Midostaurin bei FLT3-mutierter AML: Praxisnutzen der...

Wien, 29.09.2018

Midostaurin bei FLT3-mutierter AML: Praxisnutzen der ersten zielgerichteten Therapieoption

PD Dr. med. Thomas SchroederKlinik für Hämatologie, Onkologie und Klinische Immunologie

1950-1960s 1970s 1980s 1990s 2000s 2010s

Daunorubicin

Cytarabine

Daunorubicin+ Cytarabine

High-doseCytarabine

Idarubicin+ Cytarabine

Timeline of „Progress“ in AML

Decitabine

Azacitidine

Grimwade et al., Blood 2015; The Cancer Genome Atlas Research Network, NEJM 2013

1950-1960s 1970s 1980s 1990s 2000s 2010s

Daunorubicin

Cytarabine

Daunorubicin+ Cytarabine

High-doseCytarabine

Idarubicin+ Cytarabine

Timeline of „Progress“ in AML

Decitabine

Azacitidine

Midostaurin

Enasidenib

GO

Ivosidenib

CPX-351

Quizartinib

FMS-like tyrosine kinase 3 (FLT3) Mutations in AML

Small D, Hematology Am Soc Hematol Educ Program 2016; Papaemmanuil et al., NEJM 2016

Internal tandemduplications

22%

TKD mutations7.9%

• FLT3-ITD mutation has a negative impact on long-term outcomes1,2

– Compared with patients without the mutation, patients with FLT3-ITD had higher relapse rates (65% vs 44%), lower rates of disease-free survival (30% vs 46%), and lower overall survival (32% vs 44%) at 5 years2

• The prognostic role of FLT3-TKD is still under debate– Some studies show a negative impact of

FLT3-TKD on DFS, EFS, and OS,3-5 but other studies suggest FLT3-TKDs do not have a prognostic effect or even provide a benefit6,7

• Detection of FLT3 mutations has been incorporated into the recommended workup for newly diagnosed AML8,9

Prognostic significance of FLT3mutations

Figure republished with permission of American Society of Hematology. Kottaridis PD, et al. Blood. 2001;98:1752-1759.

10075

50

25

0 0 1 2 3 4 5P < .001

Years From Remission

Rel

apsi

ng, %

10075

50

25

0 0 1 2 3 4 5P < .001

Years From Remission

Dis

ease

Fre

e, %

10075

50

25

0 0 1 2 3 4 5P < .001

Years From Entry

Still

Aliv

e, %

FLT3-ITD ↑ Relapse

FLT3-ITD ↓ Disease free

FLT3-ITD ↓ Survival

FLT3-ITD Is a Negative Prognostic Factor2

DFS, disease-free survival1. Pratcorona M, et al. Blood. 2013;121:2734-2738. 2. Kottaridis PD, et al. Blood. 2001;98:1752-1759. 3. Yanada M, et al. Leukemia. 2005;19:1345-1349. 54. Whitman SP, et al. Blood. 2008;111:1552-1559. 5. Thiede C, et al. Blood. 2002;99:4326-4335. 6. Bacher U, et al. Blood. 2008;111:2527-2537. 7. Mead AJ, et al. Blood. 2007;110:1262-1270. 8. Döhner H, et al. Blood. 2017;129:424-447. 9. Arber DA, et al. Arch Pathol Lab Med. [published online ahead of print February 22, 2017]

5

MidostaurinMidostaurin is a multitargetedtyrosine kinase inhibitor of FLT3, KIT and other kinases known to be involved in cancer (eg, PDGFR and PKC)

• 1st generation TKIs non-selective, more off-target effects, only transient blast reductions when used as single agent

• 2nd generation TKIs (quitazinib [AC220], crenolanib, gilteritinib) more selective and more potent

IC50

Midostaurin and other FLT3 Inhibitors

Karaman MW et al., Nature Biotechnology 2008; Zarrinkar PP et al., Blood 2009

1st

Generation2nd

Generation

RATIFY: Schema

APL, acute promyelocytic leukemia; bid, twice daily; q12h, every 12 hours.a Documented AML (no APL or therapy-related AML).b Hydroxyurea therapy allowed ≤ 5 days prior to start of study treatment.c As determined using BM or PB samples using an assay that was later developed into the LeukStrat CDx FLT3 Mutation Assay.

Phase 3, randomized, double-blind, placebo-controlled study

7

1 cycle = 28 days.First patient enrolled July 2008, Last patient enrolled October 20113270 screened, 717 randomized

SCT was not specifically mandated. In the event that a patient received SCT directed against their leukemia, midostaurin/placebo therapy was not to be resumed

Midostaurin(50 mg bid, days 1-28)

Placebo(bid, days 1-28)

Cytarabine(200 mg/m2/day, days 1-7)

Daunorubicin(60 mg/m2/day, days 1-3)

Midostaurin(50 mg bid, days 8-21)

Placebo(bid, days 8-21)

Cytarabine(200 mg/m2/day, days 1-7)

Daunorubicin(60 mg/m2/day, days 1-3)

High-dose cytarabine

(3 g/m2/day q12h, days 1, 3, and 5)

Midostaurin(50 mg bid, days 8-21)

High-dose cytarabine

(3 g/m2/day q12h, days 1, 3, and 5)

Placebo(bid, days 8-21)

Induction (1-2 cycles)

Consolidation(up to 4 cycles)

Postconsolidation(up to 12 cycles)

CR CR

R

Double blind

Patients with newly diagnosed AML

aged ≥ 18 to < 60 years

with activating FLT3mutationsa,b

Stratification by TKD and ITDc

(ratio < 0.7 vs ≥ 0.7)

(N = 717)

Primary endpoint: OSKey secondary endpoint: EFS

Patients in the pivotal study were not rerandomized prior to postconsolidation treatment. Therefore, there are no data on the efficacy of midostaurin in this treatment stage alone.

Stone RM, et al. N Engl J Med. 2017;377:454-464.

RATIFY: Revised analysis plan

DSMB, Data Safety Monitoring Board; SCT Stem Cell Transplantationa Critical value to declare statistical significance (1-sided).

8

Statistical Plan

No. of Events

No. of Patients Accrued Power Alphaa

HR to Be Detected

Original 374 514 90% 0.025 0.71

2010 amendment 509 714 84% 0.025 0.78

2015 amendment 357 717 84% 0.0239 0.78

• The event rate (ie, deaths) reached a plateau in 2014 (6 events in 2014 and 4 events by May 2015). Alliance DSMB decided to perform the final analysis with a data cutoff of May, 2015, without achieving the required 509 OS events

− The SCT rate was higher than expected (25% at the time of amendment vs 15% anticipated)

• EFS was promoted to a key secondary endpoint to be tested in a hierarchical manner if OS was significant

*

Stone RM, et al. N Engl J Med. 2017;377:454-464.

RATIFY: Patient characteristics

a Two-sided; Kruskal-Wallis P values are presented for continuous measures (eg, age) and Chi-square values are presented for categorical counts (eg, sec).b Patients could also have FLT3-TKD. c WBC white blood cell count. d ANC absolute neutrophil countStone RM, et al. N Engl J Med. 2017;377:454-464.

9

From Stone RM, et al. N Engl J Med. 2017;377:454-464. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

*

All Patients(N = 717)

Midostaurin (n = 360)

Placebo (n = 357) P valuea

Median age (range), years 47.9 (18.0-60.9)

47.1 (19.0-59.8)

48.6(18.0-60.9) .22

Female sex, n (%) 398 (55.5) 186 (51.7) 212 (59.4) .04FLT3 stratification groups, n (%) 1.00

FLT3-TKD 162 (22.6) 81 (22.5) 81 (22.7)FLT3-ITD allelic ratio < 0.7b 341 (47.6) 171 (47.5) 170 (47.6)FLT3-ITD allelic ratio ≥ 0.7b 214 (29.8) 108 (30.0) 106 (29.7)

Median WBCc (range), × 103/μL 34.9(0.6-421.8)

35.6(0.6-421.8)

33.0(0.8-329.8) .72

Median platelet count (range), ×103/μL

50.0(2.0-461.0)

50.0(2.0-461.0)

50.0(8.0-444.0) .58

Median ANCd (range), per mm3 2.2(0-55.9)

2.2(0-55.9)

2.3(0-55.9) .65

RATIFY: Consort diagram

10References and footnotes in speaker notes.

3277 Patients screened

896 (27%) positive for FLT3 mutation

717 (80%) Randomizeda

360 Midostaurin Arm

Induction• 355 initiated induction 1

o 81 required induction 2• 274 completed induction

Consolidation• 231 initiated consolidation• 129 completed consolidation

Maintenance• 120 initiated maintenance• 69 completed maintenance

357 Placebo Arm

Induction• 354 initiated induction 1

o 101 required induction 2• 264 completed induction

Consolidation• 210 initiated consolidation• 103 completed consolidation

Maintenance• 85 initiated maintenance• 51 completed maintenance

2381 FLT3-WT

• Not treated (n = 3)

Reasons for discontinuing (n = 144):• 8 AEs • 41 alternative therapyb

• 11 death• 4 disease progression• 35 induction failurec

• 1 other disease • 12 other reasons• 32 patient withdrawal

Reasons for discontinuing (n = 125):• 9 AEs• 65 alternative therapyb

• 7 death• 27 disease progression• 1 other disease • 9 other reasons• 7 patient withdrawal

• Not treated (n = 5)

Reasons for discontinuing (n = 124):• 15 AEs• 36 alternative therapyb

• 16 death• 7 disease progression• 24 induction failurec

• 1 other disease • 13 other reasons • 12 patient withdrawal

Reasons for discontinuing (n = 111):• 8 AEs• 69 alternative therapyb

• 2 death• 19 disease progression• 1 other disease • 6 other reasons • 6 patient withdrawal

Reasons for discontinuing (n = 51):• 9 AEs• 4 alternative therapyb

• 32 disease progression• 1 other disease • 1 other reasons • 4 patient withdrawal

Reasons for discontinuing (n = 34):• 5 AEs• 1 alternative therapyb

• 27 disease progression• 1 patient withdrawal

*

36% 29%

19% 14%Stone RM, et al. N Engl J Med. 2017;377:454-464.

RATIFY: OS, noncensored for SCTPrimary endpoint22% reduced risk of death in the midostaurin arm (vs placebo)

Midostaurin 360 269 208 181 151 97 37 1Placebo 357 221 163 147 129 80 30 1

Patients,n

Median (95% CI), months

HR(95% CI)

PValuea

Midostaurin 360 74.7(31.5-NE) 0.78

(0.63-0.96) .009Placebo 357 25.6

(18.6-42.9)

0 12 24 60

Patie

nts

Surv

ivin

g, %

72 84

80

90

100

Time, months36 48 90

50

60

70

20

30

40

10

0

Patients at risk

From Stone RM, et al. N Engl J Med. 2017;377:454-464. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

11 *

NE, not estimable.a Cox model stratified on FLT3 subtype. b Stratified on FLT3 subtype; one-sided, log-rank P value. Stone RM, et al. N Engl J Med. 2017;377:454-464.

RATIFY: Consistent effect on OS by FLT3 statusSecondary endpoint

N HR (95% CI)HR

(95% CI) P Valuea

Overall (stratified) 717 0.78

(0.63-0.96) .009

FLT3-ITD high 214 0.80

(0.57-1.12) .19

FLT3-ITD low 341 0.81

(0.60-1.11) .19

FLT3-TKD 162 0.65 (0.39-1.08) .10

0,25 0,5 0,75 1 1,25Favors midostaurin Favors placebo

12

a P value is one-sided for the overall (stratified) analysis; P values are two-sided for the analyses by FLT3 subgroup.FLT3-ITD-low, FLT3-ITD/-WT allelic ratio < 0.7; FLT3-ITD-high, FLT3-ITD/-WT allelic ratio ≥ 0.7.

From Stone RM, et al. N Engl J Med. 2017;377:454-464. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Stone RM, et al. N Engl J Med. 2017;377:454-464.

Similar advantage for Event-free and Disease-free Survival

Lower Cumulative Incidence of Relapse (non-significant)

RATIFY: CR rates by armSecondary endpoint

a Two-sided Fisher’s Exact P. b Per protocol, CRs were defined as occurring within 60 days of initiating study protocol therapy. c An expanded definition of CR Included all CRs reported within 30 days of ending protocol therapy. d Kaplan-Meier estimates.

0

20

40

60

80

100

CR Within 60 Days of StartingTherapy

CR Witin 30 Days of StoppingTherapy

Patie

nts,

%

Midostaurin (n = 360) Placebo (n = 357)

59%54%

68%61%

P = .15a

P = .04a

b c

Median time to CR (range), daysd

35 (20-60)

35 (20-60)

37 (20-192)

36 (20-108)

13

Stone RM, et al. N Engl J Med. 2017;377:454-464.

RATIFY: AlloSCT rates by armSecondary endpoint

0

20

40

60

80

100

All transplants Transplants in protocol-defined CR1

Patie

nts,

%

Midostaurin (n = 360) Placebo (n = 357)

59%(95% CI, 54%-64%) 55%

(95% CI, 50%-60%)

28%(95% CI, 23%-33%) 23%

(95% CI, 18%-27%)

P = .26a

P = .10a

a Two-sided Fisher’s Exact P. b For patients who received an SCT in CR1 (101 in the midostaurin arm and 81 in the placebo arm). c Two-sided log-rank test.

14

Overall transplant rate (95% CI), %

57 (53-61)

25 (22-29)

Median OS (95% CI), monthsb

NR(69.8-NR)

NR(21.8-NR)P = .07c

*

Stone RM, et al. N Engl J Med. 2017;377:454-464.

RATIFY: OS, censored at time of SCTSecondary endpoint

a two-sided, log-rank P value, stratified on FLT3 subtype.

Midostaurin 360 136 80 64 54 35 13 1Placebo 357 97 64 57 49 32 10 1

Patients,n

Median (95% CI), months

HR(95% CI)

PValuea

Midostaurin 360 NE(NE-NE) 0.76 .08

Placebo 357 NE (27.4-NE)

0 12 24 60 72 8436 48

Patie

nts

Surv

ivin

g, %

Time, months

80

90

100

50

60

70

20

30

40

10

900

Patients at risk

15

Stone RM, et al. N Engl J Med. 2017;377:454-464.

From Stone RM, et al. N Engl J Med. 2017;377:454-464. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Similar advantage for Event-free and Disease-free Survival

RATIFY: OS by timing of SCTSecondary endpoint

16

0 12 24 60 7236 48 80

Patie

ntsS

urvi

ving

, %

Time, months

Patie

ntsS

urvi

ving

, % 80

90

100

50

60

70

20

30

40

10

0

Stone RM, et al. N Engl J Med. 2017;377:454-464.a 2-sided, log-rank P value, stratified on FLT3 subtype.

MidostaurinPlacebo

MidostaurinPlacebo

SCT outside CR1

SCT in CR1

101 71 63 21 081 50 45 12 0112 49 36 5 0115 47 37 13 0

Patients at risk

From Stone RM, et al. N Engl J Med. 2017;377:454-464. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Patients, nMedian (95% CI),

months P Valuea

SCT in CR1Midostaurin 101 NE (69.8-NE)

.07Placebo 81 NE (21.8-NE)

SCT outside CR1Midostaurin 112 14.8 (9.1-31.6)

.85Placebo 115 14.4 (10.0-22.7)

Herr L.*1983

Leukozyten 3.000/µl; Hb 6,5 g/dl; Thrombozyten 52.000/µl

* Authentisches Patientenbeispiel

Untersuchung von Blutausstrichen: Blutzellmorphologie/ Differentialblutbild• Blasten: 16• Segmentkernige: 17 z.T. mit • Segmentanomalien• Monozyten: 5• Lymphozyten: 62 z.T. atypisch• Kernhaltige Rote Vorstufen: 4• Anisozytose: +• Poikilozytose: +• Hypochromasie: +• Polychromasie: (+)• Eliptozyten: +• Thrombozyten: ausgeprägte Thrombozytopenie

Molecular Diagnostic for AML Patients

Herr L.*1983

Döhner et al., Blood 2017* Authentisches Patientenbeispiel

„3+7“*

AML Therapy AlgorithmIntensive Therapy

Diagnosis

„3+7“optional

Induction

Midostaurin

In case ofFLT3 mut

* 3+7: Standard-Chemotherapie mit Cytarabin/Daunorubicin zur Induktion

„3+7“*

HD-AraC**

AML Therapy AlgorithmIntensive Therapy

Diagnosis

„3+7“optional

Induction

Midostaurin

In case ofFLT3 mut Allo-SCT

Consolidation

Midostaurin

In case ofFLT3 mut

* 3+7: Standard-Chemotherapie mit Cytarabin/Daunorubicin zur Induktion** HD Aarc Hochdosis Cytarabin zur Konsolidierung

Prognostic Impact of FLT3-ITD Ratio

Schlenk et al., Blood 2014

HD-AraC

AML Therapy AlgorithmIntensive Therapy

Maintenance

Midostaurin

MRD

MRD

Consolidation

Midostaurin12 months

• 3+7: Midostaurin in Kombination mit einer Standard-Chemotherapie mit Cytarabin/Daunorubicin zur Induktion und einer Hochdosis-Chemotherapie mit Cytarabin zur Konsolidierung.

Clinical CourseHerr L., *1983, NPM1 mut/FLT3-ITDlow AML

Induction Consolidation

Midostaurin

Maintenance 12 months

+

RATIFY: SafetyMost common nonhematologic grade ≥ 3 AEs

25

0

20

40

60

80

100

Patie

nts,

%

Midostaurin (n = 355) Placebo (n = 354)

a Infection includes the following terms: infection with grade 3/4 neutrophils (ANC < 1.0 × 103/μL), infections with normal ANC or grade 1/2 neutrophils, infection with unknown ANC, opportunistic infection associated with grade ≥ 2 lymphopenia, and other infections. b Fatigue includes asthenia, lethargy, and malaise. c Includes pneumonitis and pulmonary infiltrates.

P = .84

P = .60

P = .35P = .92

P = .25

P = .82 P = .19 P = .008P = .53 P = .89 P = .05 P = .32 P = .67 P = .38 P = .14 P = .76

*

Stone RM, et al. N Engl J Med. 2017;377:454-464.

Top 20 Nonhematologic AEs Regardless of Attribution

Anemia grade ≥ 3 Midostaurin 92.7% vs. Placebo 87.8%, p=0.03

Time to hematopoietic recovery identical

• Nausea and Vomiting* - Antiemetic prophylaxis- Intake together with meal

• QTc Time Prolongation* - Routine Echocardiogram- >470 ms Dose reduction

>500 ms Stop• Febrile Neutropenia Ivo* - Stop

• Combination with - possible, monitor toxicityPosaconazol*

*Aktuelle Fachinformation RYDAPT®, Novartis Pharma GmbH

Side Effects of MidostaurinManagement

An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective

Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY) for Newly Diagnosed Acute

Myeloid Leukemia Patients with FLT3 Mutations

Richard A. Larson, Sumithra J. Mandrekar, Ben L. Sanford, Kristine Laumann, Susan M. Geyer, Clara D. Bloomfield, Christian Thiede, Thomas W. Prior,

Konstanze Dohner, Guido Marcucci, Francesco Lo Coco, Rebecca B. Klisovic, Andrew Wei, Jorge Sierra, Miguel A. Sanz, Joseph M. Brandwein, T. M. M de Witte, Dietger Niederwieser, Frederick R. Appelbaum, Bruno C.

Medeiros, Martin S. Tallman, Jurgen Krauter, Richard F. Schlenk, Arnold Ganser, Hubert Serve, Gerhard Ehninger, Sergio Amadori,

Hartmut Döhner, and Richard M. StoneLarson et al. ASH 2017, Abstract 145.

CALGB 10603/ RATIFY

RANDOMIZE

DNRARA-C

Midostaurin

DNRARA-C

Placebo

HidACMidostaurin

HidACPlacebo

MidostaurinMAINTENANCE

12 months

PlaceboMAINTENANCE

12 months

Stratify* FLT3ITDor

TKD

FLT3 WILD TYPE not

eligible for enrollment

X 4

X 4

CR

CR

PRE-REGISTER

FLT3

SCREEN

*Stratification: TKD vs ITD with mutant allele fraction <0.7 vs ≥0.7

28

Transplantation was not specifically mandated.

Reasons for not entering MaintenanceAll patients

N = 717

MidostaurinN = 360

N = 105

N = 105

PlaceboN = 357

N = 69

Transplants = 80.

Alternative therapy.

Progressive disease.

Withdrawal.Adverse events.Death.Other

Transplants = 69.

Alternative therapy.

Progressive disease.

Withdrawal.Adverse events.Death.Other

403 patients (56%) achieved CR within 60 days;

174 “CR60” patients began maintenance therapy still in CR1.

24% ofall patients

60% receive 12 months of maintenance

Landmark analysis of DFS during the 12 cycles of maintenance, censoring patients at the time they completed the planned maintenance or discontinued study drug early.

DFS was not different between the 2 arms during the 12 cycles ofmaintenance (HR=0.83 for Midostaurin vs Placebo [95% CI, 0.48-1.43];P=0.49). NE denotes not estimable.

acebo

Midostaurin

proportion alive and disease-free

number at risk105 98 84 79 73 62 069 58 52 51 50 45 0

Summary The results from this unplanned subset analysis of the CALGB

10603/RATIFY trial do not allow conclusions on the clinical benefit from maintenance therapy with Midostaurin.

It is difficult from this data set to isolate the clinical benefit gained from any single component of this trial or phase of therapy as the survival benefit was observed by intention-to-treat for the whole treatment plan, including the use of allogeneic transplantation.

Midostaurin was well-tolerated, but the definitive impact of maintenance strategies using Midostaurin would need to be addressed by randomization.

Alternative study designs might include a randomized, prospective discontinuation trial of patients taking long-term midostaurin maintenance while in first remission.

Mid

osta

urin

allo

wed

• FLT3-ITD mut AML CR1• Gilteritinib 120 mg/d• 24 months treatment• n=346 patients• Primary Endpoint:

Relapse-free Survival

Gilteritinib

Clinical trials gov identifier: NCT02997202

A Phase 3, Multicenter, open-label, Randomized, Study of Gilteritinib versus Midostaurin inCombination with Induction and Consolidation Therapy followed by one-year maintenance in Patientswith Newly Diagnosed Acute Myeloid Leukemia (AML) or myelodysplastic syndromes with excessblasts-2 (MDS-EB2) with FLT3 Mutations Eligible for Intensive Chemotherapy

Clinical trials gov identifier:NCT02927262

Ongoing QuANTUM-FIRST: Phase 3 trial in Newly Diagnosed FLT3-ITD mutated AML

A phase III, randomized, double-blind study of induction(daunorubicin [or idarubicin]/cytarabine) and consolidation(intermediate-dose cytarabine) chemotherapy plus midostaurin(PKC412) or chemotherapy plus placebo in newly diagnosed patientswith acute myeloid leukemia (AML) without FLT3 mutations

Novartis: data on file; clinical trials identifier: CPKC412E2301

• Ist in Kombination mit intensiver Chemotherapie der aktuelleTherapiestandard für Patienten mit FLT3-mutierter AML

• Der Einsatz erfolgt aktuell bis hin zur allogenen Transplantationoder im Falle einer konventionellen Therapie bis inklusive derErhaltungstherapie

• Die Nebenwirkungen sind akzeptabel und führen nur bei einemgeringen Teil der Patienten zum Therapieabbruch

• Midostaurin für Patienten mit FLT3-WT und andere TKI fürPatienten mit FLT3-Mutation in klinischer Prüfung

SummaryMidostaurin bei FLT3-mutierter AML