month PFS improvement Prior lenalidomide Interim analysis: ~177 PFS events Pre-medication for the D treatment group consisted of dexamethasone 2 mg a, paracetamol, and an antihistamine a On daratumumab dosing days, dexamethasone was administered 2 mg premed on Day 1 and 2 mg on Day 2; RRMM, relapsed or refractory multiple myeloma; ISS, international staging system; R, lenalidomide; D, daratumumab/lenalidomide/dexamethasone; IV, intravenous; qw, once weekly; q2w, every 2 weeks; q4w, every 4 weeks; PD, progressive disease; PO, oral; d, dexamethasone;, lenalidomide/dexamethasone; TTP, time to progression; MRD, minimal-residual disease. 5

6 Baseline Demographics and Clinical Characteristics Age, yr Median (range) 75, % ISS stage, % a I II III Characteristic D (n = 286) 65 (34-89) (n = 283) 65 (42-87) Median (range) time from diagnosis, yr Creatinine clearance (ml/min) N >3-6 >6 Prior lines of therapy, % Median (range) > (.4-27.) (1-11) ( ) (1-8) a ISS stage is derived based on the combination of serum β2-microglobulin and albumin. 6

7 Baseline Demographics and Clinical Characteristics (cont.) Characteristic D (n = 286) (n = 283) Prior ASCT, % Prior PI, % Prior IMiD, % Prior lenalidomide, % Prior PI + IMiD, % Refractory to PI, % 2 16 Refractory to last line of therapy, % ASCT, autologous stem cell transplant. 7

8 Patient Disposition Randomization: June 214 July 215 Clinical cut-off date: March 7, 216; 198 patients discontinued treatment Median follow-up: 13.5 months D (n = 286) (n = 283) Patients treated, n Patients who discontinued treatment, % Reasons for discontinuation Progressive disease Adverse event Non-compliance with study drug Withdrawal by patient Physician decision Death

9 Progression-free Survival month PFS* 18-month PFS* 83% Proportion surviving without progression % 78% D 52% Median PFS: 18.4 months.2 No. at risk HR:.37 (95% CI, ; P <.1) Months D *KM estimate; HR, hazard ratio. 63% reduction in the risk of disease progression or death for D vs 9

10 PFS: Subgroup Analysis Age <65 years years 75 years ISS stage I II III No. prior lines of tx >3 Prior lenalidomide Yes No Prior PI Yes No Refractory to PI Yes No Refractory to last line of tx Yes No Type of MM IgG IgA Serum FLC only Hazard Ratio (95% CI).4 (.24,.65).4 (.24,.67).11 (.2,.51).4 (.23,.72).29 (.17,.5).4 (.21,.76).41 (.26,.66).29 (.16,.53).36 (.13, 1.3).53 (.1, 2.87).42 (.19,.9).36 (.25,.52).37 (.26,.52).35 (.12, 1.).5 (.27,.93).27 (.17,.43).47 (.27,.8).32 (.2,.49).3 (.17,.52).44 (.22,.89).69 (.3, 1.57) Favor D Favor Higher efficacy was observed for D versus across all subgroups Tx, treatment; MM, multiple myeloma; IgG, immunoglobulin G; IgA, immunoglobulin A; FLC, free light chain. 1

11 PFS: Prior Lenalidomide Treatment Prior Lenalidomide Treatment No Prior Lenalidomide Treatment Proportion surviving without progression month PFS* 83% D 59% HR:.42 (95% CI,.19-.9; P =.228) Proportion surviving without progression month PFS* 83% D 61% HR:.36 (95% CI, ; P <.1) No. at risk D Months No. at risk D Months Treatment effect is consistent regardless of prior lenalidomide exposure *KM estimate. 11

12 Overall Response Rate a P <.1 1 ORR = 93% % ORR = 76% Overall response rate, % CR: 43%* 7% CR: 25% 19% 12% VGPR: 76%* 25% 33% 17% D (n=281) *P <.1 32% (n=276) VGPR: 44% scr CR VGPR PR Median duration of response: Not reached for D vs 17.4 months for Median time to response: 1. month for D vs 1.3 months for a When serum interference was suspected, CR was confirmed using the daratumumab interference reflex assay. 12

13 MRD-negative Rate P <.1 MRD-negative rate (%) % 8% P <.1 23% 5% P <.1 1% 2% D MRD-neg (1-4 ) MRD-neg (1-5 ) MRD-neg (1-6 ) Significantly higher MRD-negative rates for D vs Response-evaluable set. Assessed by next generation sequencing in bone marrow. 13

14 Time to Response 1. D (PR or better) Proportion surviving without progression (PR or better) D (CR or better) (CR or better) No. at risk Months (PR or better) D (PR or better) (CR or better) D (CR or better)

15 Overall Survival 18-month OS* % D Proportion of patients alive %.2 No. at risk D HR:.64 (95% CI,.4-1.1; P =.534) Months *KM estimate. 18-month overall survival: 86% in D versus 76% in 15

16 Infusion-related Reactions (IRRs) IRRs 2% Safety Analysis Set (n = 283) All grades (%) Grade 3 (%) Patients with IRRs 48 5 Cough 9 Dyspnea 9.7 Vomiting 6.4 Nausea 5 Chills 5.4 Bronchospasm 5.4 Pruritus 3.4 Throat irritation 3 Headache 3 Nasal congestion 3 Wheezing 2.7 Laryngeal edema 2.4 Rhinorrhea 2 Pyrexia 2 No grade 4 or 5 IRRs were reported 92% of all IRRs occurred during the first infusion 1 patient discontinued daratumumab due to an IRR IRRs, infusion-related reactions. 16

17 Hematologic AEs Neutropenia Febrile neutropenia Most Common AEs All-grade (%) 25% 59 6 D (n = 283) (n = 281) Grade 3/4 (%) 5% 52 6 All-grade (%) 25% 43 3 Grade 3/4 (%) 5% Anemia Thrombocytopenia Lymphopenia Non-hematologic AEs Diarrhea Fatigue Upper respiratory tract infection Constipation Cough Muscle spasms Pneumonia Infections and infestations: Grade 3 or 4: 28% patients in D vs 23% patients in The most common grade 3 or 4 infections/infestations AE was pneumonia (8% vs 8%) 17

18 Lenalidomide-based Studies POLLUX D vs ASPIRE K vs 1 ELOQUENT-2 E vs 2,3 TOURMALINE-MM1 N vs 4 PFS HR (95% CI).37 ( ).69 ( ).73 (.6-.89).74 ( ) ORR 93% VGPR 76% CR 43% Duration of response, mo NE 87% 79% 78% 7% 33% 48% 32% 4% 14% OS HR (95% CI).64 (.4-1.1).79 ( ).77 ( ) NE 1. Stewart AK, et al. N Engl J Med. 215;372(2): Lonial S, et al. N Engl J Med. 215;373(7): Dimopoulos MA, et al. Blood. 215;126(23):Abstract Moreau P, et al. N Engl J Med. 216;374(17): K, carfilzomib; E, elotuzumab; N, ixazomib. 18

19 Conclusions Daratumumab- significantly improved PFS in comparison with alone D was associated with a 63% reduction in the risk of progression or death Treatment benefit of D versus was consistent across subgroups D doubled CR/sCR rates and quadrupled MRDnegative rates D has a manageable safety profile consistent with the known safety profile of daratumumab or alone Daratumumab combined with potentially represents a new standard of care for myeloma patients after 1 prior treatment 19

20 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 18 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 2