Oncology Highlights ASCO 2011 MULTIPLE MYELOMA

Transcription

1 Oncology Highlights ASCO 211 MULTIPLE MYELOMA July 211 Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Joseph Mikhael, MD, MEd, FRCPC Staff Hematologist, Mayo Clinic Arizona Disclosures None 1

2 Objectives 1. Provide an overview of novel agents presented at the annual meeting 2. Review health outcomes research in myeloma 3. Outline results regarding the use of bisphosphonates 4. Discuss the incidence of second primary malignancies Kyle, R. A. and Rajkumar S. V. Blood 28;111:

3 NEW DRUGS Carfilzomib and PX Carfilzomib is a selective tetrapeptide epoxyketone proteasome inhibitor that displays potent and sustained proteasome inhibition. The high degree of selectivity of carfilzomib may account for its improved tolerability profile: In early clinical studies, carfilzomib has not been associated with dose-limiting peripheral neuropathy (PN). PX is an ongoing multicenter, non-randomized, open-label, l single-arm phase 2 trial of single-agent carfilzomib in patients with R/R MM who have received 1 3 prior lines of therapy. K Stewart et al ASCO Abstract 826 3

4 Study Design and Treatment Bortezomib-naïve patients (N=129) were enrolled in 2 sequential dose cohorts. In Cohort 1, patients received carfilzomib 2 mg/m 2 IV on Days 1, 2, 8, 9, 15, and 16 every 28 days, for up to 12 cycles. In Cohort 2, patients received a stepped-up, dose-escalating regimen of carfilzomib 2 mg/m 2 for Cycle 1 followed by carfilzomib 27 mg/m 2 for all subsequent treatment cycles. Dexamethasone 4 mg was administered prior to carfilzomib in Cycle 1 only to ameliorate a potential first dose effect (including fever, chills, rigors, and dyspnea). Patients completing all 12 cycles were eligible to enroll in an extension study (PX-171-1). K Stewart et al ASCO Abstract 826 Significant Responses in BTZ-naïve Patients Significant response rates were observed in both cohorts Best response Cohort 1 2 mg/m 2 Cohort 2 2/27 mg/m 2 (N=127) (N=59) (N=68) n (%) n (%) CR 2 (3) () VGPR 8 (14) 18 (26) PR 15 (25) 17 (25) CBR= 59% MR 1 (17) 8 (12) SD 13 (22) 1 (15) ORR= 42% ORR= 51% PD 7 (12) 11 (16) NE 4 (7) 4 (6) CBR= 63% *Data cut-off date 9 February patients (3%) in Cohort 2 were excluded on the basis of missing baseline or post-baseline disease assessments. Responses confirmed by Independent Review Committee K Stewart et al ASCO Abstract 826 4

5 Substantial Duration of Response Observed for Cohorts 1 and 2 * *Data cut-off date 9 February 211 K Stewart et al ASCO Abstract 826 Similar Incidence and Severity of AEs Between Cohorts There were no discontinuations of treatment due to peripheral neuropathy. In no case were any toxicities iti (any grades) >2% higher h in Cohort 2 than in Cohort 1; in general they were either similar or lower cumulative toxicities has been observed in patients continuing on extended carfilzomib treatment (PX-171-1). K Stewart et al ASCO Abstract 826 5

6 Joe Commentary - Carlfilzomib Highly active proteasome inhibitor Huge benefit of lack of neuropathy Currently still given twice weekly IV Look for enhanced dosing schedules Going to FDA this summer Pomalidomide in Len Treated Patients Patient Characteristics J Mikhael et al ASCO Abstract 867 6

7 Response rate on Pomalidomide Despite Prior Treatment with Lenalidomide J Mikhael et al ASCO Abstract 867 Joe Commentary - Pomalidomide Highly active IMID Minimal neuropathy, likely less myelosuppression than lenalidomide Active in previously len treated patients, even when refractory in about 1/3 Going to phase 3 now, FDA 212? 7

8 Elotuzumab: Background 6 Elotuzumab is a humanized IgG1 mab targeting human CS1, a cell surface glycoprotein 12 5 CS1 is highly expressed on >95% of MM cells Lower expression on NK cells 3 Little to no expression on normal tissues 2 MoA of elotuzumab is primarily through NK cell-mediated ADCC 1 against myeloma cells 1,2 In a MM xenograft mouse model, antitumor activity of elotuzumab was enhanced by the addition of lenalidomide 4 Tumor volume (mm 3 ) Lenalidomide dosing* Elotuzumab or control IgG1 dosing Control IgG1 + DMSO Elotuzumab + DMSO Lenalidomide + control IgG Elotuzumab + lenalidomide Study day *Lenalidomide dosed at 5 mg/kg. Elotuzumab dosed at 1 mg/kg (below MED of 1 mg/kg). P Richardson et al ASCO Abstract Phase 1/2 Study Design Response Assessments Elotuzumab 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 Phase 1* Dose escalation study of elotuzumab 5, 1, and 2 mg/kg IV in combination with: Lenalidomide 25 mg PO Low-dose dexamethasone 4 mg PO Phase 2 Pts randomized to elotuzumab 1 or 2 mg/kg IV as above Treatment continued until disease progression or unacceptable toxicity P Richardson et al ASCO Abstract

9 Phase 1/2 Study Design: Premedication Regimen Administered 3 6 minutes prior to elotuzumab infusion i Methylprednisolone 5 mg IV Diphenhydramine 25 5 mg PO or IV (or equivalent) Ranitidine 5 mg IV (or equivalent) Acetaminophen 65 1 mg PO A protocol amendment substituted methylprednisolone 5 mg IV with dexamethasone 8 mg IV (to align with phase 3 program) The premedication regimen was incorporated late in Phase 1 and consistently in Phase 2 P Richardson et al ASCO Abstract Phase 1/2 Key Eligibility Criteria Inclusion Relapsed and/or refractory MM with 1 3 prior therapies For Phase 1, 1 prior therapy Measurable disease by M protein Creatinine clearance 5 ml/min (Cockcroft-Gault method) Exclusion Thalidomide, bortezomib, or corticosteroids within 2 wks of the first dose Prior lenalidomide For Phase 1, within 6 wks of first elotuzumab dose P Richardson et al ASCO Abstract

10 Efficacy Best Confirmed Response (IMWG Criteria) Elotuzumab Elotuzumab 1 mg/kg 2 mg/kg Total Pts, n ORR ( PR), n (%) 36 (92) 44 (75) 8 (82) Stringent CR/CR, n (%) 5 (13) 4 (7) 9 (9) VGPR, n (%) 1 (26) 22 (37) 32 (33) PR, n (%) 21 (54) 18 (31) 39 (4) SD, n (%) 3 (8) 11 (19) 14 (14) PD, n (%) 2 (3) 2 (2) IMWG non-evaluable, n (%) 2 (3) 2 (2) P Richardson et al ASCO Abstract Conclusions Elotuzumab plus lenalidomide and low-dose dexamethasone has a high ORR in relapsed and relapsed/refractory MM 82% for all pts 42% achieved VGPR as best confirmed response Median PFS had not been reached after a median follow-up of 9.4 months The elotuzumab and lenalidomide combination was generally well tolerated Most common Grade 3/4 treatment-emergent AEs were neutropenia (19%), thrombocytopenia (17%), and lymphopenia (13%) Premedication regimen with IV corticosteroid decreased incidence and mitigated severity of infusion reactions All grade infusion reactions: 1% of pts without premedication vs 56% of pts with premedication Grade 3/4 infusion reactions:18% of pts without premedication vs 1% of pts with premedication P Richardson et al ASCO Abstract

11 Joe Commentary - Elotuzumab Theoretically excellent target for therapy First of many monoclonal Abs demonstrating activity Used in combination with novel agent, not monotherapy Will have to balance cost/toxicity with added benefit HEALTH OUTCOMES 11

12 Survival outcomes in elderly patients with plasma cell myeloma: The three-decade Eastern Cooperative Oncology Group (ECOG) experience Most of the survival benefit is seen in <65 Analyzed 4 Phase 3 clinical trials (ASCT excluded) Three cohorts: A B C E Campagnaro et al ASCO Abstract 821 Survival outcomes in elderly patients with plasma cell myeloma: The three-decade Eastern Cooperative Oncology Group (ECOG) experience E Campagnaro et al ASCO Abstract

13 Joe Commentary Health Outcomes Adds to various studies evaluating increased survival in myeloma At least doubling median OS! Greatest benefit seen in transplant eligible Await further work in elderly with use of novel agents MRC IX BISPHOSPHONATES 13

14 MRC Myeloma IX Analysis Schematic for ZOL vs CLO N = 1,96 Patients with newly diagnosed MM (stage I, II, III) R A N D O M I S A T I O N Zoledronic acid (4 mg a IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981) Bisphosphonate treatment continued at least until disease progression Clodronate (1,6 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Endpoints (ZOL vs CLO) Primary: PFS, OS, and Response Secondary: SREs (time to first SRE, SRE incidence) and Safety SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions, or the appearance of new osteolytic bone lesions. G Morgan et al ASCO Abstract 81 MRC Myeloma IX Trial Status 1,96 evaluable patients 121 centres es Median follow-up 3.7 years ZOL 3.8 years CLO Median time on study drug, days Intensive: 396 ZOL; 49 CLO Non-intensive: 32 ZOL; 36 CLO Off-study Progressed or died: 59% ZOL; 64% CLO Stopped before progression: 24% ZOL; 19% CLO Abbreviations: CLO, clodronate; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 81 14

15 MRC Myeloma IX ZOL Significantly SREs vs CLO in the Overall Population ZOL reduced the risk of SREs by 26% vs CLO (HR =.74; P =.4) % Patients with an SRE, CLO ZOL 35.3% 27.% Patients at risk, n ZOL CLO Time from randomisation, months Abbreviations: CLO, clodronate; HR, hazard ratio; SRE, skeletal-related event; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 81 ZOL Significantly OS vs CLO in Patients With Bone Disease at Baseline (n = 1,35) ate distribution function estim OS, % patients Survival Clodronate (n = 682) 1 Zoledronic acid (n = 668) + Censored P =.17 HR:.82 (95% CI:.7,.96) ZOL CLO Survival, years since initial randomisation Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 81 15

16 OS Was Similar for ZOL and CLO in Patients With No Bone Disease at Baseline (n = 578) estimate rvival distribution function e OS, % patients Sur Clodronate (n = 276) Zoledronic acid (n = 32) + Censored P =.469 HR:11(95%CI: , 14) 1.4) ZOL CLO Survival, years since initial randomisation Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 81 MRC Myeloma IX ZOL Effects on SREs vs CLO by Survival Risk Status at Baseline High-risk disease a Low-risk disease b Cumulative incidence function for 1st SRE 5.5 Clodronate Zoledronic acid Cumulative incidence function for 1st SRE Clodronate Zoledronic acid Time, months Time, months ZOL CLO ZOL CLO G Morgan et al ASCO Abstract 81 16

17 MRC Myeloma IX SRE Risk Affected by Treatment, Haematologic Parameters, and SRE History Variable P Value Bisphosphonate (ZOL vs CLO) 72 <.1 C-TD vs CVAD (intensive) C-TDa vs MP (non-intensive) Serum calcium (high vs low) Serum creatinine (high vs low) Haemoglobin (high vs low) Platelets (high vs low) History of SRE (yes vs no) 2 86 <.1 Risk of on-study SRE Risk of on-study SRE F Davies et al ASCO Abstract 811 MRC Myeloma IX ZOL Continued to 1st SREs vs CLO After Completion of 1 Year tion Cumulative Incidence Funct.2 P =.12, log rank CLO.15.1 ZOL.5 1 year Patients, n Time Since 1-Year Post-randomisation, months ZOL CLO F Davies et al ASCO Abstract

18 MRC Myeloma IX ZOL Continued to 1st SREs vs CLO After Completion of 2 Years.2 Cumulative Incidence Func ction P =.12, log rank CLO ZOL 2 years Time Since 2-Years Post-randomisation, months Patients, n ZOL CLO F Davies et al ASCO Abstract 811 MRC Myeloma IX ZOL Maintained Trend to 1st SREs vs CLO Beyond 3 Years.2 Cumulative Incidence Func ction P =.112 log rank CLO ZOL 3 years Time Since 3-Years Post-randomisation, months Patients, n ZOL CLO Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid. F Davies et al ASCO Abstract

19 Joe Commentary Bisphosphonates Intriguing data regarding possible survival benefit - sustained Most dramatically seen in pts with bone disease Caution regarding population of patients enhanced with thalidomide? Requires further corroboration with other studies, but swings pendulum back somewhat (ONJ) SECOND PRIMARY SECOND PRIMARY MALIGNANCIES 19

20 MM15: Progression-Free Survival 39 All Patients 6% Reduced Risk of Progression Years of Age 69% Reduced Risk of Progression Median PFS Median PFS 1 MPR-R MPR MP 31 months 14 months 13 months 1 MPR-R MPR MP Not reached 14.7 months 12.4 months Patients (%) 75 5 HR.395 P < HR.315 P <.1 25 HR.796 P = HR.675 P = Time (Months) Time (Months) Data cutoff : May 11, 21 A Palumbo et al ASCO Abstract 87 MM-15: SPM Analysis Methods 4 All MM-15 patient records were examined for SPM incidence in active treatment and long-term follow-up study phases Efficacy & PFS data cutoff: May 11, 21 (adjudicated assessment) Median of 25 months SPM & OS data cutoff: February 28, 211 Median of 3 months SPMs were identified by review of MedDRA terms under the Neoplasm System Organ Class SPM incidence rates per 1 person-years were calculated for hematologic and solid tumor malignancies MedDRA, Medical Dictionary for Regulatory Activities. A Palumbo et al ASCO Abstract 87 2

21 MM-15: SPM Data Cut-Off February 28, SPM, n (%) MPR-R (n = 15) MPR (n = 152) MP (n = 153) Total Invasive SPMs 12 (8.) 9 (5.9) 4 (2.6) Hematologic Malignancies 7 (4.7) 5 (3.3) 1 (.7) AML 4 (2.7) 2 (1.3) MDS to AML 1 (.7) 1 (.7) MDS 2 (1.3) 1 (.7) T-ALL 1 (.7) CMML 1(7) (.7) B-cell malignancy Solid tumors 5 (3.3) 4 (2.6) 3 (2.) Non-melanoma skin cancer 1 (.7) 4 (2.6) 5 (3.3) Median follow-up: 3 months A Palumbo et al ASCO Abstract 87 MM15: Risk for SPM vs PD/Death (Safety Population) 42 MPR-R MPR MP Patients (%) Time (Months) Time (Months) Time (Months) PD/Death Hematologic SPM Solid Tumor PD, progressive disease. A Palumbo et al ASCO Abstract 87 21

22 Retrospective Study Design 43 9 EMN experimental trials 2459 NDMM Patients CRD/CPR: n = 287 MPR: n = 685 ASCT-R maint: n = 484 VMPT: n = MP: n = 164 MPT: n = VMP: n = analyzed patients (with at least 1 year of follow-up) 661 excluded patients (diagnosed in the last year; after Mar 15, 21) Times of observation were censored on Mar 15, Palumbo A, et al. Blood. 28;112: Palumbo A, et al. J Clin Oncol. 21;28: Gay F, et al. Eur J Haematol. 21;85: A Palumbo et al ASCO Abstract 87 Incidence of Second Primary Malignancies in Normal Population 44 INCIDENCE Age Specific Rates (per 1 PY) Inc cidence Rate (per 1 PY Y) Years of Age Piedmont Cancer Registry, Italy, City of Turin, PY, person-year. A Palumbo et al ASCO Abstract 87 22

23 Second Primary Malignancies and MM Death Risk All patients Lenalidomide No Lenalidomide 45 Proportion of patients months months months Death Solid SPMs Hematologic SPMs A Palumbo et al ASCO Abstract 87 Comparison of Observed to Expected Rate of Second Primary Malignancies 46 SPMs observed in Italian patients SPMs expected from Italian Cancer Registry (age- and sex-adjusted) All Patients SPMs Observed a SPMs Expected b SIR 95% CI All patients Male Female Lenalidomide-treated patients SPMs SPMs Observed a Expected b SIR 95% CI Lenalidomide-treated patients Male Female CI, confidence interval; SIR, standardized incidence rate A Palumbo et al ASCO Abstract 87 23

24 Objectives & Methods 47 Assess and compare SPM incidence rates between the Len + Dex and PBO + Dex arms of MM-9/1 Compare the incidence rates of SPM in MM-9/1 to the incidence rate of invasive cancer occurring among similarly aged persons in the general population Incidence rates of SPMs per 1 person-years a were evaluated during active, double-blind treatment b and during long-term follow-up Median follow-up for survival: 48 months Data cut-off SPM analysis: February 211 M Dimopoulos et al ASCO Abstract 89 Incidence Rates for SPM During Active Treatment Phase (Safety Population) Len + Dex (N = 353) PBO + Dex (N = 35) SPM n (%) Incidence Rate 95% CI n (%) Incidence Rate 95% CI (per 1 PY) (per 1 PY) Invasive SPM 8 (2.3) , (.6).91.23, 3.66 Hematologic 2 (.6).42.11, 1.69 (.). -- AML (.). -- (.). -- MDS 2 (.6).43.11, 1.7 (.) B-cell malignancies (.). -- (.). -- Solid Tumors 6 (1.7) , (.6).91.23, 3.66 Non-Invasive SPM 11 (3.1) , (.6).91.23, 3.66 Non-melanoma skin cancer 11 (3.1) 2 (.6) TOTAL SPM 18 (5.1) a , (.9) a , 4.27 a 1 patient in each Len/Dex and PBP/Dex groups who had both a solid tumor and a non-melanoma skin cancer. These patients are counted only once in the total; The 2 Len + Dex pts who developed MDS both had hypoplastic bone marrow at study entry and had received prior ASCT with high-dose melphalan CI, confidence interval; MDS, myelodysplastic syndromes; PY, person-year; M Dimopoulos et al ASCO Abstract 89 24

25 Incidence Rates of Invasive SPM a During Treatment & Follow-up Phases 49 Double-blind phase Long-term follow-up only PBO + Dex (n = 35) SPM = 2 IR:.91 (95% CI ) 218 PY SPM = IR: 599 PY 817 PY total Len + Dex (n = 353) SPM = 8 IR: 1.71 (95% CI ) SPM = IR: 467 PY 419 PY 886 PY total Person-Years a Includes MDS and breast carcinoma in situ, excludes non-melanoma skin cancers. IR, incidence rate per 1 person-years; M Dimopoulos et al ASCO Abstract 89 SPM in RRMM: MM-9/1 Time to Invasive SPM (treatment period) 5 Patients (%) 5 25 Len + Dex PBO + Dex Hazard ratio: (95% CI ) P=.649 No. at Risk Time (months) Len + Dex PBO + Dex M Dimopoulos et al ASCO Abstract 89 25

26 Time to Progression or Second Primary Malignancy 51 Patients (%) 5 25 Treatment Median TTP/SPM P Value Len + Dex 12.4 months <.1 PBO + Dex 4.6 months Hazard ratio:.355 (95% CI ) Time (months) No. at Risk Len + Dex PBO + Dex An analysis of TTP including invasive SPMs as events demonstrated that treatment Len + Dex treatment maintains a favorable benefit-risk profile M Dimopoulos et al ASCO Abstract 89 Overall Survival Benefit from Len + Dex Including Data After Crossover Treatment Median OS P Value Len + Dex 38. months.45 PBO + Dex 31.6 months HR:.822 (95% CI ) Patients (%) Logrank P =.45 Wilcoxon P = Pepe-Fleming P = Overall Survival (months) Dimopoulos MA, et al. Leukemia. 29;23:

27 Long-term safety of lenalidomide in relapsed/refractory multiple myeloma patients: Analysis of pooled data 11 Celgene sponsored clinical trials At least 24 months of treatment SPM in per 1 person years Compared to SEER 3,839 patients LEN (n = 729; 19.1%) and LEN + dex (n = 3,83; 8.9%) Median LEN treatment duration 5 mos (range ) 313 (8.2%) pts receiving 24 mos of treatment B. G. Durie et al ASCO Abstract 886 Long-term safety of lenalidomide in relapsed/refractory multiple myeloma patients: Analysis of pooled data A total of 57 SPMs were identified 8 MDS 1 AML 2 B-cell malignancies 46 solid tumors Of these, 22/313 (7%) were in pts with 24 mos of LEN treatment (4 MDS, 1 AML, 17 solid tumors) Overall SPM IR was 2.35 for 24 mos of treatment Standardized incidence ratio (SIR) was.77 (CI ) IR for all invasive cancers reported from SEER (range per 1 PY for all persons ages 6-85+). B. G. Durie et al ASCO Abstract

28 Long-term safety of lenalidomide in relapsed/refractory multiple myeloma patients: Analysis of pooled data B. G. Durie et al ASCO Abstract 886 Joe Commentary Second Primary Malignancy Difficult to genuinely attribute increased risk due to lenalidomide Confounders include: Age of patients Use of alkylators Lack of detailed capture of all malignancies Need more careful data collection Place into context of known benefit of novel agent 28

29 Conclusions Survival in myeloma is improving, due to both novel agent use and stem cell transplant The most promising new agents include carlfilzomib and pomalidomide Bisphosphonates may improve survival in myeloma and remain effective in patients with bone disease Second primary malignancies in pts treated with lenalidomide may be increased but likely only marginally if at all 29