update on mds 2015 - prime oncology...garcia-manero, et al. blood. 2016;128: abstract 345. phase ii...
TRANSCRIPT
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Myelodysplastic Syndromes
Guillermo Garcia-Manero, MDUniversity of Texas
MD Anderson Cancer CenterHouston, Texas
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Natural History of MDS After Incorporation of HMAs
ProdromeICUS, CHIP
LR-MDS HR-MDS
AMLHMA failure?
HMA failureAML-like??
UntreatedHMA?lenalidomide
UntreatedHMA AML-likeSCT
HMA lower-risk failure survival: 14-17 monthsHMA higher-risk failure survival: 4-6 months
Jabbour E, et al. Cancer. 2015;121(6):876-882. Jabbour E, et al. Cancer. 2010;116(16):3830-3834. Steensma DP, et al. Blood. 2015;126(1):9-16.
AML, acute myeloid leukemia; CHIP, clonal hematopoiesis of indeterminate potential; HMA, hypomethylating agents; HR, high risk; ICUS, idiopathic cytopenias of undetermined significance; LR, low risk; MDS, myelodysplastic syndrome; SCT, stem cell transplant
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Genomics of MDS
Papaemmanuil E, et al. Blood. 2013;122(22):3616-3627.
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Jaiswal S, et al. N Engl J Med. 2014;371(26):2488-2498.
Frequency of Clonal Hematopoiesis
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Comorbidities and MDSPrognosticFactor
Coefficient Score
Age >65 0.582 2
ComorbidityScore (ACE -27)
Mild or moderate
0.301 1
Severe 0.782 3
IPSS Int 2 0.512 2High 0.769 3
Naqvi K, et al. J Clin Oncol. 2011;29(16):2240-2246.
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Fuster JJ, et al. Science. 2017;355(6327):842-847.
Clonal Hematopoiesis and Atherosclerosis
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Implications of Clonal Hematopoiesis
• Abstract #115: (Severson et al): CHIP and solid tumors
• Abstract #421: (Molenar et al): TET2 mutations and atherosclerosis
• Abstract #424: (Madanat et al): Mutations and smoking
• Abstract #426: (Cook et al): CHIP and inflammation
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Non-del5q- Lower-Risk MDS• Phase III CC-486 (oral azacitidine)• Attenuated schedules of HMA• Phase III oral decitabine E7727• Phase III ACE-536• PD1/PDL1 inhibition• Splicing inhibitors (H3Bio)• LSD1 inhibitor• antiCD38, antiCD123
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Phase I Oral Aza Study Response to Therapy (N = 41)
DispositionMDS
N = 29N (%)
CMML N = 4 N (%)
AML N = 8N (%)
Ongoing 8 (28) 2 (50) 2 (25)Terminated 21 (72) 2 (50) 6 (75)
Median duration of oral therapy, # of cycles, (range) 6.0 (1–23+) 7.0 (3–17+) 4.5 (1– 14+)
Cycle 7 response assessment* 13 (45) 2 (50) 2 (25)CR / PR / HI 4 (31) 1 (50) 0 (0)SD 8 (61) 1 (50) 2 (100)†
Progression 1 (8) 0 (0) 0 (0)Garcia-Manero G, et al. Leukemia. 2016;30(4):889-896. Garcia-Manero G, et al. J Clin Oncol. 2011;29(18):2521-2527.
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ResponseDAC
N = 70n (%)
AZA N = 39n (%)
P
CR 26 (37) 14 (36) .90mCR 6 (9) 2 (5)HI 17 (24) 3 (8)ORR 49 (70) 19 (49) .03SD 18 (26) 17 (44)PD 3 (4) 3 (8)
DAC vs AZA in LR-MDS: Response (IWG)
Median number of cycles: 9 (range: 1-41)Jabbour E, et al. Blood. 2017;130(13):1514-1522.
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Jabbour E, et al. Blood. 2017;130(13):1514-1522.
DAC vs AZA in LR-MDS: OS
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Successful Emulation of IV Decitabine Pharmacokinetics With an Oral Fixed-Dose Combination
of the Oral Cytidine Deaminase Inhibitor (CDAi) E7727 With Oral Decitabine, in Subjects With Myelodysplastic
Syndromes (MDS): Final Data of Phase I Study
Garcia-Manero G, Odenike O, Amrein P, Steensma DP, DeZern A, Michaelis LC, Faderl S, Kantarjian H, Lowder JN, Taverna P, Oganesian
A, Zhang X, Azab M, Savona MR; ASTX727 Investigative Team
ASH 2016 Abstract 114
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ASTX727 Phase I Results 5 Days Total DAC AUC: Oral/IV ASTX727 Oral Dose (mg) 5-Days Total (AUC last) % of AUC
Cohort DAC1 E7727 N Oral IV (Oral/IV)1 20 40 52 260 753 35%2 20 60 6 346 899 39%3 20 100 6 482 992 49%4 40 100 6 1120 775 144%5 30 100 193 701 852 85%
1DAC oral dose not adjusted by weight or BSA 2One significant outlier excluded from the PK analysis 3Includes 13-patient dose expansion
• Cohort 4 oral DAC (at 40 mg) exposure achieved primary objective and exceeded that of IV DAC at 20 mg/m2 (Oral/IV 144%)
• Cohort 5 oral DAC (at 30 mg) exposure was 85% of IV DAC at 20 mg/m2
• Oral DAC dose of 35 mg in ASTX727 (ongoing phase II) should achieve AUC of ~ 85%-140% of IV DAC
Garcia-Manero G, et al. Blood. 2016;128: Abstract 114.
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• ASTX727 cohorts 4 and 5 achieved LINE-1 demethylation from baseline of >10% (comparable to historical data of DAC IV)
ASTX727 Phase I Results PD (LINE-1 Demethylation) by Cohort
Garcia-Manero G, et al. Blood. 2016;128: Abstract 114.
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Luspatercept Increases Hemoglobin and Reduces Transfusion Burden in Patients With
Low-Intermediate Risk Myelodysplastic Syndromes (MDS): Long-Term Results From
Phase 2 PACE-MDS Study
Platzbecker U, Germing U, Gotze K, Kiewe P, Wolff T, Mayer K, Chromik J, Radsak M, Donovan E, Wilson DM, Zhang X, Laadem A, Sherman ML, Attie KM,
Giagounidis A
ASH 2016 Abstract 3168
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Increase in Mean Hemoglobin in LTB Patients With >3 Months of Treatment (Extension Study)
LTB: Low transfusion burden patients (<4 units/8 wk, Hb <10 g/dL)
Months# patients
Hem
oglo
bin
Cha
nge
(SE)
Fro
m B
asel
ine
(g/d
L)4
3
2
1
0
• 16/22 (73%) HI-E responders; median time to response: 2.2 months
Data as of 09 Sep 2016Platzbecker U, et al. Blood. 2016;128: Abstract 3168.
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LR-MDS
Transfusion dependent
Transfusion independent
AZA x 3 daysDAC X 3 daysAZAX 5 days
Observation
Early Intervention in LR MDS(US North American MDS Consortium)
NCT02269280. Funded Edward P Evans FoundationCleveland Clinic: M. Sekeres; Dana Farber Cancer Center: D. Steensma; Johns Hopkins: A Dezern; MD Anderson: Garcia-Manero; Moffitt Cancer Center: R Komrokji; Weill-Cornell: G Roboz
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HMA Failure Lower-Risk MDS
• PD1/PDL1 inhibition
• Toll-like receptor inhibition: OPN-305
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n events mos290 204 15290 201 17
LR MDS Post HMA Failure: Outcome
Jabbour EJ, et al. Cancer. 2015;121(6):876-882.
• Median follow-up: 16 (1-80) months• Median TFS and OS: 15 and 17 months
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OPN-305 in MDS: Clinical Activity Response N (%)HI-E major 3 (20)HI-E minor 5 (33)Stable disease 4 (27)No response 2 (13)Progressive disease 3 (20)Too early 5 (25)Median number courses to response 2 (2-7)IWG 2006 criteria. 3 of 5 TE patients technically HI-E Major
8 (53)
Garcia-Manero G, et al. Blood. 2016;128: Abstract 227.
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Higher-Risk MDS
• PD1/PDL1 Inhibition • SGI-110 (guadecitabine)• Ph II AZA +/- durvalumab• Ph II Aza + rigosertib• Ph II ruxolitinib + AZA• Aza + Abt-199
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Initial Results of a Phase 2 Study of Guadecitabine (SGI-110), A Novel Subcutaneous Hypomethylating
Agent, for Patients With Previously Untreated Intermediate-2 or High Risk Myelodysplastic
Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)
Montalban-Bravo G, Bose P, Alvarado Y, Daver N, Ravandi F, Borthakur G, Takahashi K, Andreeff M, Cortes J, DiNardo C, Jabbour E, Kadia T, Kornblau S, Ohanian M, Alfonso A, Huang X, Nogueras-Gonzalez GM, Bodden K, Littles K,
Pierce S, Bueso-Ramos C, Kantarjian H, Garcia-Manero G
ASH 2016 Abstract 346
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Response Category
Global [n = 44]N (%)
MDS [n = 38]N (%)
CMML [n = 6]N (%)
ORR 31 (71) 26 (68) 5 (83)CR 14 (32) 12 (32) 2 (33)mCR 14 (32) 11 (29) 3 (50)HI 3 (7) 3 (8) 0 (0)CR + mCR 28 (64) 23 (61) 5 (83)CCyR 7/33 (21) 7/28 (25) 0 (0)
• Median number of cycles: 6 (range 1-20)• Median number of cycles to response: 3 (range 1-6)• Median number of cycles to complete cytogenetic response: 4 (range 1-7)• Median response duration: 4 cycles (0-14)• Stopping rule for response not met
Montalban-Bravo G, et al. Blood. 2016;128: Abstract 346.
SGI-110: Response
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Higher-Risk MDS HMA Failure• Ph III rigosertib• PD1/PDL1 inhibition• Ph II omacetaxine (Short et al, ASH 2017, Abstract #2967)
– ORR 34%– 7.6-month median survival– 22% 1-year OS
• Ph II CC-486• Aza+ABT-199 failures• SGI-110 failures
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Targeting Hypomethylating Failure
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Overall Survival and Subgroup Analysis From a Randomized Phase III Study of Intravenous
Rigosertib vs Best Supportive Care in Patients With Higher-Risk Myelodysplastic Syndrome
After Failure of Hypomethylating Agents (ONTIME Trial of ON 01910)
Garcia-Manero G, et al. Lancet Oncol. 2016;17(4):496-508.
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ONTIME Trial: Median Overall Survival for Patients With Primary HMA Failure - Blinded, Centralized Assessment
Per Prebet 2011, “Primary HMA Failure” was defined as either no response to or progression during HMA therapy
Garcia-Manero G, et al. Lancet Oncol. 2016;17(4):496-508.
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Post-HMA HR-MDS (N = 225)
Key Eligibility Criteria:- Failed HMA <9 months DoT- <80 years of age
Randomization2:1
IV rigosertib +
BSCN = 150
Overall Survival
- Interim analysis (86 events)
- Intent-to-treat analysis (171 events)
• Stratification at randomization− Very High Risk vs other IPSS-R− US vs Europe vs Asia
• Statistical analysis– α for ITT = .0397; α for IPSS-R VHR = .01– Trial can succeed in two ways
Physician’s Choice
+BSC
N = 75
Follow-up
Design of New Phase III INSPIRE Trial
29
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02468
101214
0 2 3 5 6 8 10 11 15 17 21 22 24 28 31
Rel
ativ
e ex
pres
sion
Days on Therapy
PD-L1
Sequential PD1/PDL1 Activation Post HMA
0
10
20
30
40
50
60
0 2 3 5 6 8 10 11 15 17 21 22 24 28 31
Rel
ativ
e Ex
pres
sion
Days on Therapy
PD-1
Yang H, et al. Leukemia. 2014;28(6):1280-1288.
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Safety of Pembrolizumab in Patients With Myelodysplastic Syndrome After Failure of
Hypomethylating Agents: A Phase 1b Study
Garcia-Manero G, Tallman M, Martinelli G, Ribrag V, Yang H, Balakumaran A, Chlosta S, Zhang Y, Smith BD
ASH 2016 Abstract 345
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• 3 (11%) patients experienced hematologic improvement– Erythroid response in 2 (7%) patients– Platelet response in 1 (4%) patient
aPer IWG 2006 criteriaData cut-off: May 27, 2016
Best Overall Responsea N = 27n % (90% CI)
Overall response rate 1 4 (0-16)
Complete response 0 0 (0-10)
Partial response 1 4 (0-16)
Bone marrow complete response 3 11 (3-26)
Stable disease 14 52 (35-69)
Progressive disease 9 33 (19-51)
Clinical Activity of Pembrolizumab
Garcia-Manero, et al. Blood. 2016;128: Abstract 345.
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*SD as best response†Withdrew from study or was lost to follow-upData cut-off: May 27, 2016
0 20 40 60 80 100 120
mCR
PD
PR
Completed
DeathIPSS-HiIPSS-Intermediate-2IPSS-Intermediate-1
Missing
SD
†
†
†
Time of Last Assessment, Weeks
*
Exposure and Best Response
Garcia-Manero, et al. Blood. 2016;128: Abstract 345.
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Phase II Study of Nivolumab or Ipilimumab With Azacitidine In
Patients With MDS
Garcia-Manero G, Daver N, Montalban-Bravo G, Jabbour E, DiNardo C, Kornblau S, Bose P, Alvarado Y, Ohanian M, Borthakur G, Cortes JE, Naqvi K, Pemmaraju N, Huang
X, Nogueras-Gonzalez GM, Bueso-Ramos CE, Gasior Y, Bayer VR, Pierce S, Yang H, Colla S, and Kantarjian HM
ASH 2016 Abstract 344
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ICPI in MDS: Study DesignHMA Failure Cohorts Previously Untreated CohortsCohort #1: Single-agent nivolumab
Cohort #4: 5-azacitidine + nivolumab
Cohort #2: Single-agent ipilimumab
Cohort #5: 5-azacitidine + ipilimumab
Cohort #3: Combination nivolumab and ipilimumab
Cohort #6: 5-azacitidine + nivolumab and ipilimumab
• Each cohort max of 20 patients• In HMA failure cohorts: add back azacitidine after 6 cycles of ICPI if
no response• Stopping rules for toxicity and response
Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.
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CR mCR NR PD SD HI-N HI-P TE ORR
Nivo [N = 15] 0 0 8 (53) 6 (40) 1 (6) 0
Ipi [N = 18] 1 (6) 2 (12) 9 (56) 2 (12) 2(12) 2 (11) 5 (30)
Aza+Nivo [N = 20] 6 (35) 6 (35) 2 (11) 2 (11) 1 (5) 3 (15) 13 (80)
Aza+IPI [N = 20] 6 (29) 4 (20) 2 (10) 2 (10) 2 (10) 1 (5) 3 (15) 13(62)
ICPI in MDS: Clinical Responses
Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.
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Survival Nivolumab Cohort in MDS
Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.
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Survival Ipilimumab Cohort in MDS
Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.
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Survival Azacitidine and Ipilimumab Cohort
Garcia-Manero G, et al. Blood. 2016;128: Abstract 344. ASH 2017.
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Results of a Phase II Study of Guadecitabine (SGI-110) in Higher Risk MDS, CMML or Low Blast Count AML Patients Refractory to or
Relapsing After Azacitidine (AZA) Treatment
Sebert M, Bally C, Peterlin P, Beyne-Rauzy O, Legros L, Gourin MP, Sanhes L, Wattel E, Gyan E, Park S, Stamatoullas A, Banos A, Laribi K, Jueliger S, Bevan L, Chaffaut C, Sapena R, Samey B, Chermat F, Chevret S, Ades L,
Fenaux P
ASH 2016 Abstract 347
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Median OS of Responders: 19.7 mo
Median OS of Nonresponders : 5.7 mo
Survival
Sebert M, et al. Blood. 2016;128: Abstract 347.
• Median follow-up 11.9 months• Median OS from inclusion: 6.7 months (95% CI [5.6-11.8])
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CLO and LDAC in HR MDS Post HMA: Survival by Response Status
Jabbour E, et al. Cancer. 2017;123(4):629-637.
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FLT3 Inhibitors Under Development
Preclinical Phase I Phase II Phase III
VX-322 IMC-EB10 Sorafenib Midostaurin
VX-398 KW-2449 MLN-518 CEP-701
MC-2002 AP-24534 Quizartinib
MC-2006 CHIR-258 Crenolanib
PLX3397 FLX925
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Ready to Open Targeted Trials in MDS
• IDH-2 inhibition (MDACC 2016-0981)
• Two ABT-199 MDS studies– AZA+ABT-199 front line– AZA+ABT-199 HMA failure MDS
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Practical use of NGS in MDSGene Implication
CHIP/CCUS (DNMT3A, TET2,ASXL1,JAK2,SF3B1,P53,PPMD1)
ObservationIncreased risk of T-MN
P53 Favor HMAPoor outcome alloSCT
Flt-3 At HMA failure
IDH-2 Consider IDH2 inhibitor
IDH-1 Consider clinical trial
NPM1 Consider ARA-C based therapy
RAS At HMA failureConsider clinical trial
≥3 mutations Poor prognosis
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Conclusion and Needs• Increased role of genomic annotation in MDS• New targets: CD33, CD123, Bcl-2, TGF-b, TLR, SF3B1,IDH, Flt-3,
NPM1• Lower-dose HMAs for lower-risk MDS• Potent oral forms of HMAs: CC-486, ASTX727• Second-generation HMAs: SGI-110• Combinations: + PD1/PDL1 inhibitors• 5 ongoing phase III trials: CC-486, rigosertib, ACE-536, SGI-110 for
failures, ASTX7727• Need: p53, RAS, transplant integration