Novel treatment strategies for multiple myeloma: a focus on oral proteasome inhibitors

Transcription

1 Novel treatment strategies for multiple myeloma: a focus on oral proteasome inhibitors Antonio Palumbo M.D. Takeda Pharmaceuticals International AG

2 Introduction

3 Multiple genetically-distinct subclones can occur in multiple myeloma Multiple genetically-distinct subclones are present at diagnosis 1 4 These evolve over time due to selective pressures from treatment and factors in the microenvironment 1,4 This clonal evolution can result in disease progression and treatment resistance 5 Figure adapted from: Bahlis N et al. Blood 2012;120: Bahlis N et al. Blood 2012;120:927 8; 2. Keats JJ et al. Blood 2012;120: ; 3. Bianchi G, Ghobrial IM. Curr Cancer Ther Rev 2014;10:70 9; 4. Bolli N et al. Nat Commun 2014;5:2997; 5. Brioli A et al. Br J Haematol 2014;165:

4 Acquired mutations through disease progression Median number of mutations Circos plots of translocations detected in SMM-MM pair samples Green lines in SMM only Red lines in both SMM and MM Orange lines in MM only MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; PCL, plasma cell leukemia; SMM, smoldering multiple myeloma. Walker BA et al. Leukemia 2014;28:

5 Most patients experience patterns of relapse and remission in multiple myeloma Disease progression in multiple myeloma 1 Adapted from Durie, Due to the multiple periods of response and remission, optimal treatment sequencing is an important consideration for patients throughout the continuum of care 1,2 References: 1. Durie BGM. Concise review of the disease and treatment options. International Myeloma Foundation. Accessed January 4, Mohty B et al. Leukemia. 2012;26(1):

6 PFS probability MRD and PET-CT sensitivity Serum tools 1.0 Negative PET-CT and MRD (47.7% of patients) vs positive PET-CT or MRD In the IFM/DFCI 2009 trial % Assay sensitivity Immunophenotype RQ-PCR NEXT-GENERATION SEQUENCE Cure P = % Time PET/CT: sensitivity of 50.0% CT, computed tomography; MRD, minimal residual disease; PET, positron emission tomography; PFS, progression-free survival; RQ-PCR, real-time quantitative polymerase chain reaction. 1. Paiva B et al. Blood 2015;125: ; 2. Moreau P et al. Presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5 8, 2015; Orlando, FL. Oral session 731, Number 395.

7 Patients (%) Continuous vs fixed duration: PFS advantage 72 wks Rd vs Rd18 vs MPT 1 MPR-R vs MPR vs MP 2 VMPT-VT vs VMP 3 Median (mo) Rd 25.5 Rd MPT 21.2 Median (mo) MPR-R 31 MPR 14 MP 13 Median (mo) VMP-VT 35.3 VMP Time (months) Time (months) Time (months) mo, months; MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide and lenalidomide maintenance; MPT, melphalan, prednisone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone; VMP, bortezomib, melphalan, prednisone; VMPT-VT, bortezomib, melphalan, prednisone, thalidomide and bortezomib, thalidomide maintenance. 1. Benboubker L et al. N Engl J Med 2014;371:906 17; 2. Palumbo A et al. N Engl J Med 2012;366: ; 3. Palumbo A et al. JCO 2014;32:

8 Continuous therapy vs fixed-duration therapy PFS and OS Pooled analysis of 3 phase III trials: (Italian Group for Hematologic Diseases in Adults [GIMEA] MM-03-05, RV-MM-PI-209, and CC MM-015) CT=continuous therapy; FDT=fixed-duration therapy; PD=progressive disease. Reference: 1. Palumbo A et al. J Clin Oncol. 2015;33(30):

9 PFS probability OS probability Maintenance vs no maintenance in patients achieving a complete response 1.00 PFS 12-month landmark analysis N = OS 12-month landmark analysis Median follow-up 43 months N = 1964 Maintenance P = HR = 0.58 Maintenance 0.50 P = 0.03 HR = 0.57 No maintenance year PFS: 42% vs 21% No maintenance Months Months HR, hazard ratio; OS, overall survival; PFS, progression-free survival. Cerrato C et al. Poster presented at: 57th American Society of Hematology (ASH) Annual Meeting & Exposition; December 5 8, 2015; Orlando, FL. Poster 1974.

10 Ixazomib clinical overview efficacy

11 TOURMALINE-MM1 evaluated long-term treatment* with ixazomib+lenalidomide+dexamethasone A global, phase 3, double-blind, placebo-controlled study of patients with relapsed and/or refractory multiple myeloma (N=722) Ixazomib Primary endpoint is PFS; secondary endpoints included OS, OS in del(17), ORR, PFS in patients with high-risk cytogenetics, and safety 2 Patients who were refractory to lenalidomide or PIs were excluded from the study *Defined as treatment to disease progression or unacceptable toxicity. Stratification: 1 vs 2 or 3 prior therapies; PI exposed vs PI naïve; and ISS stage I or II vs III. Defined as patients with del(17), t(4;14), and/or t(14;16). ECOG=Eastern Cooperative Oncology Group; ISS=International Staging System; ORR=overall response rate; OS=overall survival; PFS=progression-free survival; PI=proteasome inhibitor. References: 1. Data on File 103, Takeda Pharmaceuticals International Co. 2. Data on File 100, Takeda Pharmaceuticals International Co. 3. Data on File 101. Takeda Pharmaceuticals International Co. 10

12 TOURMALINE-MM1 included a broad range of patients Patients who were refractory to lenalidomide or PIs were excluded from the study *Stratification factor. len+dex=lenalidomide+dexamethasone. 11

13 TOURMALINE-MM1 included patients with renal impairment, primary refractory multiple myeloma, high-risk cytogenetics, and free light chain disease Many patients had decreased kidney function 23% of patients had light chain disease and 12% of patients had free light chain measurable only disease Primary refractory was defined as best response of stable disease or disease progression on all prior lines of therapy. Primary refractory status was documented in 7% and 6% of patients in the NINLARO (ixazomib) regimen and the placebo regimen, respectively. 12

14 The Ixazomib regimen extended median PFS by ~6 months vs the placebo regimen At a median follow-up of 23 months, a planned interim OS analysis and noninferential PFS analysis were conducted No OS advantage was observed; data were immature and the study remains ongoing The PFS analysis supported a clinical benefit of the NINLARO regimen (median PFS: 20 months vs 15.9 months; HR=0.82 [95% CI, ]) NE=not evaluable. Reference: 1. Moreau P et al. N Engl J Med. 2016;374(17):

15 The ixazomib regimen extended median PFS by ~6 months vs the placebo regimen At a median follow-up of 23 months, a planned interim OS analysis and noninferential PFS analysis were conducted No OS advantage was observed; data were immature and the study remains ongoing The PFS analysis supported a clinical benefit of the NINLARO regimen (median PFS: 20 months vs 15.9 months; HR=0.82 [95% CI, ]) NE=not evaluable. Reference: 1. Moreau P et al. N Engl J Med. 2016;374(17):

16 Response rates demonstrated in TOURMALINE-MM1 ~50% of patients achieved VGPR with the ixazomib regimen. *ORR=CR+PR, including VGPR. CR=complete response; PR=partial response; VGPR=very good partial response. 15

17 Responses deepened with continued ixazomib treatment The study was not powered to detect differences in response rates Responses improved over time in both arms of the study Reference: 1. Moreau P et al. N Engl J Med. 2016;374(17):

18 PFS analysis in select patient populations 1 This study was not powered to show significance in PFS across these prespecified subgroups Other prespecified subgroups not included in this figure were gender, race, region, Western countries, prior bortezomib exposure, thalidomide refractory, creatinine clearance at baseline, and ECOG performance status 2 The PFS results in these subgroups were consistent with those represented in this figure 2 ECOG=Eastern Cooperative Oncology Group; ISS=International Staging System; PI=proteasome inhibitor; PFS=progression-free survival. References: 1. Moreau P et al. N Engl J Med. 2016;374(17): Data on File 120, Takeda Pharmaceuticals International Co. 17

19 Positive PFS trends seen across select prespecified subgroups Median PFS in prespecified subgroups (months) 1-3 Cytogenetic risk data were not available for 24% of patients in the study 1 *Defined as patients with del(17p), t(4;14), and/or t(14;16). ECOG=Eastern Cooperative Oncology Group; PFS=progression-free survival. References: 1. Moreau P et al. N Engl J Med. 2016;374(17): Data on File 121, Takeda Pharmaceuticals International Co. 3. Richardson PG et al. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2016; Chicago, IL. 18

20 Ixazomib clinical overview safety Important Safety Information will be discussed throughout this presentation. Please see NINLARO full Prescribing Information provided at this presentation.

21 Summary of most common nonhematologic ARs Nonhematologic ARs occurring in 5% of patients with a 5% difference between the NINLARO (ixazomib) regimen and placebo+len+dex *Represents a pooling of preferred terms. ARs=adverse reactions. 20

22 Pooled hematologic adverse events and laboratory data Thrombocytopenia associated with the NINLARO (ixazomib) regimen followed a cyclical pattern and typically recovered to baseline by the start of the next cycle Rates of platelet transfusions were 6% and 5% in the NINLARO regimen and the placebo regimen, respectively Discontinuations due to thrombocytopenia were <1% and 2%, respectively Incidence of neutropenia was similar among both arms 21

23 Additional information about thrombocytopenia 1 Rates of thrombocytopenia (including both adverse events and lab abnormalities) were 78% for the NINLARO (ixazomib) regimen and 54% for placebo+len+dex (grade 3-4: 26% vs 11%, respectively) Rates of platelet transfusions were 6% and 5%, respectively Reference: 1. Data on File 110, Takeda Pharmaceuticals International Co. 22

24 Administration guidelines 23

25 Important Safety Information Warnings and Precautions: Gastrointestinal Toxicities Gastrointestinal toxicities include diarrhea, constipation, nausea and vomiting and were reported with ixazomib May occasionally require the use of antidiarrheal and antiemetic medications, and supportive care Diarrhea resulted in the discontinuation of one or more of the three drugs in 1% of patients in the ixazomib regimen and < 1% of patients in the placebo regimen Adjust dosing for severe symptoms *Occurring in 5% of patients with a 5% difference between the Ixazomib regimen and the placebo regimen. Important Safety Information continues on next slide. 24

26 The NINLARO (ixazomib) regimen demonstrated a safety profile amenable to treatment to progression The most common ARs ( 20%) in the NINLARO regimen and greater than the placebo regimen, respectively, were diarrhea (42%, 36%), constipation (34%, 25%), thrombocytopenia (78%, 54%; pooled from adverse events and laboratory data), peripheral neuropathy (28%, 21%), nausea (26%, 21%), peripheral edema (25%, 18%), vomiting (22%, 11%), and back pain (21%, 16%). Serious ARs reported in 2% of patients included thrombocytopenia (2%) and diarrhea (2%). ARs=adverse reactions. Reference: 1. Data on File 117, Takeda Pharmaceuticals International Co. Please see additional Important Safety Information throughout and full Prescribing Information provided at this presentation. 25

27 Sample schedule of the NINLARO (ixazomib) dosing regimen Administration schedule for days 1, 8, and 15 of a 28-day schedule Dexamethasone should be taken with food. Patients may benefit from the antiemetic properties of dexamethasone 1 Taking lenalidomide in the evening is suggested because of its sedative effect 2 *Dexamethasone is taken on days 1, 8, 15, and 22 of a 28-day treatment cycle. NINLARO is taken on days 1, 8, and 15 of a 28-day treatment cycle. Lenalidomide is taken daily on days 1 to 21 of a 28-day treatment cycle. References: 1. Chu C-C et al. Eur J Pharmacol. 2014;722: Drug record: thalidomide, lenalidomide. National Institutes of Health. Accessed January 4,

28 Dosing considerations No body surface area dosing is required *Creatinine clearance <30 ml/min. 27

29 Dose modification guidelines *For the second occurrence, repeat steps except resume NINLARO at the next lower dose and resume lenalidomide at its most recent dose. For additional occurrences, alternate dose modification of NINLARO and lenalidomide. Refer to the NINLARO (ixazomib), lenalidomide, and/or dexamethasone Prescribing Information for full details. 28

30 Dose modification guidelines (cont d) Refer to the NINLARO (ixazomib), lenalidomide, and/or dexamethasone Prescribing Information for full details. PN=peripheral neuropathy. 29

31 Concomitant medications may be given for prophylaxis and/or management of symptoms These medications and supportive therapies are examples of appropriate supportive care that were permitted in the phase 3 trial Proactively managing symptoms may help patients with NINLARO (ixazomib) treatment References: 1. Data on File 113, Takeda Pharmaceuticals International Co. 2. Data on File 109, Takeda Pharmaceuticals International Co. 3. Data on File 114, Takeda Pharmaceuticals International Co. 4. Data on File 115, Takeda Pharmaceuticals International Co. Please see Important Safety Information throughout and full Prescribing Information provided at this presentation. 30

32 Special populations to consider Hepatic Impairment: Reduce the NINLARO (ixazomib) starting dose to 3 mg in patients with moderate or severe hepatic impairment. No dose adjustments for patients with mild hepatic impairment Renal Impairment: Reduce the NINLARO starting dose to 3 mg in patients with severe renal impairment or end-stage renal disease requiring dialysis. No dose adjustments for patients with mild or moderate renal impairment Refer to the lenalidomide Prescribing Information for dosing recommendations in patients with renal impairment NINLARO is not dialyzable and therefore can be administered without regard to the timing of dialysis Lactation: Advise nursing women not to breastfeed during treatment with NINLARO and for 90 days after the last dose. Please see full Prescribing Information provided at this presentation. 31

33 Ixazomib clinical overview conclusion Important Safety Information will be discussed throughout this presentation. Please see NINLARO full Prescribing Information provided at this presentation.

34 3 major independent classes of drugs Is 3 drug combo better than two drug combo? PI IMIDs MoAb Agents Administration Treatment duration Limiting toxicities Bortezomib IV/SC Fix Periph. Neuropathy Thalidomide Oral Continuous Periph. Neuropathy Elotuzumab IV Fix Inf.Reaction Agents Administration Treatment duration Limiting toxicities Carfilzomib IV Fix Cardiovascular Lenalidomide Oral Continuous SPM Daratumumab IV Fix IR Agents Administration Treatment duration Limiting toxicities Ixazomib Oral Continuous GI Pomalidomide Oral Continuous Infections All three classes of drugs are essential in the treatment of MM In the clinic synergistic activities with the combination of different classes 33

35 TUMOR BULK Is response.. % of treatment efficacy?? Is continuous therapy..% of treatment efficacy?? Presentation 10 9 PR VGPR CR Induction 2. Transplant 3. Consolidation Relapse 4. Continuous therapy Relapse scr Relapse Potentialcure? Relapse Potential cure? CR, complete response; scr, stringent complete response; VGPR, very good partial response Confidential and Proprietary Business Information. For Internal Use Only. Time to progression Morgan GJ. Blood 2013;122:1332 4

36 OS Probability (%) Is continuous therapy is even more important in real words?? When duration of therapy is much shorter than in clinical trials? 16 months Kaplan-Meier Estimate of Overall Survival in a Meta-analysis of Clinical Trials 1 n Death Continuous therapy Fixed-duration therapy HR, 0.69; 95% CI, ; P= Months Probability of Treatment Discontinuation (%) 100 Kaplan-Meier Estimates of Duration by Regimen in Real Life 2 Median duration of therapy Lenalidomide-based (10.1 mo Bortezomib-based (6.6 mo) Other regimens (4.8 mo) Carfilzomib-based (4.6 mo) Months Adapted from Palumbo et al, J Clin Oncol, Romanus D st European Hematology Association Congress

37 36 Duration of therapy and PFS ASPIRE (KRd vs Rd in Relapsed MM) POLLUX (DRd vs Rd in RRMM) ALCYONE (D-VMP vs VMP in NDMM) Though these studies were not designed to show impact of long duration treatment, does the change of shape of the PFS curves impact how you think about using these agents? References: 1. Dimopoulos MA et al. N Engl J Med Oct 6;375(14): Mateos MV et al. Engl J Med Feb 8;378(6): Stewart AK et al. N Engl J Med Jan 8;372(2):

38 Conclusion Continuous therapy more effective than fixed duration Efficacy: 3 drugs > 2 drugs, all oral PI/IMiD triplet HR for PFS similar among different studies (except daratumumab) Safety: good safety profile among PI/IMiD triplet Convenience: all oral, simple, fix dose, weekly administration Future: improve clinical efficacy PI/MoAb triplet 37