Methods: Studies included in the analysis

Transcription

1 Efficacy and safety of long-term ixazomib maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing transplant: An integrated analysis of four phase 1/2 studies Meletios A. Dimopoulos, 1 Jacob Laubach, 2 Maria Asuncion Echeveste Gutierrez, 3 Norbert Grząśko, 4 Craig C. Hofmeister, 5 Jesus F. San Miguel, 6 Shaji K. Kumar, 7 Vickie Lu, 8 Zhaoyang Teng, 8 Guohui Liu, 8 Catriona Byrne, 8 Deborah Berg, 8 Richard Labotka, 8 Helgi van de Velde, 8 Paul G. Richardson 2 1 National and Kapodistrian University of Athens, Athens, Greece; 2 Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 3 Hospital Universitario Donostia, San Sebastian, Spain; 4 St. John s Cancer Center and Medical University of Lublin, Lublin, Poland; 5 The Ohio State University, Columbus, OH, USA; 6 Clínica Universidad de Navarra, Centro Investigación Medica Aplicada (CIMA), IDISNA, CIBERONC, Pamplona, Spain; 7 Mayo Clinic, Rochester, Minnesota, USA; 8 Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited

2 Introduction There is increasing evidence for the clinical benefit of long-term, continuous therapy for newly diagnosed multiple myeloma (NDMM) patients 1,2 Proteasome inhibitors (PIs) form a backbone of therapy for multiple myeloma patients (MM) 1,2 However, long-term therapy with the PIs bortezomib and carfilzomib may be limited due to toxicity and the need for regular parenteral administration, which can increase treatment burden 3 7 Ixazomib is the first oral PI to be approved in MM, for use in combination with lenalidomide-dexamethasone (Rd) in patients who have received 1 line of prior therapy 8 Ixazomib has been studied in NDMM in four phase 1/2 studies: 9 13 Once- or twice-weekly ixazomib plus Rd, melphalan-prednisone, or cyclophosphamide-dexamethasone was administered as induction therapy (~1 year), followed by single-agent ixazomib maintenance We report an integrated analysis of patients from these studies who did not undergo autologous stem cell transplant (ASCT) and received ixazomib maintenance therapy 1. Moreau P, et al. Ann Oncol 2;28:iv52 iv61; 2. Palumbo A, et al. J Clin Oncol 214;32:587 6; 3. Sonneveld P, et al. J Clin Oncol 212;3: ; 4. Sun CY, et al. Biosci Rep 2;37; 5. Niesvizky R, et al. J Clin Oncol 215;33:3921 9; 6. Bonnet A, et al. Expert Opin Drug Saf 2;16:973 8; 7. Kumar SK, et al. Leukemia 2;:243 51; 8. NINLARO (ixazomib) capsules, for oral use. US PI 216; 9. Dimopoulos MA, et al. Haematologica 2;12:111; 1. Kumar SK, et al. Haematologica 2;12:142 3; 11. Kumar SK, et al. Lancet Oncol 214;15:153 12; 12. Richardson PG, et al. Haematologica 2;12:3 8; 13. San Miguel JF, et al. Haematologica 2;12:111 2.

3 Methods: Studies included in the analysis Study C165 (NCT12957) C168 (NCT ) C166 (NCT13685) C162 (NCT2467) Phase ASCT eligibility 1/2 Eligible or ineligible 1/2 Eligible or ineligible Induction treatment Weekly ixazomib + Rd Up to 12 x 28-d cycles of IRd Ph.1: weekly ixazomib mg/m² Ph.2: RP2D 4. mg Twice-weekly ixazomib + Rd Up to 16 x 21-d cycles of IRd Ph.1: twice-weekly ixazomib mg Ph.2: RP2D 3. mg 1/2 Ineligible Once-/twice-weekly ixazomib + MP 13 x 28-d cycles or 9 x 42-d cycles of IMP Ph.1: ixazomib mg weekly, or mg twice-weekly Ph.2: RP2D 4. mg weekly 2 Ineligible Weekly ixazomib + Cd Ixazomib 4. mg for up to 13 x 28-d cycles of ICd Patients completing induction with SD and who were not withdrawn for ASCT in the IRd studies (C165 and C168) proceeded to maintenance Maintenance treatment: single-agent ixazomib Weekly: day 1, 8, and 15, in 28-d cycles Twice-weekly: day 1, 4, 8, and 11, in 21-d cycles Weekly: day 1, 8, and 15, in 28-d cycles Weekly: day 1, 8, and 15, in 28-d cycles At the last tolerated dose during induction Until PD, death, or unacceptable toxicity Cd, cyclophosphamide and low-dose dexamethasone; d, day; ICd, ixazomib plus cyclophosphamide and low-dose dexamethasone; IMP, ixazomib plus melphalan and prednisone; IRd, ixazomib plus lenalidomide and low-dose dexamethasone; MP, melphalan and prednisone; PD, progressive disease; Rd, lenalidomide and low-dose dexamethasone; RP2D, recommended phase 2 dose; SD, stable disease.

4 Methods: Outcomes and analyses Patient eligibility criteria Age 18 years Previously untreated, symptomatic MM Measurable disease ECOG PS 2 Adequate renal, hepatic, and hematologic function No grade 2 PN C165 (NCT12957) Weekly ixazomib + Rd C168 (NCT ) Twice-weekly ixazomib + Rd C166 (NCT13685) Once-/twice-weekly ixazomib + MP C162 (NCT2467) Weekly ixazomib + Cd Pooled integrated analysis Non-ASCT NDMM patients who completed induction with SD and received 1 dose of single-agent ixazomib maintenance therapy* Outcomes and analyses PFS and OS: From start of study treatment From start of maintenance Response Safety *During maintenance, single-agent ixazomib was given at the last tolerated dose during induction. Patients from study C162 were not included in the OS analysis because OS was not a protocol-specified endpoint in this study. ECOG PS, Eastern Cooperative Oncology Group performance status; OS, overall survival; PFS, progression-free survival; PN, peripheral neuropathy.

5 121 patients proceeded to single-agent ixazomib maintenance therapy Characteristic Weekly IRd (n=25) Twice-weekly IRd (n=18) IMP (n=) ICd (n=43) All patients (N=121) Median age (range), years 69. (34 77) 65. (53 78) 74. (63 9) 73. (61 84) 72. (34 9) Age 65 years, % Male, % White, % Type of myeloma, % IgG/IgA/Other* LC only kappa/lambda 6/2/4 8/8 61/28/ 6/6 6/37/ 3/ 65/26/2 7/ 62/28/2 6/2 ISS stage I/II/III, % 56/4/4 44/44/11 4/29/31 49/3/21 47/34/19 ECOG PS /1/2, % 64/32/4 56/44/ 23/66/11 33/47/21 4/49/12 Creatinine clearance, % 6 ml/min >6 ml/min High-risk cytogenetics, n (%) 2 (8) 3 () 2 (6) 5 (12) 12 (1) *Includes: IgD, IgM and unknown. Include: del(p), t(4;14), and/or t(14;16). Ig, immunoglobulin; ISS, International Staging System; LC, light chain.

6 Treatment exposure to single-agent ixazomib maintenance Treatment exposure* Maintenance (N=121) Median duration of maintenance, months (range) 1.6 ( ) Weekly IRd Twice-weekly IRd IMP ICd 26.7 ( ) 12. ( ) 1.6 ( ) 9.9 ( ) Ixazomib maintenance treatment for >2 years, n (%) 25 (21) Mean ixazomib RDI, % (SD) 89.1 (15.3) Ixazomib dose reductions, n (%) 19 (16) Ixazomib treatment discontinuations, n (%) 94 (78) PD 66 (55) AEs 8 (7) Patient withdrawal 6 (5) Study terminated by sponsor 4 (3) Other reasons 1 (8) * Data cut-off dates: C168 and C165: October 18, 216; C166: December 29, 216; C162: June 29, 216. Overall median treatment duration was 23. (range ) months across all treatment (induction + maintenance). Ixazomib dose reductions occurred in 5 (41%) patients overall across all treatment (induction + maintenance). AEs, adverse events; RDI, relative dose intensity; SD, standard deviation.

7 Efficacy: PFS from time of study entry Probability of PFS Median PFS (95% CI), months Overall: 33.8 ( ) Weekly IRd: 37.2 ( ) Twice-weekly IRd: 37.6 (18.9 NE) IMP: 27.5 ( ) ICd: NE (21.8 NE) Time (months) No. of patients at risk: All C C168 C C Study: All C165 C168 C166 C162 Median PFS from time of study entry for patients receiving weekly ixazomib 4. mg during maintenance: 37.2 months (95% CI: ) Overall 2-year PFS from time of study entry was 61% 2-year PFS estimate for patients with high-risk cytogenetics (n=12) was 51% (95% CI: 18 77) Median follow-up: 52.9 months. PFS measured from the start of all treatment (induction + maintenance). NE, not estimable.

8 Landmark analysis: PFS from start of single-agent ixazomib maintenance Probability of PFS No. of patients at risk: All C165 C168 C166 C162 Median PFS (95% CI), months Overall: 21.4 ( ) Weekly IRd: 25.8 ( ) Twice-weekly IRd: 26.3 (5.7 NE) IMP: 15.4 ( ) ICd: NE (9.7 NE) Time (months) Study: All C165 C168 C166 C162 Median PFS from start of maintenance for patients receiving weekly ixazomib 4. mg during maintenance: 25.3 months (95% CI: ) 2-year PFS in the combined population from start of maintenance was 47% 2-year PFS estimate for patients with high-risk cytogenetics (n=12) was 56% (95% CI: 24 79) Median follow-up: 41.2 months.

9 Landmark analysis: OS from start of single-agent ixazomib maintenance 1. Survival probability No. of patients at risk: All C165 C168 C166 Median OS (95% CI), months Overall: NE (NE NE) Weekly IRd: NE (NE NE) Twice-weekly IRd: NE (3.9 NE) IMP: NE (39.1 NE) Time (months) Study: All C165 C168 C166 3-year OS estimate from start of maintenance for patients receiving weekly ixazomib 4. mg during maintenance: 92% (95% CI: 71 98) Combined 3-year OS from start of maintenance: 82% (95% CI: 71 89) Median OS was not reached

10 Best confirmed response Patients (%) ORR 93% ORR 94% 7 15 VGPR 57% VGPR 63% scr CR VGPR PR SD Best confirmed response during induction (N=121)* Best confirmed response overall (N=121)* *One patient had no response evaluations during maintenance because they were belatedly found to have progressed at the end of induction, and were taken off study after one dose of maintenance therapy; they are therefore regarded as not evaluable in this analysis of best response to induction and maintenance. CR, complete response; ORR, overall response rate; PR, partial response; scr, stringent complete response; VGPR, very good partial response.

11 Responses deepened with single-agent ixazomib maintenance 1 8 ORR 93% ORR 94% 7 15 n=4 n=7 18 n=8 scr CR VGPR Patients (%) 6 4 n=1 n=6 28 PR SD 2 36 n= Best confirmed response during induction (N=121)* Best confirmed response overall (N=121)* 28 (23%) patients improved their response during ixazomib maintenance *One patient had no response evaluations during maintenance because they were belatedly found to have progressed at the end of induction, and were taken off study after one dose of maintenance therapy; they are therefore regarded as not evaluable in this analysis of best response to induction and maintenance.

12 Single-agent ixazomib maintenance treatment has a positive safety profile Summary of AEs during induction and maintenance Patients with 1 AE, n (%) During induction (N=121) During maintenance (N=121) Any grade AE 119 (98) 111 (92) Drug-related any grade AE 112 (93) 89 (74) Grade 3 AE 9 (74) 58 (48) Drug-related grade 3 AE 75 (62) 29 (24) Serious AE 52 (43) 26 (21) Drug-related serious AE 23 (19) 6 (5) AE resulting in study drug dose reduction 68 (56) 18 (15) AE resulting in study drug discontinuation 3 (2) 6 (5) On-study deaths 1 (<1)* Lower incidence of any-grade AEs, grade 3 AEs, SAEs, and AEs resulting in study drug dose reductions, during ixazomib maintenance than during induction *Not considered related to ixazomib; due to pulmonary edema in an 81-year-old patient with a history of cardiovascular comorbidities. SAE, serious adverse event.

13 Most common grade 3 drug-related AEs reported during induction and maintenance Patients with 1 AE,* n (%) During induction (N=121) During maintenance (N=121) Neutropenia 27 (22) 3 (2) Thrombocytopenia 2 () 3 (2) Lymphopenia 11 (9) 3 (2) Fatigue 1 (8) 1 (<1) Leukopenia 7 (6) 1 (<1) Anemia 5 (4) 2 (2) Maculo-papular rash 4 (3) 2 (2) Papular rash 4 (3) Grade 3 AEs were generally less common during maintenance than during induction No grade 3 drug-related cardiac events reported with ixazomib maintenance Events with an incidence of 3% in either period are shown. *Preferred terms.

14 AEs of clinical importance reported during induction and maintenance New-onset AE during New-onset AE during Patients with 1 AE of any grade,* n (%) induction (N=121) maintenance (N=121) Rash 57 (47) 24 (2) Nausea 53 (44) 21 () Peripheral neuropathies NEC 52 (43) 16 (13) Diarrhea 51 (42) 33 (27) Thrombocytopenia 42 () (14) Neutropenia 41 (34) 11 (9) Vomiting 38 (31) 14 (12) Cardiac arrhythmias 26 (21) 16 (13) Acute renal failure 1 (8) 9 (7) Hypotension 9 (7) 5 (4) Liver impairment 8 (7) 4 (3) Heart failure 3 (2) 3 (2) New primary malignancy 1 (1) 6 (5) Myocardial infarction 1 (1) AEs of clinical importance were generally less common during maintenance than during induction, or had similar incidence in the two treatment phases Maintenance therapy was not associated with cardiac or thromboembolic safety concerns *Higher-level terms, incorporating multiple preferred terms. The incidence of grade 3 drug-related PN was 1 (1%) during induction and 2 (2%) during maintenance; the incidence of any grade PN was 29 (24%) during induction and 9 (7%) during maintenance; the incidence of any grade peripheral sensory neuropathy was 25 (21%) during induction and 7 (6%) during maintenance. Squamous cell carcinoma. Four patients with basal cell carcinoma of the skin, one with squamous cell carcinoma of the skin, and one with gastro-esophageal cancer.

15 Immune reconstitution suggested by recovery of non-involved immunoglobulins during single-agent ixazomib maintenance IgA levels over time in patients with IgG myeloma IgG levels over time in patients with IgA myeloma 2. Combination therapy Single-agent ixazomib maintenance Overall 2 Combination therapy Single-agent ixazomib maintenance Overall Median quantitative IgA result (g/l) * Median quantitative IgG result (g/l) *. Baseline Visit (month) EOT Baseline Visit (month) EOT EOT, end of treatment.

16 Conclusions In this integrated analysis, prolonged single-agent ixazomib maintenance therapy following ixazomib-based induction was associated with deepening of responses and favorable long-term outcomes in NDMM patients not undergoing ASCT After induction, ORR was 93% (57% CR+VGPR and 22% CR) Following maintenance, 23% of patients improved their response (63% VGPR and % CR) High response rates translated into a favorable median PFS: 33.8 and 21.4 months, from the start of induction and single-agent ixazomib maintenance, respectively Single-agent ixazomib is feasible for long-term administration based on a positive safety profile and limited new-onset grade 3 AEs during maintenance Grade 3 drug-related AEs and SAEs were less common during maintenance than during induction These outcomes appear similar to other studies involving maintenance approaches in NDMM The results support the ongoing phase 3, randomized, placebo-controlled, double-blind trials which are currently evaluating the efficacy and safety of ixazomib maintenance in NDMM patients after ASCT (NCT ) and in NDMM patients not treated with ASCT (NCT and NCT185524)

17 Acknowledgments We thank all patients and their families, and investigators at all clinical sites for their participation in the study We would also like to acknowledge Laila Cancian, PhD, of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this presentation, which was funded by Millennium Pharmaceuticals, Inc., and complied with Good Publication Practice 3 ethical guidelines (Battisti et al., Ann Intern Med 215;163:461 4).