Elotuzumab is a humanized monoclonal antibody designed to treat multiple myeloma (MM)

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1 A Phase 2 Study of in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/ Refractory Multiple Myeloma: Updated Results Paul G. Richardson, 1,2 Sundar Jagannath, 2,3 Philippe Moreau, 4 Andrzej J. Jakubowiak, 2,5 Marc S. Raab, 6 Thierry Facon, 7 Ravi Vij, 2,8 Darrell White, 9 Donna E. Reece, 10 Lotfi Benboubker, 11 Jeffrey Zonder, 2,12 Wei Deng, 13 Glenn Kroog, 14 Anil K. Singhal, 13 Sagar Lonial, 2,15 on behalf of the 1703 Study Investigators 1 Dana-Farber Cancer Institute, Boston, MA, USA; 2 Multiple Myeloma Research Consortium, Norwalk, CT, USA; 3 Mount Sinai Medical Center, New York, NY, USA; 4 Hematology Department, University Hospital, Nantes, France; 5 University of Chicago, Chicago, IL, USA; 6 Universitaetsklinikum Heidelberg, Heidelberg, Germany; 7 Hopital Claude Huriez, Service des Maladies du Sang, Lille, France; 8 Washington University School of Medicine, St. Louis, MO, USA; 9 Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; 10 Princess Margaret Hospital, Toronto, Ontario, Canada; 11 CHU Tours-Hopital Bretonneau, Tours, France; 12 Karmanos Cancer Institute, Detroit, MI, USA; 13 Abbott Biotherapeutics Corporation, Redwood City, CA, USA; 14 Bristol-Myers Squibb, Princeton, NJ, USA; 15 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA 1

2 is a humanized monoclonal antibody designed to treat multiple myeloma (MM) specifically targets CS1, which is highly expressed on the surface of myeloma cells enhances NK cell-mediated killing of myeloma cells primarily via ADCC1,2 1. Hsi et al. Clin Cancer Res. 2008; 2. Tai et al. Blood ADCC = antibody-dependent cellular cytotoxicity. 2

3 Study Design: Phase II (Study 1703) Phase 1* N=28 Phase 2 N=73 R A N D O M I Z E 10 mg/kg IV + Len/dex n=36 20 mg/kg IV + Len/dex n=37 P R O G R E S S I O N N Phase 2: Pts (n=73) with relapsed and/or refractory MM with 1-3 prior therapies were randomized to elotuzumab 10 or 20 mg/kg IV combined with Lenalidomide 25 mg PO Low-dose dexamethasone 40 mg PO Endpoints Primary: ORR ( PR per IMWG Criteria) Key secondary endpoints: PFS and safety Len/dex: lenalidomide plus low dose dexamethasone Progression defined by IMWG Criteria. *Lonial et al. J Clin Oncol

4 Dose and Schedule Phase II (Study 1703) Response Assessments Dosing CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 4 CYCLE N-1 5 CYCLE 6N Lenalidomide daily dose daily dose daily dose daily dose daily dose daily dose Cycle day Dexamethasone Treatment continued until disease progression or unacceptable toxicity Pre-medication (30-60 min prior) included: methylprednisolone 50 mg IV or dexamethasone 8 mg IV, diphenhydramine mg PO or IV (or equivalent), ranitidine 50 mg IV (or equivalent), and acetaminophen mg PO Current data as of October 19,

5 Key Eligibility Criteria Phase II (Study 1703) Inclusion Relapsed and/or refractory MM with 1-3 prior therapies Measurable disease by M protein Creatinine clearance 50 ml/min (Cockcroft-Gault method) Exclusion Prior lenalidomide Thalidomide, bortezomib, or corticosteroids within 2 weeks of the first elotuzumab dose 5

6 Baseline Demographics Phase II (Study 1703) 10 mg/kg 20 mg/kg Total Patients, n Age, median years (range) 63 (39-77) 63 (41-82) 63 (39-82) Years since first diagnosis, median (range) 4.7 ( ) 4.4 ( ) 4.5 ( ) 2 prior therapies, n (%) 20 (56) 20 (54) 40 (55) Prior transplant (autologous), n (%) 32 (89) 28 (76) 60 (82) Refractory to last therapy, n (%) 12 (33) 12 (32) 24 (33) High-risk cytogenetics*, n (%) 8 (22) 2 (5) 10 (14) β2 microglobulin 3.5 mg/l, n (%) 18 (50) 15 (41) 33 (45) Prior bortezomib, n (%) 22 (61) 22 (60) 44 (60) Prior thalidomide, n (%) 21 (58) 24 (65) 45 (62) * Defined as del13q by metaphase or t(4;14), t(14;16) or del17p by fluorescence in situ hybridization. 6

7 Patient Disposition Phase II (Study 1703) 10 mg/kg 20 mg/kg Total Total enrolled (ITT population), n Number of cycles*, median (range) 21.5 (3-34) 16 (1-35) 17 (1-35) Still on study (receiving study drugs), n (%) 14 (39) 10 (27) 24 (33) Treatment cessation, n (%) 22 (61) 27 (73) 49 (67) Disease progression Adverse event Other *28 days per cycle. Reasons include: investigator decision (n=4; M-protein level progression, patient eligible for transplant, little biological progression, clinical and radiological progression), patient decision (n=7; relocation [n=2], consent withdrawn [n=2], declined further treatment [n=2], distance/financial impact). ITT = intent-to-treat 7

8 Efficacy: Best Response Phase II (Study 1703) 10 mg/kg 20 mg/kg Total Patients, n ORR ( PR), n (%) 33 (92) 28 (76) 61 (84) CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12) VGPR, n (%) 17 (47) 14 (38) 31 (43) PR, n (%) 11 (31) 10 (27) 21 (29) <PR, n (%) 3 (8) 9 (24) 12 (16) Overall median time to response: 1 month (range, ) Overall median time to best response: 2.5 months (range, ) Median duration of objective response: 17.8 months (range, ) 8

9 Efficacy: Maximum Percent Reduction in Serum M Protein* Percentage Change from Baseline mg/kg (n=36) mg/kg (n=29) Percentage Change from Baseline *Maximum percentage decrease from baseline to 60 days after permanent discontinuation of elotuzumab or start of new line of MM therapy. Eight pts without measurable disease (baseline and all on-study serum M-protein levels <0.5 g/dl) were not included. 9

10 Progression Free Survival Proportion of Progression Free Patients (%) Median Time to Progression/Death: 10 mg/kg (n=36): not yet reached 20 mg/kg (n=37): 18.6 mos (95% CI ) 10 mg/kg Number at Risk: Months At a median follow-up of 20.8 months, median PFS has not been reached in the 10 mg/kg arm 20 mg/kg Preliminary median PFS of 26.9 months was reported in the abstract; after 2.7 months of additional follow-up, no new PD or death reported. These pts had an increased PFS duration, and in the updated analysis, median PFS was not yet reached 10

11 Best Response by Number of Prior Therapies No. of Prior Therapies 1 Parameter 10 mg/kg 20 mg/kg Total Patients, n ORR ( PR), n (%) 16 (100) 14 (82) 30 (91) VGPR, n (%) 11 (69) 7 (41) 18 (55) Patients, n ORR ( PR), n (%) 17 (85) 14 (70) 31 (78) VGPR, n (%) 11 (55) 11 (55) 22 (55) Median PFS was 29.7 months for pts treated with 1 prior therapy and 19.5 months for pts treated with 2 prior therapies ORR = objective response rate; PR = partial response; VGPR = very good partial response 11

12 Best Response and PFS by Cytogenetics n (%) High risk* n = 10 Standard risk n = 63 ORR ( PR) 8 (80) 53 (84) VGPR 5 (50) 35 (56) Median PFS (months) *Defined as del13q by metaphase or t(4;14), t(14;16) or del17p by FISH Compared to 54% at previous data cut (April 27, 2012) 1 FISH = fluorescence in situ hybridization; ORR = objective response rate; PFS = progression free survival; PR = partial response; VGPR = very good partial response 1. Moreau P et al. J Clin Oncol 2012;Abstract

13 Treatment-emergent AEs (Any Grade 25% or Grade 3/4 5%) 10 mg/kg, n=36 20 mg/kg, n=37 Preferred Term, n (%) Any Grade Grade 3/4 Any Grade Grade 3/4 Diarrhea 21 (58) 3 (8) 23 (62) 2 (5) Muscle spasms 20 (56) 2 (6) 23 (62) 0 Fatigue 21 (58) 3 (8) 17 (46) 2 (5) Constipation 17 (47) 0 19 (51) 0 Nausea 16 (44) 0 16 (43) 1 (3) Upper respiratory tract infection 18 (50) 1 (3) 14 (38) 1 (3) Pyrexia 14 (39) 1 (3) 16 (43) 1 (3) Anemia 16 (44) 5 (14) 12 (32) 5 (14) Insomnia 10 (28) 0 13 (35) 1 (3) Peripheral edema 13 (36) 0 10 (27) 1 (3) Back pain 15 (42) 2 (6) 7 (19) 1 (3) Hyperglycemia 8 (22) 2 (6) 12 (32) 5 (14) Thrombocytopenia 13 (36) 6 (17) 7 (19) 6 (16) Lymphopenia 11 (31) 9 (25) 8 (22) 5 (14) Neutropenia 11 (31) 6 (17) 8 (22) 7 (19) Leukopenia 8 (22) 3 (8) 5 (14) 4 (11) Hypokalemia 6 (17) 3 (8) 6 (16) 1 (3) Pneumonia 4 (11) 3 (8) 5 (14) 2 (5) Infusion reactions 6 (17) 1 (3) Rash 4 (11) 0 *Grade 5: 1 patient, pneumonia complicated by cellulitis and sepsis leading to multi-organ failure AEs identified by the investigator as likely to be infusion reactions. Pts were premedicated with a steroid-based regimen to reduce the frequency and severity of infusion reactions. The 4 most common AEs of any Grade and Grade 3/4 are highlighted. SPM, 4 cases (1 prostate, 1 bladder, 1 MDS, 1 nasal squamous cell). 13

14 Conclusions Phase II (Study 1703) plus lenalidomide and low-dose dexamethasone has a high ORR in relapsed and relapsed/refractory MM* overall 84% ORR, with 92% for pts treated with elotuzumab 10mg/kg (dose in the Phase III program) overall ORR of 91% in pts who had received only 1 prior therapy Median PFS for elotuzumab 10mg/kg + Len/dex was not yet reached (median follow-up of 20.8 months)* median PFS was 29.7 months for pts treated with 1 prior therapy median PFS for elotuzumab 20 mg/kg + Len/dex was 18.6 months + Len/dex was generally well tolerated at both the 10 and 20 mg/kg doses most common Grade 3/4 treatment-emergent AEs : lymphopenia (19%), neutropenia (18%), and thrombocytopenia (16%) *An ORR of 60-61% and median TTP of months was observed in two randomized Phase III studies of lenalidomide plus high dose dexamethasone with similar patient populations. 1,2 Across 10 and 20 mg/kg doses. 1. Weber, et al. N Engl J Med 2007; 2. Dimopoulos, et al. N Engl J Med

15 Future Directions Two Phase III trials of 10 mg/kg elotuzumab plus Len/dex are ongoing ELOQUENT 1 in previously untreated MM pts (CA ; NCT ) ELOQUENT 2 in relapsed/refractory MM pts (CA ; NCT ) Additional trials of elotuzumab in MM are ongoing Bortezomib + dex ± elotuzumab in relapsed/refractory MM (CA ; NCT ) + thalidomide + dex in relapsed/refractory MM (CA ; NCT ) in high-risk smoldering MM (CA ; NCT ) + Len/dex in MM with impaired renal function (CA ; NCT ) Additional combination studies are planned 15

16 Acknowledgments The authors and sponsors wish to thank the patients and their families, as well as the 1703 study investigators and the Multiple Myeloma Research Consortium for their participation in this study The investigational drug elotuzumab is being developed in a partnership between Bristol-Myers Squibb and Abbott Biotherapeutics Corp. This study was sponsored by Bristol-Myers Squibb and Abbott Biotherapeutics Corp. Editorial support and graphic services were provided by StemScientific and funded by both companies Centers: CHU Tours-Hôpital Bretonneau, Tours, France; Dana-Farber Cancer Institute, Boston, MA Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA; Hôpital Claude Huriez, Service des Maladies du Sang, Lille, France. Karmanos Cancer Institute, Detroit. Mt Mount Sinai Medical Center, New York, NY Princess Margaret Hospital, Toronto, Ontario, Canada; Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada. Universitaetsklinikum Heidelberg, Heidelberg, Germany. University Hospital, Nantes, France University of Michigan Comprehensive Cancer Center, Ann Arbor, MI; Washington University School of Medicine, St. Louis, MO 16

Novel Therapeutics for Multiple Myeloma

Novel Therapeutics for Multiple Myeloma Marc S. Raab, MD Max-Eder-Group Experimental Therapies for Hematologic Malignancies Department of Medicine V, Heidelberg University Medical Center & German Cancer