1. RATIFY: Midostaurin Added to Standard Chemotherapy Prolongs OS in Patients With Newly Diagnosed FLT3-Mutated AML
New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
AML, acute myeloid leukemia.
This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

2. RATIFY: Midostaurin in FLT3-Mutated AML
25% pts with AML have activating FLT3 ITD mutation, which is a poor prognostic indicator, with higher incidence of relapse[1]
FLT3 inhibitor midostaurin (PKC412) demonstrated:
Activity against ITD-mutated leukemic cell lines[2]
Clinical benefit but no CR as single agent in FLT3-ITD AML[3,4]
High CR and OS with chemotherapy in phase Ib study of AML[5]
Current study investigated midostaurin added to standard chemotherapy in FLT3-mutated AML[6]
AML, acute myeloid leukemia; ITD, internal tandem duplication.
1. Ofran Y, Rowe JM. Br J Haematol. 2013;160: Weisberg E, et al. Cancer Cell. 2002;1: Stone RM, et al. Blood. 2005;105: Fischer T, et al. J Clin Oncol. 2010;28: Stone RM, et al. Leukemia. 2012;26: Stone RM, et al. ASH Abstract 6.
Slide credit: clinicaloptions.com

3. Stratified by ITD/TKD; randomized
RATIFY: Study Design
Induction*
(1-2 cycles)
Consolidation
(up to 4 cycles)
Maintenance
(12 cycles)
Stratified by ITD/TKD; randomized
Daunorubicin
60 mg/m2 IVP D1-3 +
Cytarabine
200 mg/m2/d IVCI D1-7 +
Midostaurin
50 mg PO BID D8-21
(n= 360)
Cytarabine
3 g/m2 over 3h q12h
D1,3,5 +
Midostaurin
50 mg PO BID D8-21
(n = 231)
Midostaurin
50 mg PO BID D1-28
(n = 120) CR
18-60 yrs of age with
FLT3-mutated
(non-APL) AML
(N = 717)
Daunorubicin
60 mg/m2 IVP D1-3 +
Cytarabine
200 mg/m2/d IVCI D1-7 +
Placebo
D8-21
(n = 357)
Cytarabine
3 g/m2 over 3h q12h
D1,3,5 +
Placebo
D8-21
(n = 210)
Placebo
D1-28
(n = 85) CR
AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; EFS, event-free survival; ITD, internal tandem duplication; IVCI, intravenous continuous infusion; IVP, intravenous push; SCT, stem cell transplantation; TKD, tyrosine kinase domain.
*Hydroxyurea allowed for ≤ 5 days prior to induction therapy.
Double-blind, placebo-controlled, randomized phase III study
Primary endpoint: OS (not censored for SCT)
Secondary endpoint: EFS
Slide credit: clinicaloptions.com
Stone RM, et al. ASH Abstract 6.

4. RATIFY: Baseline Characteristics
Midostaurin + Chemo
(n = 360)
Placebo + Chemo
(n = 357)
Median age, yrs (range)
47.1 ( )
48.6 ( )
Female, n (%)
187 (52)
212 (59)
FLT3 stratification groups, n (%)
FLT3 TKD (no ITD)
ITD allelic ratio < 0.7 ± FLT3 TKD
ITD allelic ratio ≥ 0.7 ± FLT3 TKD
81 (23)
171 (48)
108 (30)
170 (48)
106 (30)
ITD, internal tandem duplication; TKD, tyrosine kinase domain.
Slide credit: clinicaloptions.com
Stone RM, et al. ASH Abstract 6.

5. RATIFY: Efficacy *HR: 0.77. †HR: 0.75.
Characteristic
Midostaurin + Chemo
(n = 360)
Placebo +
Chemo
(n = 357)
P Value
Median OS, mos (range)
74.7 (31.7-NE)
25.6 ( )
4-yr OS, % (95% CI)
Uncensored*
Censored for SCT†
51.4 ( )
63.8 ( )
44.2 ( )
55.7 ( )
.0074
.04
SCT, n (%)
Any time
CR1 only
212 (59)
100 (28)
196 (55)
79 (22)
.28
.08
CR, n (%)
By Day 60
In induction/consolidation
239 (66)
191 (53)
211 (59)
.15
.045
Median EFS‡, mos (range)
Overall
CR in induction/consolidation
8.0 ( )
11.3 ( )
3.0 ( )
6.1 ( )
.0025
.0002
DFS, mos (range)
25.9 (19.4-NE)
14.4 ( )
.002
DFS, disease-free survival; EFS, event-free survival; SCT, stem cell transplantation; NE, not estimable.
*HR: †HR: 0.75.
‡Event: no CR within 60 days, relapse, or death.
Slide credit: clinicaloptions.com
Stone RM, et al. ASH Abstract 6.

6. RATIFY: Outcomes by FLT3 Status
Longer OS shown in midostaurin arm in all FLT3 cohorts
FLT3-ITD high, HR: 0.80 (95% CI: ; P = .09)
FLT3-ITD low, HR: 0.80 (95% CI, ; P = .08)
FLT3-TKD, HR: 0.65 (95% CI: ; P = .05)
4-yr EFS rate was 28% with midostaurin vs 20% in placebo, regardless of FLT3 status
EFS, event-free survival; ITD, internal tandem duplication; TKD, tyrosine kinase domain.
Slide credit: clinicaloptions.com
Stone RM, et al. ASH Abstract 6.

7. RATIFY: Safety
Grade 3/4 Nonhematologic AEs (≥ 10% Pts), %
Midostaurin + Chemo
(n = 360)
Placebo + Chemo
(n = 357)
P Value
Febrile neutropenia 81 82
.92
Infection 40 38
.49
Diarrhea 15 16
1.00
Hypokalemia 13 17
.17
Pain
.91
Rash/desquamation 8
.02
ALT/SGPT 12 9
.23
Fatigue (asthenia, lethargy, malaise) 11
.53
AE, adverse event; ALT, alanine aminotransferase; CNS, central nervous system; SGPT, serum glutamic pyruvic transaminase.
Deaths: 5% (18/360) in midostaurin arm vs 5.3% (19/357) in placebo; leading causes: infection (4 midostaurin, 7 placebo), pneumonitis (3 midostaurin, 0 placebo), hemorrhage, CNS (1 midostaurin, 2 placebo)
Slide credit: clinicaloptions.com
Stone RM, et al. ASH Abstract 6.

8. RATIFY: Conclusions
Midostaurin added to standard chemo in pts with newly diagnosed FLT3-mutated AML
Improved OS and EFS, regardless of ITD/TKD stratification group and despite high SCT rate (57%), vs placebo
Reduced risk of death by 23% vs placebo
Safety/tolerability similar in midostaurin and placebo arms
Study investigators suggest midostaurin addition to current standard chemo with 1-yr subsequent maintenance as a new standard of care for these pts
AML, acute myeloid leukemia; EFS, event-free survival; ITD, internal tandem duplication; SCT, stem cell transplantation; TKD, tyrosine kinase domain.
Slide credit: clinicaloptions.com
Stone RM, et al. ASH Abstract 6.

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