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Srdan (Serge) VerstovsekM.D., Ph.D.
Professor of MedicineDepartment of Leukemia
University of TexasMD Anderson Cancer Center
Houston, Texas, USA
ASH 2012: New JAK Inhibitors for Myelofibrosis
Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, Catalano JV, Deininger MW, Miller CB, Silver RT, Talpaz M, Winton EF, Harvey JH Jr, Arcasoy MO, Hexner EO, Lyons RM, Paquette R, Raza A, Vaddi K, Erickson-Viitanen S,
Sun W, Sandor V, Kantarjian HM
Long-Term Outcome of Ruxolitinib Treatment in Patients With
Myelofibrosis: Durable Reductions in Spleen Volume, Improvements in
Quality of Life, and Overall Survival Advantage in COMFORT-I
Abstract 800
COMFORT-ICOMFORT-IBackground•Placebo-controlled, randomized, double-blind, phase III study•Ruxolitinib starting doses:
– Baseline platelet count 100-200×109/L: 15 mg BID– Baseline platelet count >200×109/L: 20 mg BID
•Doses individually titrated based on safety and efficacy•Ruxolitinib treatment significantly reduced spleen size and improved myelofibrosis (MF_-related symptoms and QoL and was also associated with a survival advantage relative to placebo1
Objective •To describe long-term efficacy and safety of ruxolitinib with 1 year of additional follow-up beyond previously published data (median follow-up ~24 months)
3
Data cutoff for current analysis: March 1, 2012.
1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.
Patient Disposition at Current AnalysisPatient Disposition at Current Analysis
Patients, n (%)Ruxolitinib
(n = 155)Placebo(n = 151)
Placebo Ruxolitinib
(n=111)
Still on treatment 100 (64.5) 0 73 (65.8)
Discontinued 55 (35.5) 40 (26.5) 38 (34.2)
Crossed over 111 (73.5)
Primary reasons for discontinuation
Death 13 (8.4) 10 (6.6) 11 (9.9)
Adverse event 11 (7.1) 9 (6.0) 7 (6.3)
Consent withdrawn 9 (5.8) 6 (4.0) 9 (8.1)
Disease progression 12 (7.7) 12 (7.9) 5 (4.5)
Other 10 (6.5) 3 (2.0) 5 (4.5)
Noncompliance with study medication ̶K ̶K 1 (0.9)
4
• All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis
• Median time to crossover: 41.1 weeks
Spleen Volume ReductionSpleen Volume Reduction
• Majority of ruxolitinib-treated patients maintained a spleen volume reduction
• Majority of crossover patients experienced spleen volume reduction relative to original baseline (median follow-up on ruxolitinib: ~14 months)
– Lesser degree of reduction likely because these patients experienced a period of spleen growth on placebo before starting ruxolitinib
5
Primary Analysis (Week 24)1
(Median follow-up ~7 months)*80
60
40
0
-80
Ch
ang
e F
rom
Bas
elin
e, %
Individual Patients
-20
20
-40
-60
35% Decrease
Ruxolitinib (n = 154) Placebo (n = 153)
-100
Last Available Measurement†
(Median follow-up ~24 months)*80
60
40
0
-80
Ch
ang
e F
rom
Bas
elin
e, %
Individual Patients
-20
20
-40
-60
Ruxolitinib (n = 154) Crossover (n = 111)
-100
35% Decrease
*Median follow-up for patients originally randomized to ruxolitinib†Change from baseline to last available spleen volume measurement1. Verstovsek S, et al. N Engl J Med. 2012;366(9):799-807.
1. Mesa R, et al. Blood. 2011;118: Abstract 3842.
Total Symptom Score
Me
an
% C
ha
ng
e F
rom
B
as
eli
ne
± S
EM
70
30
-10
-50
-70
50
10
-30
n = 99
n = 20P = .0004
n = 46P<.0001
n = 60P<.0001
All Placebo
Ruxolitinib Spleen Volume Reduction
<10% 10 to <35% ≥35%
Imp
rove
men
tW
ors
enin
g
Total Abdominal Symptom Score
n = 96
n = 20P = .0304
n = 44P = .001
n = 59P<.0001
All Placebo
Ruxolitinib Spleen Volume Reduction
<10% 10 to <35% ≥35%
Imp
rove
men
tW
ors
enin
g
70
30
-10
-50
-70
50
10
-30
Me
an
% C
ha
ng
e F
rom
B
as
eli
ne
± S
EM
Reduction in MF-Related Symptoms by Spleen Volume Reduction at Week 241
P value vs all placebo.Total Abdominal Symptom Score: abdominal pain, pain under left ribs, and early satiety.
Durability of Spleen Volume ReductionDurability of Spleen Volume Reduction
7
• 90/155 (58%) had a 35% reduction at any time point during the study
• 64% maintained a ≥35% reduction for at least 2 years≥35% reduction: Time from first 35% reduction to <35% reduction and 25% increase from nadir.≥10% reduction: Time from first 35% reduction to <10% reduction from baseline.
≥10% reduction (n = 90)
≥35% reduction
1.0
0.8
0.6
0.4
0.2
00 8 16 24 32 40 48 72 80 88 104 112
Pro
bab
ilit
y
Weeks From Onset
9656 64
84 75 72 63 57 52 47 41 35 4
No. at risk
90 4 443
EORTC QLQ-C30 Over TimeEORTC QLQ-C30 Over Time
8
Ruxolitinib Placebo
Global Health Status/QoL
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
BL 12 24 36 48 60 72 84 96
Weeks
20
10
0
-5
-10
-15
15
5
Physical Functioning
10
-10
15
-5
0
5
BL 12 24 36 48 60 72 9684Weeks
Fatigue
BL 12 24 36 48 60 72 84 96
10
0
-10
-15
-20
-25
5
-5
Weeks
Arrows indicate improvement.
Role Functioning
15
Me
an
Ch
an
ge
Fro
m B
as
eli
ne
10
-10
0
-20BL 12 24 36 48 60 72 9684
Weeks
5
-5
-15
Overall Survival: ITT PopulationOverall Survival: ITT Population
9
Note: For this unplanned analysis, P-values are descriptive and nominally significant.*Age was the only baseline characteristic that differed significantly between treatment groups as reported in Verstovsek S, et al. N Engl J
Med. 2012;366(9):799-807 (median age: ruxolitinib, 66 years; placebo, 70 years; P<.05).
Placebo
Ruxolitinib
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84 96 108 120 132
Su
rviv
al P
rob
abil
ity
Weeks
148 142 133 117 111 102 95 74 32 7Placebo
154 148 145 136 125 121 113 96 44 6Ruxolitinib
No. at risk
154
155
HR = 0.58 (95% CI: 0.36, 0.95); P = .028
Age-adjusted HR* = 0.61 (95% CI: 0.37, 0.99); P = .040
No. of deaths: Ruxolitinib = 27; Placebo = 41
Median follow-up: 102 weeks
Incidence of New Onset Nonhematologic Adverse Events Regardless of CausalityIncidence of New Onset Nonhematologic Adverse Events Regardless of Causality
10
Percent of Patients0–<6
Months6–<12 Months
12–<18 Months
18–<24 Months
≥24 Months
RUX PBO RUX RUX RUX RUX
Fatigue 25.7 31.9 5.8 7.9 8.4 5.4
Diarrhea 23.2 22.9 5.7 5.7 3.4 10.3
Ecchymosis 18.1 9.2 5.5 4.3 1.6 0
Dyspnea 16.8 16.1 4.5 6.4 4.8 4.9
Peripheral edema 16.7 23.2 5.3 6.3 4.8 5.1
Headache 15.5 5.0 0.9 2.1 1.5 0
Dizziness 14.2 6.5 5.3 6.5 3.2 4.5
Nausea 12.8 17.0 5.2 3.0 0 8.0
Constipation 12.0 12.1 4.2 5.9 4.3 8.7
Vomiting 12.0 10.8 2.5 1.0 0 4.0
Pain in extremity 11.4 10.7 8.5 4.3 1.6 0
Pyrexia 11.3 6.4 2.4 3.7 6.7 8.2
Insomnia 10.7 10.7 4.2 2.0 2.8 4.1
Abdominal pain 10.1 40.7 5.0 4.9 0 8.2
Arthralgia 10.1 7.9 2.5 5.0 0 4.4
•No reports of a specific withdrawal syndrome after discontinuation of ruxolitinib
Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time
Incidence of New Onset Grade 3 or 4 Anemia and Thrombocytopenia Over Time
29.0
4.1 4.8 5.3
0
11.5
3.41.9
0 00
5
10
15
20
25
30
35
40
45
50
0–<6 6–<12 12–<18 18–<24 ≥24
Pe
rce
nta
ge
of P
ati
en
ts
Months
8.7
1.6 1.90 0
3.41.6 0.9 0 0
0
5
10
15
20
25
30
35
40
45
50
0–<6 6–<12 12–<18 18–<24 ≥24
Pe
rce
nta
ge
of P
ati
en
ts
Months
Anemia Thrombocytopenia
• All patients receiving placebo at the primary analysis crossed over or discontinued within 3 months of the primary analysis; therefore, data for patients receiving placebo is shown for 0–<6 months only
Ruxolitinib Grade 4Ruxolitinib Grade 3
Placebo Grade 3 Placebo Grade 4
9.9
2.90.7 0
Mean Hemoglobin Levels Over TimeMean Hemoglobin Levels Over Time
12
• Mean hemoglobin nadirs after 8–12 weeks of therapy and recovers to a new steady state which remains stable with longer-term therapy
Mea
n P
erc
enta
ge
Ch
ang
e F
rom
B
asel
ine
5
-5
-15
-20
0
-10
BL 12 24 36 48 60 72 84 96
Weeks
Ruxolitinib Placebo
Median hemoglobin at baseline: Ruxolitinib, 105 g/L; Placebo, 105 g/L
Hemoglobin Levels Over Time by Ruxolitinib Titrated Dose
Hemoglobin Levels Over Time by Ruxolitinib Titrated Dose
13
Titrated dose is defined as the average dose patients received between Weeks 8 and 56.Hemoglobin levels within 60 days of transfusion are not included.
• Patients titrated to 10 mg BID after nadir hemoglobin showed faster and more complete return of hemoglobin to pretreatment levels
BL
10 mg BID<10 mg BID ≥20 mg BID15 mg BID
Efficacy by Titrated DoseEfficacy by Titrated Dose
Titrated dose is defined as the average dose patients received in the last 4 weeks before assessment.
n=101
n=24 n=26 n=23 n=39 n=21
Spleen Volume
n=103
n=22 n=26 n=23 n=38 n=20
Total Symptom Score
n=35
n=28 n=20 n=31 n=17n=24
Week 24
Week 48
Verstovsek S, et al. Blood. 2012;120: Abstract 800.
Long-Term Efficacy, Safety, and Survival Findings From COMFORT-II,
a Phase 3 Study Comparing Ruxolitinib With Best Available Therapy for the
Treatment of Myelofibrosis
Long-Term Efficacy, Safety, and Survival Findings From COMFORT-II,
a Phase 3 Study Comparing Ruxolitinib With Best Available Therapy for the
Treatment of Myelofibrosis
Cervantes F, Kiladjian J-J, Niederwieser D, Sirulnik A, Stalbovskaya V, McQuitty M, Hunter DS, Levy RS, Passamonti F, Barbui T, Barosi G,
Gisslinger H, Vannucchi AM, Knoops L, Harrison CN
Abstract 801
Patient DispositionPatient Disposition
n (%)Ruxolitinib(n = 146)
BAT(n = 73)
Ruxolitinib After Crossover
From BAT(n = 45)
Still on treatment 81 (55.5) 0 26 (57.8)
Discontinued 65 (44.5) 73 (100.0) 19 (42.2)
Crossed over -- 45 (61.6) --
Primary reasons for discontinuation
Adverse event 20 (13.7) 5 (6.8) 5 (11.1)
Consent withdrawn 8 (5.5) 9 (12.3) 0
Protocol deviation 2 (1.4) 0 5 (11.1)
Disease progression 16 (11.0) 4 (5.5) 5 (11.1)
Noncompliance with study medication 3 (2.1) 0 1 (2.2)
Noncompliance with study procedures 0 1 (1.4) 0
Unsatisfactory therapeutic effect 2 (1.4) 0 1 (2.2)
Other 14 (9.6) 9 (12.3) 2 (4.4)
The majority of patients randomized to ruxolitinib remained on treatment after more than 2 years on study
Mean % Change From Baseline in Spleen Volume Over Time
136 125 111 98 78 64 53Ruxolitinib, 42 31n = 146 10
60 44 39 34 24 16 6 2 073 0n =
BAT patients who crossed over to ruxolitinib had reductions in spleen volume after crossover
Excluding patients who crossed over to ruxolitinibBAT
n = 60 45 40 34 24 20 15 8 1173 3Including patients who crossed over to ruxolitinibBAT
Overall SurvivalOverall Survival
Suggests a relative reduction in the risk of death with ruxolitinib compared with BAT (HR = 0.51; 95% CI, 0.26-0.99; log-rank test P = .041)a
1.0
BAT
Ruxolitinib
14673
138 30109127 117 061 124551 49 0
n =
Lost to follow-up (cumulative)
No. of PatientsEventsCensored
14620 (13.7%)
126 (86.3%)
7316 (21.9%)57 (78.1%)
Ruxolitinib BAT
3.4% 14.4%9.6% 11.0%13.7% 27.4%24.7% 26.0%
a P values are provided for descriptive purposes and were not adjusted for multiple comparisons.
14.4%27.4%
Efficacy, Hematologic Effects, and Dose of Ruxolitinib in Myelofibrosis Patients with Low Starting Platelet
Counts (50–100×109/L)
Abstract 176
Talpaz M, Paquette R, Afrin L, Hamburg S, Jamieson K, Terebelo H, Ortega G, Lyons RM, Tiu R, Winton E, Natrajan K, Odenike O, Peng W, O’Neill P, Erickson-Viitanen S, Leopold L,
Sandor V, Levy R, Kantarjian H, Verstovsek S
Distribution of Ruxolitinib Dose Over Time
• In patients who completed 24 weeks of treatment, most have optimized their dose of ruxolitinib to 10 mg BID or higher
n values represent patients with available dose information at the time of data analysis.
Data shown for each time point represent the dose that patients were on during the previous 4 weeks.
15 BID
10 BID
5 BID
15 BID
10 BID
5 BID
10 / 15
10 BID
5 BID
10 BID
5 BID
10 BID
5 BID
5 / 10
5 BID
10 / 1510 / 15
5 / 10
5 / 105 / 10
n = 41
n = 39n = 32
n = 28n = 28 n = 18
n = 38n =35
n = 31n = 27
n = 24n = 18
Total Symptom Score Spleen Length
Percent change from baseline is not calculated for patients with a “0” TSS or palpable spleen size of “0 cm” at baseline. Mean and median dose shown for patients with available dosing information.TDD, total daily dose.
Weeks 4 8 12 16 20 24
TDD, mg
Mean 10.0 13.2 15.1 16.8 18.3 19.1
Median 10 15 15 20 20 20
Reductions in Total Symptom Score and Spleen Length
Weeks 4 8 12 16 20 24
TDD, mg
Mean 10.0 13.2 15.1 16.8 18.3 19.1
Median 10 15 15 20 20 20
Change From Qualifying Platelet Count to Nadir and to Week 24 of Individual Patients
22
Qualifying to Nadir Qualifying to Week 24
Individual Patients
160
140
120
100
80
60
40
20
0
Pla
tele
t C
ou
nt.
×1
09 /
L
Individual Patients
160
140
120
100
80
60
40
20
0
Pla
tele
t C
ou
nt
(×1
09 /
L)
Phase III Study SAR302503 vs. placebo
Multinational, multicenter, randomized, double-blind, placebo-controlled
●No Stratification factors●Randomization 1/1/1●1 cycle = 28 days
RANDOMIZ A TION
Q4 weeks
SAR302503 500mg
Daily oral doses
Q4 weeks
SAR302503 500mg
Daily oral doses
n=75
n=75
- Intermediate-2 or high-risk Primary MF
-Post-Polycythemia Vera MF
-Post-Essential Thrombocythemia MF
- Intermediate-2 or high-risk Primary MF
-Post-Polycythemia Vera MF
-Post-Essential Thrombocythemia MF
Cross over 1/1
EOTn=75 Q 4 weeks
SAR302503 400mg
Daily oral doses
Q 4 weeks
SAR302503 400mg
Daily oral doses
Q 4 weeks
Placebo
Daily oral doses
Q 4 weeks
Placebo
Daily oral dosesEnd of C6 or progressive
disease
End of C6
●225 patients at ~128 sites ●Recruitment: 8 months, 25 countries●Safety data monitored by DMC (~Q6 months)●Cross over possible
Enrollment Completed
(Sept 2012)
Enrollment Completed
(Sept 2012)
A Phase II Randomized Dose-Ranging Study of the JAK2-Selective Inhibitor
SAR302503 in Patients With Intermediate-2 or High-Risk Primary
Myelofibrosis (MF), Post-Polycythemia Vera MF, or Post-Essential
Thrombocythemia MF
Abstract 2837
Talpaz M, Jamieson C, Gabrail NY, Lebedinsky C, Neumann F, Gao G, Liu F, Tefferi A, Pardanani A
ARD11936 Study Design• Intermediate-2 or high-risk
primary MF (IWG-MRT criteria)
• Post-polycythemia vera myelofibrosis according to the 2008 World Health Organization (WHO) criteria
SAR302503 300 mg orally once daily
SAR302503 400 mg orally once daily
SAR302503 500 mg orally once daily
Patients who continued to benefit clinically could remain on study until the occurrence of disease progression or unacceptable toxicity1 cycle = 28 days
• % change in spleen volume at EOC 3 by central review assessed by MRI
• % of patients who achieve ≥35% reduction in spleen volume from baseline• To measure improvement in baseline MPN-associated symptoms• Safety (NCI CTCAE v4.03), PK/PD
Primary endpoint:
Secondary endpoints:
EOC, end of cycle; MF, myelofibrosis; MPN-SAF, myeloproliferative neoplasm symptom assessment form; MRI, magnetic resonance imaging; PK/PD, pharmacokinetics/pharmacodynamics
Percent Change in Spleen Volume From Baseline in Individual Patients at the End of Cycle 3
• There was a dose-dependent increase in spleen response with increasing doses of SAR302503.
35%
SAR302503300 mg (n = 8)
SAR302503400 mg (n = 10)
SAR302503500 mg (n = 10)
30 –
20 –
10 –
0 –
-10 –
-20 –
-30 –
-40 –
-50 –
-60 –
-70 –
-80 –
Symptom Reduction at the End of Cycle 3 by the MPN-SAF in Patients With Symptoms
Present at Baselinea
aA response was defined as a 2-point improvement in or resolution of the symptom.MPN-SAF: Myeloproliferative Neoplasm Symptom Assessment Form
SAR302503
300 mg n = 10
400 mgn = 10
500 mg n = 11
Proportion of patients with ≥50% reduction in total MPN-SAF score from baseline n (%) [95% CI]
5 (50)[19 - 81]
5 (50)[19 - 81]
4 (36)[11 - 69]
Symptom Response,a n/N
Night sweats 5/5 (100%) 5/6 (83%) 4/4 (100%)
Itching 6/7 (86%) 1/3 (33%) 3/4 (75%)
Abdominal discomfort 4/7 (57%) 3/7 (43%) 3/6 (50%)
Abdominal pain 3/6 (50%) 4/7 (57%) 3/5 (60%)
Bone pain 2/3 (67%) 1/4 (25%) 1/3 (33%)
Early satiety 3/7 (43%) 4/7 (57%) 3/4 (75%)
Inactivity 2/6 (33%) 3/7 (43%) 3/5 (60%)
SAR302503
300 mg n = 10
400 mgn = 10
500 mg n = 11
n (%) All grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4
Fatigue 3 (30) 1 (10) 1 (10) 0 4 (36) 0
Diarrhea 7 (70) 1 (10) 9 (90) 2 (20) 6 (55) 0
Nausea 6 (60) 1 (10) 5 (50) 1 (10) 8 (73) 0
Vomiting 5 (50) 1 (10) 4 (40) 1 (10) 7 (64) 0
Constipation 2 (20) 0 3 (30) 0 1 (9) 0
Pruritis 1 (10) 0 2 (20) 0 1 (9) 0
Edema, peripheral 2 (20) 0 3 (30) 0 1 (9) 0
Infections 0 0 1 (10) 1 (10) 3 (27) 1 (9)
Hyperkalemia 2 (20) 1 (10) 1 (10) 0 1 (9) 1 (9)
Paresthesia 1 (10) 0 2 (20) 0 2 (18) 0
Dyspnea 1 (10) 0 3 (30) 0 2 (18) 0
Cough 2 (20) 0 1 (10) 0 2 (18) 0
Most Common Nonhematologic Adverse Eventsa
aReported in ≥10% of patients across all dose groups. Safety was assessed in patients who received at least one dose of study drug.
• Anemia was the most common hematologic toxicity.
• Grade 3/4 thrombocytopenia was minimal.
Laboratory Abnormalities
aData available for 9 patients in the 300 mg groupaData available for 9 patients in the 300 mg group
SAR302503
300 mg n = 10
400 mgn = 10
500 mg n = 11
n (%)All
gradesGrade
3/4All
GradesGrade
3/4All
GradesGrade
3/4
Anemia 9 (100)a 3 (33)a 10 (100) 3 (30) 10 (91) 6 (55)
Neutropenia 1 (10) 0 0 0 0 0
Thrombocytopenia 5 (50) 2 (20) 3 (30) 0 6 (55) 1 (9)
