ClinicalTrials.gov Identifier: NCT

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1 Efficacy of Daratumumab, Bortezomib, and Dexamethasone Versus Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma Based on Prior Lines of Therapy: Updated Analysis of CASTOR Maria-Victoria Mateos, Jane Estell, 2 Wolney Barreto, 3 Paolo Corradini, 4 Chang-Ki Min, 5 Eva Medvedova, 6 Ming Qi, 7 Jordan Schecter, 8 Himal Amin, 8 Xiang Qin, 7 William Deraedt, 9 Tineke Casneuf, 9 Christopher Chiu, 7 A. Kate Sasser, 7 Ajay Nooka University Hospital of Salamanca/IBSAL, Salamanca, Spain; 2 Haematology Department, Concord Cancer Centre, Concord Hospital, Concord, NSW, Australia; 3 Hospital Santa Marcelina, Sao Paulo, Brazil; 4 Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy; 5 Seoul St. Mary s Hospital, The Catholic University of Korea, Seoul, South Korea; 6 Oregon Health & Science University, Portland, Oregon, USA; 7 Janssen Research & Development, LLC, Spring House, PA, USA; 8 Janssen Research & Development, LLC, Raritan, NJ, USA; 9 Janssen Research & Development, Beerse, Belgium; Winship Cancer Institute, Emory University, Atlanta, GA, USA. ClinicalTrials.gov Identifier: NCT23634

2 Background Daratumumab Human monoclonal antibody targeting CD38 Direct on-tumor and immunomodulatory MoA -5 Approved As monotherapy for heavily pretreated RRMM by the FDA, EMA, Health Canada, Mexico, and Singapore Combo with standard of care regimens for RRMM after prior therapy (POLLUX and CASTOR) by the FDA Early phase study of daratumumab in combination with bortezomib 6 Deep and durable responses Well tolerated with manageable adverse events CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated phagocytosis. MoA, mechanism of action; RRMM, relapsed or refractory multiple myeloma ; FDA, Food and Drug Administration; EMA, European Medicines Agency; CDC, complement-mediated cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cellular phagocytosis.. Lammerts van Bueren J, et al. Blood. 24;24. Abstract Overdijk MB, et al. J Immunol. 26;97(3): de Weers M, et al. J Immunol. 2;86(3): Overdijk MB, et al. MAbs. 25;7(2): Krejcik J, et al. Blood. 26;28(3): Mateos MV, et al. Presented at the 2 th Congress of the European Hematology Association; -4 June 25; Vienna, Austria. P275. 2

3 Study Design Multicenter, randomized, open-label, active-controlled, phase 3 study N = 498 Key eligibility criteria RRMM prior line of therapy Prior bortezomib exposure, but not refractory R A N D O M I Z E : (n = 25) Daratumumab (6 mg/kg IV) Every week: Cycles -3 Every 3 weeks: Cycles 4-8 V:.3 mg/m 2 SC on Days, 4, 8, and of Cycles -8 d: 2 mg PO-IV on Days, 2, 4, 5, 8, 9,, and 2 of Cycles -8 (n = 247) V:.3 mg/m 2 SC on Days, 4, 8, and of Cycles -8 d: 2 mg PO-IV on Days, 2, 4, 5, 8, 9,, and 2 of Cycles -8 D only Every 4 weeks: Cycles 9+ Obs only Primary endpoint PFS Secondary endpoints TTP OS ORR, VGPR, CR MRD Stratification factors ISS (I, II, and III) Number of prior lines ( vs 2 or 3 vs >3) Prior bortezomib (no vs yes) Cycles -8: repeat every 2 days Cycles 9+: repeat every 28 days Statistical analyses Planned to enroll 48 patients Primary analysis: ~77 PFS events Premedication for the treatment group consisted of dexamethasone 2 mg, acetaminophen, and an antihistamine, daratumumab, bortezomib and dexamethasone; IV, intravenous; V, bortezomib; SC, subcutaneously; d, dexamethasone; PO, orally; VD, bortezomib and dexamethasone; D, daratumumab; Obs, observation; PFS, progression-free survival; TTP, time to progression; OS, overall survival; ORR, overall response rate; VGPR, very good partial response; CR, complete response; MRD, minimal residual disease; ISS, International Staging System. 3

4 Baseline Demographic and Clinical Characteristics Characteristic (n = 25) (n = 247) Characteristic (n = 25) (n = 247) Age, y Median (range) 75, n (%) ISS staging, n (%) a I II III 64 (3-88) 23 (9) 98 (39) 94 (38) 59 (24) 64 (33-85) 35 (4) 96 (39) (4) 5 (2) Prior lines of therapy, n (%) Median 2 3 >3-3 c 2 (-9) 22 (49) 7 (28) 37 (5) 22 (9) 229 (9) 2 (-) 3 (46) 74 (3) 32 (3) 28 () 29 (89) Creatinine clearance (ml/min), n (%) N >3-6 > (2) 86 (77) (25) 63 (7) Prior ASCT, n (%) 56 (62) 49 (6) Prior PI, n (%) 69 (67) 72 (7) Prior IMiD, n (%) 79 (7) 98 (8) Median time from diagnosis, y (range) Cytogenetic profile, n (%) b N Standard risk High risk 3.87 (.7-2.7) (74) 44 (26) 3.72 (.6-8.6) (73) 5 (27) Prior PI + IMiD, n (%) 2 (45) 29 (52) Refractory to IMiD only, n (%) 74 (3) 9 (36) Refractory to last line of therapy, n (%) 76 (3) 85 (34) ASCT, autologous stem cell transplantation; PI, proteasome inhibitor; IMiD, immunomodulatory drug. a ISS staging is derived based on the combination of serum β2-microglobulin and albumin. b Centralized analysis using next-generation sequencing. Patients with high risk had t(4;4), t(4;6), or del7p abnormalities. c Exploratory. 4

5 Primary Analysis Results The primary endpoint was met at the primary analysis (7.4 months of median follow-up) Hazard ratio (HR):.39; 6% reduction in the risk of progression or death with versus Significantly higher and deeper responses for versus At the primary analysis, the independent data and safety monitoring committee recommended that patients with progressive disease receive daratumumab monotherapy CI, confidence interval; scr, stringent complete response; PR, partial response.. Palumbo A, et al. N Engl J Med. 26;375(8):

6 Objectives Updated outcome of the total patient cohort with longer-term follow-up Outcome in different subgroups of patients according to: Number of prior lines of therapy Minimal residual disease status Cytogenetic abnormalities Updated safety profile 6

7 Updated Efficacy % surviving without progression No. at risk 2-month PFS a 6% 22% HR:.33 (95% CI, ; P <.) Median: 7. months ORR, % CR 26% b ORR = 84% 7% 9% 35% 22% P <. VGPR 62% b CR % ORR = 63% 2% 8% 9% 34% (n = 24) (n = 234) VGPR 29% scr CR VGPR PR Median (range) follow-up: 3. (-2.3) months An additional 7% of patients receiving achieved CR with longer follow up Responses continue to deepen in the group with longer follow-up ITT, intent to treat. Note: PFS: ITT population; ORR: response-evaluable population. a Kaplan-Meier estimate. b P <. for versus. 7

8 PFS: Prior Lines of Treatment prior line 2 to 3 prior lines 2-month PFS a 2-month PFS a % surviving without progression % 25% Median: 7.9 months % surviving without progression Median: 9.8 months 44% 22% Median: 6.3 months No. at risk 3 22 HR:.22 (95% CI,.4-.34; P <.) HR:.5 (95% CI, ; P =.2) is superior to regardless of prior lines of therapy, with greatest benefit observed in prior line 27 4 a Kaplan-Meier estimate. 8

9 PFS by Prior Bortezomib Exposure: Prior Line Population % surviving without progression No prior bortezomib Prior bortezomib No prior bortezomib Prior bortezomib No. at risk No prior bortezomib - No prior bortezomib Prior bortezomib - Prior bortezomib provides treatment benefit regardless of prior bortezomib exposure 9

10 Time From Last Line of Therapy to Study Treatment of > or 2 >2 2 HR:.27 (95% CI,.7-.43; P <.) 2-month PFS a HR:.34 (95% CI, ; P <.) 2-month PFS a % surviving without progression % 32% Median: 9.4 months % surviving without progression % 3% Median:.3 months Median: 5.2 months No. at risk No. at risk is superior to regardless of time since last therapy a Kaplan-Meier estimate.

11 ORR by Prior Lines a prior line 2 to 3 prior lines P =.4 P =.22 ORR, % CR: 36% b ORR = 9% CR: 5% VGPR: 75% c ORR = 74% (n = 9) (n = 9) VGPR: 42% scr CR VGPR PR ORR, % CR: 9% d ORR = 79% VGPR: 52% c CR: 7% ORR = 58% 6 37 (n = 99) (n = ) VGPR: 2% scr CR VGPR PR More patients achieve a deeper response with after prior line of treatment a Response-evaluable population. b P =.6 for vs. c P <. for vs. d P =.33 for vs.

12 MRD rates by prior lines of therapy ITT (N = 498) prior line (n = 235) *** ** ** *** ** NS 25 5.X 4.3X 5.5X 6.6X 4.6X 3.2X MRD-negative rate, % Sensitivity MRD was evaluated by ClonoSEQ-NGS-based assay in a central lab at three sensitivity thresholds, for patients with suspected CR and also for patients who maintain CR at C9 and C5 MRD-negative rates for were 3-fold higher across all thresholds MRD-negative rate, % threshold ***P <.; **P <.; NS, not significant. P values calculated using likelihood-ratio chi-square test. MRD-negativity rate = proportion of patients with negative MRD test results at any time during treatment. 2

13 PFS: MRD Status ( 5 ) ITT prior line MRD negative MRD negative MRD negative MRD negative % surviving without progression MRD positive % surviving without progression MRD positive MRD positive MRD positive MRD negativity is associated with better outcomes 3

14 PFS: Cytogenetic Risk in All Evaluable Patients a % surviving without progression No. at risk std risk std risk high risk high risk std risk high risk std risk high risk High risk b Standard risk Median PFS, mo HR (95% CI) P value ORR, % P value n = 44 n = 23 n = 35 NR (.2-.43) <. n = 8 n = n = 5 Median PFS, mo HR (95% CI) P value.49 ( ).67 n = 44 n = 47 ORR, % P value.39 improves outcomes regardless of cytogenetic risk NR, not reached. a ITT/Biomarker risk evaluable analysis set. b Central next-generation sequencing. High-risk patients had any of t(4;4), t(4;6), or del7p. Standard-risk patients had an absence of high-risk abnormalities. 4

15 OS ITT OS events 8 37 (5%) in % surviving patients (24%) in OS HR for versus by prior lines: prior line = HR:.42 (95% CI,.9-.93) 2-3 prior line = HR:.54 No. at risk HR:.63 (95% CI, ) (95% CI, ) Curves are beginning to separate, but OS data are immature Median OS was not reached; results did not cross the prespecified stopping boundary. 5

16 Most Common TEAEs (All Patients): Updated Analysis (n = 243) (n = 237) Hematologic, n (%) All-grade Grade 3/4 All-grade Grade 3/4 25% a 5% a 25% a 5% a Thrombocytopenia 45 (6) (45) 5 (44) 78 (33) Anemia 67 (28) 36 (5) 75 (32) 38 (6) Neutropenia 45 (9) 32 (3) 23 () (5) Lymphopenia 32 (3) 24 () 9 (4) 6 (3) Nonhematologic, n (%) Peripheral sensory neuropathy 2 (49) (5) 9 (38) 6 (7) Diarrhea 83 (34) 9 (4) 53 (22) 3 () Upper respiratory tract infection 72 (3) 6 (3) 43 (8) (.4) Cough 66 (27) 3 (3) Fatigue 53 (22) 2 (5) 58 (25) 8 (3) Pneumonia 33 (4) 22 (9) 28 (2) 23 () Hypertension 22 (9) 6 (7) 8 (3) 2 (.8) Grade 3/4 TEAEs: 79% of patients versus 63% of patients Discontinuations due to TEAEs: 9% of patients versus 9% of patients b No new IRRs; incidence remains stable with longer follow up (45%) TEAE, treatment-emergent adverse event; IRR, infusion-related reaction. a Common TEAEs listed are either 25% all grade OR 5% grade 3/4. b arm treated for 8 cycles and arm treated until progressive disease, per protocol. 6

17 Conclusions PFS benefit continues to be maintained with over time is superior to regardless of prior lines of therapy Largest magnitude of benefit with is observed in patients with prior line of therapy 78% reduction in risk of progression or death for versus More patients in achieved deeper responses with longer follow-up Higher CR and MRD-negative rates MRD negativity translated into longer PFS is superior to regardless of cytogenetic risk or time since last therapy No new safety signals were reported These data further support the use of this newly approved regimen of in RRMM, with most benefit in patients with prior line of therapy 7

18 Acknowledgments Patients who participated in this study Investigators Data and safety monitoring committee Staff members involved in data collection and analyses David Soong and Christopher Velas 6 countries This study was funded by Janssen Research & Development, LLC Medical writing and editorial support were provided by Jason Jung, PhD, of MedErgy, and were funded by Janssen Global Services, LLC 8