“Terapias alvo nas síndrome mielodisplásicas. Algo além do...

“Terapias alvo nas síndrome mielodisplásicas. Algo além do 5q- ? ”

Breno Moreno de GusmãoBP, a Beneficência Portuguesa de São Paulo

Hospital Santa Lúcia – [email protected]

@morenodegusmao

mailto:[email protected]

Conflitos de interesse

• Speaker: Amgen, Celgene, Janssen, MSD, United medical

• Ad. Board: Libbs, Gilead

Clasificación FAB% blastos sp % blastos mo % Sb en anillo

en moMonocitos sp

AR < 1 < 5 < 15 < 1x109 / L

ARSA < 1 < 5 ≥ 15 < 1x109 / L

AREB < 5 5 – 20 Indiferente < 1x109 / L

AREB-t ≥ 5 21 – 30 Indiferente < 1x109 / L

LMMCMD: < 13 × 109 leucocitos/LMP: > 13 × 109 leucocitos/L

< 5 0 – 20 Indiferente ≥ 1x109 / L

AR: Anemia Refractaria Simple.ARSA: Anemia Refractaria con Sideroblastos en Anillo.AREB: Anemia Refractaria con Exceso de Blastos.AREB-t: Anemia Refractaria con Exceso de Blastos en transformación.LMMC: Leucemia MieloMonocítica Crónica.

OMS 2008

% blastos sp % blastos

mo

% Sb en anillo

en moCitopenias Displasia

AR < 1 < 5 < 15 Anemia Sólo eritroide

ARSA 0 < 5 ≥ 15 Anemia Sólo eritroide

CRDM < 1 < 5 < 15 Bicitopenia o pancitopenia

≥ 2 líneas

CRDM con

Sb en anillo< 1 < 5 ≥ 15 Bicitopenia o

pancitopenia≥ 2 líneas

AREBTipo1 Tipo2

< 5 5 - 19

5 – 9 10 – 19

Indiferente Citopenia /s Indiferente

Sd. 5q- < 5 < 5 Indiferente Anemia Indiferente

SMD

inclasificable< 1 < 5 Indiferente Citopenia /s 1 línea

CRDM: Citopenia Refractaria con Displasia Multilínea.

CRDM con Sb en anillo: Citopenia Refractaria con Displasia Multilínea y Sideroblastos en anillo.

Sd. 5q-: Síndrome 5q- (presencia de la alteración citogenética aislada 5q-).

SMD inclasificable: Síndrome Mielodisplásico Inclasificable.

NOTA: los SMD que comparten signos de mielodisplasia y mieloproliferación se encuadran en la categoría de SMD / SMP), cuyo prototipo es la LMMC.

OS Transformation to AML

Schanz J, et al. J Clin Oncol. 2012;30:820-829.

IPSS-R: OS and Transformation to AML by Risk Group

1.0

0.8

0.6

0.4

0.2

0

Frac

tio

n S

urv

ival

35050 100 150 200 250 300

Mos

Very good (n = 81; events: 34)

Good (n = 1809; events: 890)

Intermediate (n = 529; events: 312)

Poor (n = 148; events: 109)

Very poor (n = 187; events: 158)

Log-rank P < .001

1.0

0.8

0.6

0.4

0.2

0

Frac

tio

n A

ML-

Free

Su

rviv

al

35050 100 150 200 250 300

Mos

Very good (n = 72; events: 6)Good (n = 1611; events: 284)Intermediate (n = 457; events: 145)Poor (n = 129; events: 56)Very poor (n = 167; events: 47)

Log-rank P < .001

0 0

Papaemmanuil E, et al. Blood. 2013.

Genomic and Epigenomic Landscapes of Adult De Novo Acute Myeloid Leukemia

N Engl J Med 2013

Impact on survival of mutation TP53 mutations in patients

with MDS treated with allogeneic stem cell transplantation

N Engl J Med. 2017;376(6):536–547

Luspatercept in Ring Sideroblast+ Myelodysplastic Syndrome (MEDALIST): Background

• MDS characterized by ineffective erythropoiesis, anemia requiring lifelong RBC transfusions

• Anemia treatment is unmet need in lower-risk transfusion-dependent MDS that is refractory to ESAs

• Luspatercept: first-in-class erythroid maturation agent

• Blocks aberrant Smad2/3 signaling to augment late-stage erythropoiesis

• Promising clinical activity in lower-risk MDS patients with anemia[1]

• MEDALIST: randomized, double-blind, placebo-controlled phase III trial evaluating safety and efficacy of luspatercept in pts with very low- to intermediate-risk MDS with ring sideroblasts who require regular RBC transfusions[2]

1. Platzbecker. Lancet Oncol. 2017;18:1338. 2. Fenaux. ASH 2018. Abstr 1.

MEDALIST: Study Design• International, randomized, double-blind, placebo-controlled phase III trial

Slide credit: clinicaloptions.comFenaux. ASH 2018. Abstr 1. NCT02631070.

Primary endpoint: RBC TI for ≥ 8 wks between Wk 1 and Wk 24

Secondary endpoints: RBC TI for ≥ 12 wks between Wk 1 and Wk 24, modified hematologic improvement–erythroid response per IWG 2006 criteria, DoR, Hb change from baseline

Patients ≥ 18 yrs of age with non-del(5q) MDS and ring

sideroblasts per WHO 2016 criteria; IPSS-R risk that is very

low, low, or intermediate; refractory, intolerant, or ineligible for ESAs; RBC transfusion dependent

(N = 229)

Luspatercept1.0 mg/kg* SC Q3W for ≥ 24

wks (n = 153)

PlaceboSC Q3W for ≥ 24 wks

(n = 76)

Randomized 2:1

*Could be titrated up to 1.75 mg/kg if needed.

Treatment continued

until lack of clinical

benefit or PD

http://www.clinicaloptions.com/

MEDALIST: EfficacyOutcome, %

Luspatercept(n = 153)

Placebo(n = 76)

P Value

RBC TI ≥ 8 wks in Wks 1-24 37.9 13.2 < .0001

RBC TI ≥ 12 wks in Wks 1-24 28.1 7.9 .0002

RBC TI ≥ 12 wks in Wks 1-48 33.3 11.8 .0003

mHI-E* ≥ 8 wks in Wks 1-24

Reduction of ≥ 4 RBC units/8 wks

Hb increase of ≥ 1.5 g/dL

52.948.663.0

11.814.35.0

< .0001

mHI-E* ≥ 8 wks in Wks 1-48

Reduction of ≥ 4 RBC units/8 wks

Hb increase of ≥ 1.5 g/dL

58.854.269.6

17.121.45.0

< .0001

Fenaux. ASH 2018. Abstr 1.

*Defined as transfusion reduction of ≥ 4 units/8 wks or mean hemoglobin increase ≥ 1.5 g/dL/8 wks in absence of transfusions

Among primary endpoint responders, the median duration of RBC TI response was 30.6 wks in the luspatercept arm vs 13.6 wks in the placebo arm

MEDALIST: Conclusions• Luspatercept significantly reduced RBC transfusion burden

compared with placebo in transfusion-dependent patients with very low- to intermediate-risk MDS with RS

• Met primary endpoint of improving proportion of patients achieving RBC transfusion independence for ≥ 8 wks in Wks 1-24

• Significantly more patients achieved RBC transfusion independence for ≥ 12 wks in Wks 1-24 and in Wks 1-48

• Significantly more patients achieved increase in Hb of ≥ 1.5 g/dL

• Luspatercept significantly improved mHI-E of ≥ 8 wks

• Treatment generally well tolerated

• Investigators conclude that luspatercept may offer new treatment option for transfusion-dependent anemia in lower-risk RS-positive MDS patients

Slide credit: clinicaloptions.comFenaux. ASH 2018. Abstr 1.


Venetoclax + HMAs in Elderly Patients With Untreated AML: Background• BCL-2: antiapoptotic protein overexpressed in AML, including AML stem

cells[4]

• Venetoclax: oral BCL-2 inhibitor • Promising activity seen when combined with HMAs in elderly patients with

untreated AML[5]

• Venetoclax in combination with azacitidine or decitabine or low-dose cytarabine granted accelerated approval in November 2018 by FDA for treatment of newly diagnosed AML in patients aged ≥ 75 yrs or who have comorbidities preventing use of intensive induction chemotherapy[6]

• Current dose-escalation and dose-expansion study assessed safety of venetoclax with azacitidine or decitabine in older patients with untreated AML ineligible for intensive chemotherapy[5,7]

• CR/CRi rate: 67%; median DoR: 11.3 mos; median OS: 17.5 mos; venetoclax 400 mg established R2PD[5]

• Current analysis reports data from expansion cohort of patients receiving venetoclax 400 mg + HMA[7]

1. National Cancer Institute. AML Stats. 2018. 2. Kantarjian. Blood. 2010;116:4422. 3. Krug. Dtsch Arztebl Int. 2011;108:863. 4. Tzifi. Adv Hematol. 2012;2012:524308. 5. DiNardo. Blood. 2018;[Epub]. 6. FDA. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm. 7. Pollyea. ASH 2018. Abstr 285. Slide credit: clinicaloptions.com


Venetoclax + HMAs in Elderly Patients With Untreated AML: Study Design

Multicenter, open-label phase Ib dose-escalation and dose-expansion study

Endpoints: Safety, CR/CRi, OS, DoRPollyea. ASH 2018. Abstr 285. Slide credit: clinicaloptions.com

Patients aged ≥ 60 yrs with untreated AML ineligible for

standard induction therapy;

ECOG PS 0-3; no favorable risk cytogenetics or

active CNS involvement

Safety, PK, dose

finding

Expansion stage:

safety and efficacy

confirmation

Venetoclax 400 mg + DEC(n = 6)

Venetoclax 400 mg + AZA(n = 4)






Escalation PhaseExpansion Phase

Analysis population includes only the

400-mg venetoclax dose patient cohort:

VEN + AZA, n = 84VEN + DEC, n = 31

Dosing: Venetoclax 100 mg Day 1, 200 mg Day 2, 400 mg Days 3-28; azacitidine 75 mg/m2 Days 1-7; decitabine 20 mg/m2 Days 1-5.Main exclusion criteria: previous treatment for AML or other hematologic disorder; favorable risk cytogenetic (NCCN); CNS involvement; WBC > 25 x 109/L; HIV, HBV, or HCV coinfection.


Venetoclax + HMAs in Elderly Patients With Untreated AML: Patient Population

Text…

Pollyea. ASH 2018. Abstr 285. Slide credit: clinicaloptions.com

Characteristic

Venetoclax 400 mg +

AZA(n = 84)

Venetoclax 400 mg +

DEC(n = 31)

Median age, yrs (range) ≥ 75 yrs, n (%)

75 (61-90)42 (50)

72 (65-86)8 (26)

ECOG PS, n (%) 0-1 2

58 (69)24 (29)

27 (87)4 (13)

Baseline BM blasts, n (%) < 30% ≥ 31% to <

50% ≥ 50%

24 (29)29 (34)31 (37)

7 (23)14 (45)10 (30)

Characteristic

Venetoclax 400 mg +

AZA(n = 84)

Venetoclax 400 mg +

DEC(n = 31)

Mutational analyses, mutated/tested (%)

TP53 IDH1/2 FLT3 NPM1

20/74 (27)20/74 (27)11/74 (15)14/74 (19)

7/22 (32)5/22 (23)3/22 (14)3/22 (14)

Cytogenetic risk, n (%) Intermediate Poor

50 (60)33 (39)

16 (52)15 (48)

Secondary AML, n (%)

21 (25) 9 (29)


Venetoclax + HMAs in Untreated AML: Responses

Slide credit: clinicaloptions.com

OutcomeVenetoclax 400 mg +

AZA(n = 84)

Venetoclax 400 mg + DEC

(n = 31)

CR 44 55

CRi 27 19

Median time to CR, mos (range) 1.2 (0.7-5.5) 1.9 (0.9-4.6)

Median no. treatment cycles in patients with CR, n (range)

6 (1-32) 6 (1-29)

Median DoR after CR/CRi, mos (95% CI) 12-mo EFS in patients with CR/CRi, % (95% CI)

21.2 (14.4-30.2)69 (52-80)

15.0 (5.0-22.5)57 (32-76)

12-mo overall EFS, % (95% CI) 12-mo EFS in patients with CR/CRi, % (95% CI) 12-mo EFS in patients with no CR/CRi, % (95%

CI)

57 (46-67)72 (58-81)19 (6-37)

61 (42-76)74 (51-87)25 (4-56)

Median overall OS, mos (95% CI) Median OS in patients with CR/CRi, mos (95% CI) Median OS in patients with no CR/CRi, mos (95%

CI)

16.9 (11.3-NR)40.3 (16.9-NR)

4.5 (2.4-8.9)

16.2 (9.1-27.8)18.2 (12.3-42.7)

4.8 (0.7-17.0)

MRD negativity, n/n (%) 29/60 (48) 9/23 (39)

Pollyea. ASH 2018. Abstr 285.


Venetoclax + HMAs Venetoclax + HMAs in Elderly Patients With Untreated AML: CR/CRi by Subgroup


Patient Group, CR/Crin/n (%) of Each Subgroup

Venetoclax 400 mg + AZA

Venetoclax 400 mg + DEC

Cytogenetic risk

Intermediate 38/50 (76) 11/16 (69)

Poor 22/33 (67) 12/15 (80)

AML type

de novo 48/63 (76) 16/22 (73)

Secondary 12/21 (57) 7/9 (78)

Mutations

TP53 13/20 (65) 6/7 (86)

IDH1/2 18/20 (90) 5/5 (100)

FLT3 8/11 (73) 1/3 (33)

NPM1 11/14 (79) 3/3 (100)Pollyea. ASH 2018. Abstr 285.


Venetoclax + HMAs in Elderly Patients With Untreated AML: Investigator Conclusions

• In older patients with untreated AML ineligible for intensive chemotherapy, venetoclax 400 mg with azacitidine or decitabine was active and tolerable

• CR/CRi: 71% vs 74% with venetoclax + azacitidine or decitabine, respectively• Baseline genetic mutations, cytogenetic risk had little effect on CR/CRi rates

• 12-mo DoR: 69% vs 57% with venetoclax + azacitidine or decitabine, respectively

• Median OS: 16.9 vs 16.2 mos with venetoclax + azacitidine or decitabine, respectively

• Most common serious AEs• Febrile neutropenia: 31% vs 45% with venetoclax + azacitidine or decitabine,

respectively• Pneumonia: 23% vs 29% with venetoclax + azacitidine or decitabine,

respectively • Ongoing phase III trial evaluating venetoclax 400 mg plus azacitidine in

untreated AML ineligible for standard induction therapy (NCT02993523)

Slide credit: clinicaloptions.comPollyea. ASH 2018. Abstr 285.


Immune Checkpoint Inhibitors in MDS: Background

PD-1, PD-L1, and CTLA-4 are expressed by CD34+ MDS cells

‒ Overexpressed in the presence of HMAs both in vitro and in vivo[1]

Immune checkpoints: emerging therapeutic targets in many cancers

New therapies needed for treating MDS in frontline setting and after HMA failure

Current analysis evaluated safety and efficacy of ICI treatment, alone for MDS after HMA failure or in combination with an HMA for frontline treatment of patients with MDS[2]

1. Yang. Leukemia. 2014;28:1280. 2. Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com


Checkpoint Inhibitors in MDS: Study Design

Garcia-Manero. ASH 2018. Abstr 465. Slide credit: clinicaloptions.com

Exploratory phase II basket trial*

Patients ≥ 18 yrs of age with WHO MDS,

untreated or HMA failure; acceptable PS,

hepatic, and renal function; no prior inflammatory or

autoimmune disease(N = 76†) 5-azacitidine 75 mg/m2 IV x 5 days Q28d +

Nivolumab 3 mg/kg IV Days 6, 20

(n = 20)

5-azacitidine 75 mg/m2 IV x 5 days Q28d +

Ipilimumab 3 mg/kg IV Days 6

(n = 21)

*Data for 2 cohorts (ipilimumab + nivolumab and 5-azacitidine + ipilimumab + nivolumab) not included in this analysis. †Maximum 20 patients/ cohort. ‡5-azacitidine added back if no response after 6 cycles of ICI.

Untreated

HMA failure

Nivolumab 3 mg/kg IV Q2W‡

(n = 15)

Ipilimumab 3 mg/kg IV Q3W‡

(n = 20)Stopping rules for toxicity and

response

Primary endpoints:

ORR (CR + PR + HI) in patients with HMA failure

ORR in untreated patients


Checkpoint Inhibitors in MDS: Response

3 patients were not evaluable

Median number of cycles: 4 (range: 1-29)

Median number of cycles to response: 3 (reang: 1-15)


Response, n (%)

Frontline HMA Failure

Nivo + AZA(n = 20)

Ipi + AZA(n = 21)

Nivo(n = 15)

Ipi(n = 20)

ORR 14 (70) 13 (62) 0 6 (30)

CR 8 (40) 3 (14) 0 0

mCR + HI 2 (10) 0 0 1 (5)

mCR 3 (15) 7 (33) 0 3 (15)

HI 1 (5) 3 (14) 0 3 (15)

SD 0 1 (5) 0 0

NR 5 (25) 5 (24) 15 (100) 13 (65)


Checkpoint Inhibitors in MDS: OS in Untreated Patients


Median OS, MosNot reached

11.8

1-Yr OS, %6850

2120

1417

1110

48

04

01

1.00

0.75

0.50

0.25

0

OS

0 6 12 18 24 30Mos

P = .36

StrataAZA + IpilimumabAZA + Nivolumab

Number at risk

AZA + IpilimumabAZA + Nivolumab


Checkpoint Inhibitors in MDS: OS after HMA Failure


1-Yr OS, %4525

Median OS, Mos8.5 8.0

2015

127

93

63

32

00

1.00

0.75

0.50

0.25

0

OS

0 6 12 18 24 30Mos

StrataIpilimumabNivolumab

P = .48

IpilimumabNivolumab

Number at risk


Checkpoint Inhibitors in MDS: Conclusions Treatment with immune checkpoint inhibitors showed significant activity

in MDS, both as single agents and in combination with 5-AZA

‒ Single-agent activity of ipilimumab after HMA failure: ORR, 30%; 1-yr OS, 45%

‒ High response rates with nivolumab + AZA: CR, 40%; ORR, 70%

‒ Median OS not reached with ipilimumab + AZA

Acceptable toxicity profile

Investigators concluded that the incorporation of ipilimumab or nivolomab into treatment of MDS is feasible, but further randomized studies needed



Ivosidenib in Mutant IDH1 AML:

Background Somatic mutations in enzymes IDH1 and IDH2 cause accumulation of

oncometabolite 2-HG[1]

– 2-HG accumulation results in epigenetic changes and impaired cellular differentiation

mIDH has been found in solid and hematologic tumors, including AML

– mIDH1 found in approximately 6% to 10% AML pts

– mIDH2 found in approximately 9% to 13% AML pts

Ivosidenib (AG-120), investigational, first-in-class, oral, reversible targeted inhibitor of mIDH1 enzyme[2]

Current phase I study investigating dosage, safety, and clinical activity of ivosidenib in pts with mIDH1-positive R/R AML, untreated AML, and other hematologic malignancies[3]

1. Dang L, et al. Ann Oncol. 2016;27:599-608. 2. Birenda KC, et al. Clin Lymphoma

Myeloma Leuk. 2016;16:460-465.3. DiNardo CD, et al. ASH 2017. Abstract 725. Slide credit: clinicaloptions.com



Phase I

Study Design Multicenter, open-label, dose-escalation/expansion trial

Pts with mIDH1

advanced

hematologic

malignancies

Ivosidenib PO daily, 28-day cycles

100 mg BID, or 200 mg, 500 mg,

800 mg, or 1200 mg QD

(n = 78)

Dose Escalation

Primary endpoints: safety and tolerability, MTD and/or RP2D, and clinical activity* in mIDH1 R/R AML

Secondary endpoints: DLTs, PD, PK, preliminary clinical activity in advanced hematologic malignancies

Exploratory endpoints: determination of comutations and mIDH1 VAFIvosidenib 500 mg PO QD

28-day cycles

(n = 180)

DiNardo CD, et al. ASH 2017. Abstract 725.

Dose Expansion

Pts with R/R AML in second

relapse, relapse after SCT,

refractory to induction or

reinduction, relapse ≤ 1 yr

(n = 126)Pts with untreated AML

ineligible for SoC (n = 25)

Pts with non-AML mIDH1

R/R advanced

hematologic malignancy

(n = 11)Pts with R/R AML not

eligible for other R/R AML

arm (n = 18)


*CR CRh



Baseline Characteristics

CharacteristicPrimary R/R AML Set

(n = 125)

Median age, yrs (range) 67.0 (18-87)

Male, % 52

ECOG PS 0 at screening, %

ECOG PS1 at screening, %

21.6

51.2

De novo AML, %

Secondary AML, %

History of MDS, %

Therapy-related AML, %

66.4

33.6

14.4

11.2

Median no. of previous

therapies (range)2.0 (1-6)

Earlier AML therapy

outcomes,* %

Relapsed after transplant

In second or later relapse

Refractory to initial

induction/reinduction

therapy

Relapsed ≤ 1 yr of initial

therapy

28.8

16.0

68.8

10.4

CharacteristicPrimary R/R AML Set

(n = 125)

Cytogenetic risk status,†%

Favorable

Intermediate

Poor

Unknown

Missing

0

52.8

30.4

3.2

13.6

Comutation rates,‡%

FLT3

• FLT3-ITD

• FLT3-TKD

NPM1

CEBPA

8.1

2.4

5.6

19.4

2.4

DiNardo CD, et al. ASH 2017. Abstract 725.

*Not mutually exclusive. Individual pt may be in

> 1 category.†Determined by investigator.‡n = 124.



Median treatment duration for primary R/R AML set: 3.9 mos (range: 0.1-25.8)

Ivosidenib in Mutant IDH1 AML: Response in

Primary R/R AML Set

Duration of Best Overall Response in

Responders (n = 52)

Duration of

Response

CR +

CRhCR All

Median, mos 8.2 9.3 6.5

At 6 mos, % 59.3 67.5 55.0

At 12 mos, % 32.4 41.2 24.6

OutcomePrimary R/R AML Set

(n = 125)

CR + CRh, % (95% CI)

Median time to CR/CRh, mos (range)

Median duration of CR/CRh, mos (range)

30.4 (22.5-39.3)

2.7 (0.9-5.6)

8.2 (5.5-12.0)

CR, % (95% CI)

Median time to CR, mos (range)

Median duration of CR, mos (95% CI)

21.6 (14.7-29.8)

2.8 (0.9-8.3)

9.3 (5.6-18.3)

CRh, %* 8.8

ORR, % (95% CI)

Median time to first response, mos

(range)

Median duration of response, mos (95%

CI)

41.6 (32.9-50.8)

1.9 (0.8-4.7)

6.5 (4.6-9.3)

Best response, %

CR

CRi or CRp

MLFS

SD

PD

NA

21.6

12.8

7.2

35.2

10.4

12.8

DiNardo CD, et al. ASH 2017. Abstract 725. Slide credit: clinicaloptions.com

*6 pts w/investigator-assessed

CRi/CRp, 5 w/MLFS


Ivosidenib in Mutant IDH1 AML: OS and

Transfusion Independence in R/R AML


Independence from Transfusion by

Best Response*

OS by Best Response (n = 125)Median OS,

Mos

NE

9.3

3.9

8.8

Pts, n

38

14

73

125

Pro

ba

bil

ity o

f S

urv

iva

l

CR + CRh

Non-CR/CRh

responders

Nonresponders

Overall

Censored

CR

CRh

Non-CR/CRh

responders

Nonresponders

Overall

Po

stb

as

eli

ne

Tra

ns

fus

ion

Ind

ep

en

de

nc

e (

%)

Platelet

(n = 69)

RBC

(n = 68)

*Transfusion independence: no transfusion for at least 1 56-day period.

1.0

0.8

0.6

0.4

0.2

0

0.9

0.7

0.5

0.3

0.1

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32

Mos

100100

80

60

40

20

0

84.6

71.475.0

58.3

50.0

16.7 15.4

39.1 39.7


Ivosidenib in Mutant IDH1 AML: Response in

Untreated AML and MDS

Outcome Untreated AML (n = 34) MDS (n = 12)

Median age, yrs (range) 76.5 (64-87) 72.5 (52-78)

Male, % 55.8 75

ECOG PS 0 at screening, n (%)

ECOG PS 1 at screening, n (%)

8 (23.5)

20 (58.8)

4 (33.3)

6 (50.0)

Previous MDS, n (%) 18 (52.9) NA

ORR, % (95% CI)

Median duration of response, mos (95% CI)

Median duration of CR, mos (95% CI)

55.9 (37.9-72.8)

9.2 (1.9-NE)

NE (5.5-NE)

91.7 (61.5-99.8)

NE (2.3-NE)

NE (2.8-NE)

Best response, n (%)

CR

CRi or CRp

PR

MLFS

SD

PD

NA

7 (20.6)

7 (20.6)

1 (2.9)

4 (11.8)

10 (29.4)

3 (8.8)

2 (5.9)

5 (41.7)

NA

NA

6 (50.0)

0

1 (8.3)

0




Conclusions

Ivosidenib was well tolerated, most AEs grade 1/2

In pretreated pts with IDH1-positive R/R AML, ivosidenib associated with durable responses

– CR + CRh: 30.4%; duration: 8.2 mos

– ORR: 41.6%; duration: 6.5 mos

Transfusion independence achieved across best response categories

Preliminary evidence of durable responses in pts with untreated AML

Young G, et al. ASH 2017. Abstract 85. Slide credit: clinicaloptions.com


Enasidenib in mIDH2 MDS: Background

• IDH2 gene mutated in approximately 5% of MDS pts[1]

• Critical for the citric acid cycle; mutant form can alter gene expression, block differentiation of hematopoietic progenitor cells

• mIDH2 produces 2-HG, an oncometabolite that blocks cellular differentiation by altering DNA methylation

• May represent a therapeutic target

• Enasidenib (AG-221): first-in-class, potent oral inhibitor of mIDH2enzyme[2]

• Current analysis assessed efficacy, safety of enasidenib in MDS ptswith mIDH2[3]

1. Medeiros BC, et al. Leukemia. 2016;[Epub ahead of print]. 2. Chen J, et

al. Mini Rev Med Chem. 2016;16:1344-1358. 3. Stein EM, et al. ASH

2016. Abstract 343. Slide credit: clinicaloptions.com

http://www.clinicaloptions.com/oncology

Enasidenib in mIDH2 MDS: Study Design

• Subset analysis of open-label phase I/II dose escalation/expansion study of enasidenib in hematologic malignancies with IDH2 mutation (N = 239)

• MDS pts with mIDH2 R/R RAEB-1/RAEB-2, IPSS-R high-risk disease, or ineligible for other treatment (n = 17)

• Oral daily enasidenib (50-650 mg in dose escalation; 100 mg in expansion) in continuous 28-day cycles

• Key endpoints: safety, tolerability, ORR per local investigator (IWG 2006 MDS criteria)

• Co-molecular profiling with next-generation sequencing

Slide credit: clinicaloptions.comStein EM, et al. ASH 2016. Abstract 343.


Enasidenib in mIDH2 MDS: Baseline Characteristics

Characteristic MDS Pts

(N = 17)

Median age, yrs (range) 67 (45-78)

Male, % 71

Mean time since diagnosis, mos (SD) 16.8 (14.5)

IDH2 mutation: R140/R172, % 88/12

Prior anticancer regimens: 0/1/≥ 2, % 24/41/35

Hematology, median (range)

ANC, 109/L

Platelets, 109/L

WBC, 109/L

Hemoglobin, g/dL

0.7 (0.2-32.1)

71 (19-246)

2.1 (0.5-44.4)

8.9 (7.3-12.2)

ECOG PS 0-1/2, % 76/24


*Data missing for 4 of 17 pts.†Sorafenib, n = 2; cytarabine + clofarabine,

pracinostat, epoetin alfa, rigosertib, ruxolitinib,

vosaroxin, n = 1 each.

Characteristic, % MDS Pts (N = 17)

IPSS risk status*

Intermediate-1/intermediate-2 or

high29/47

MDS cytogenetic risk*

Good/intermediate/poor 47/24/6

IPSS-R risk status*

Low/intermediate/high or very

high 18/12/47

Prior treatment

HMA

Lenalidomide

Other†

None

76

12

47

24


Response, n/N (%) MDS Pts

(N = 17)

ORR* 10/17 (59)

CR† 1/11 (9)

PR† 1/11 (9)

mCR† 3/11 (27)

Any HI

Erythrocytes

Platelets

Neutrophils

Trilineage

improvement

Bilineage improvement

5/17 (29)

3/15 (20)

4/12 (33)

4/10 (40)

2/5 (40)

2/5 (40)

Enasidenib in mIDH2 MDS: Response

• 7 of 13 pts (54%) with prior HMA responded to enasidenib

• Median time to response: 21 days (range: 10-87)


*CR + PR + mCR + HI.†Investigator-assessed; pts had ≥ 5%

BM blasts at BL.


Enasidenib in mIDH2 MDS: OS• Median OS not

reached at median follow-up of 7.5 mos

Slide credit: clinicaloptions.comStein EM, et al. ASH 2016. Abstract 343. Reproduced with permission.

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Pts at

Risk, n 1

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0

1

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Novel approaches to MDS currently in clinicle trials.

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