1. Simplify 1: Momelotinib vs Ruxolitinib in JAK Inhibitor–Naive Myelofibrosis
CCO Independent Conference Highlights* of the 2017 ASCO Annual Meeting; June 2-6, 2017; Chicago, Illinois
*Clinical Care Options (CCO) is an independent medical education organization that provides conference coverage and other unique educational programs for healthcare professionals
This activity is supported by educational grants from AbbVie, Amgen, AstraZeneca, Celgene Corporation, Genentech, Halozyme, Incyte, and Merck & Co., Inc.

2. Role of JAK Inhibition in Myelofibrosis: Background
More than one half of MF pts possess a JAK2 V617F mutation, with other common driver mutations (eg, CALR, MPL) also activating JAK-STAT signaling[1]
JAK1/2 inhibitor ruxolitinib approved for the treatment of intermediate or high-risk MF[2]
Momelotinib: oral, small-molecule inhibitor of JAK1/2
In phase I/II trials, momelotinib shown to reduce spleen volume, improve constitutional symptoms, and improve RBC transfusion requirements in MF pts[3,4]
Momelotinib has also shown anemia benefit in previous trials, potentially explained by off-target effects that ultimately lead to increased plasma iron[5,6]
Phase III Simplify 1 study evaluated momelotinib vs ruxolitinib in the treatment of JAK inhibitor-naive MF pts[7]
MF, myelofibrosis; RBC, red blood cells.
1. Rumi E, et al. Blood. 2014;124: Lancman G, et al. Expert Rev Hematol. 2017;10: Pardanani A, et al. Leukemia : Gupta V, et al. Haematologica. 2017;102: Asshoff M, et al. Blood. 2017;129: Pardanani A, et al. Am J Hematology. 2013;86: Mesa RA, et al. ASCO Abstract 7000.
Slide credit: clinicaloptions.com

3. Simplify 1: Study Design
Multicenter, randomized, double-blind, active controlled phase III study
Stratified by RBC transfusion dependence (yes or no), PLT count (< 100 x 109/L, ≥ 100 to ≤ 200 x 109/L, or > 200 x 109/L)
Wk 24
JAK inhibitor–naive, transplant-ineligible pts with primary MF or post-ET/PV MF; high, int-2, or symptomatic int-1 risk; palpable splenomegaly ≥ 5 cm; PLT ≥ 50 x 109/L; PB blasts < 10%
(N = 432)
Momelotinib 200 mg QD 
(n = 215)
Optional open-label momelotinib 200 mg QD through Wk 192
Ruxolitinib 20 mg BID 
(n = 217)
BL, baseline; ET, essential thrombocythemia; int, intermediate; MF, myelofibrosis; MRI, magnetic resonance imaging; PB, peripheral blood; PLT, platelet; PV, polycythemia vera; RBC, red blood cell; SRR, splenic response rate; TSS, total symptom score.
Primary endpoint: SRR at Wk 24, defined as ≥ 35% reduction in volume from BL by MRI or CT (noninferiority)
Secondary endpoints: TSS improvement rate at Wk 24 (noninferiority); RBC transfusion rate, RBC transfusion independence rate, and RBC transfusion dependence rate at Wk 24 (superiority)
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract 7000.

4. Simplify 1: Baseline Characteristics
Momelotinib (n = 215)
Ruxolitinib (n = 217)
Median age, yrs (IQR)
67 (59-72)
66 (59-71)
Male, % 58 55
MF subtype: primary/post-ET/post-PV, %
60/18/22
54/23/23
Median time since MF diagnosis, yrs (IQR)
1.6 ( )
1.5 ( )
TSS
Mean (SD)
Median (IQR)
19 (13)
17 (8-28)
18 (11)
16 (9-25)
Transfusion dependent, % 25 24
Transfusion independent, % 68 70
Characteristic
Momelotinib (n = 215)
Ruxolitinib (n = 217)
Palpable spleen size ≥ 10 cm, % 64 63
Platelet count, %
< 100 x 109/L
≥ 100 to ≤ 200 x 109/L
> 200 x 109/L 8 31 61 11 29 60
Hemoglobin < 8 g/dL, % 13 10
IPSS high/int-2/int-1, %
43/35/21
49/31/20
JAK2 V617F mutation positive/negative, %
58/28
65/24
ET, essential thrombocythemia; IPSS, International Prognostic Scoring System; IQR, interquartile range; MF, myelofibrosis; PV, polycythemia vera; SD, standard deviation; TSS, total symptom score.
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract 7000.

5. Simplify 1: Splenic Response Rate (Primary Endpoint)
Momelotinib is noninferior to ruxolitinib
Momelotinib
(n = 215; 184 evaluable)
Ruxolitinib
(n = 217; 204 evaluable)
Δ Spleen Volume From BL (%)
P = .011
150
100 50
-50
-100
SRR* = 26.5%
SRR* = 29.0%
BL, baseline; SRR, splenic response rate.
*Pts missing spleen volume assessments at BL or Wk 24 considered nonresponders.
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract Reproduced with permission.

6. Simplify 1: Total Symptom Score (Key Secondary Endpoint)
Momelotinib is inferior to ruxolitinib
150
Momelotinib
(n = 211; 174 evaluable)
Ruxolitinib
(n = 211; 190 evaluable)
100 50
Δ Total Symptom Score From BL (%)
BL, baseline; TSS, total symptom score.
-50
-100
TSS response rate* = 28.4%
TSS response rate* = 42.2%
P = .98
*Pts with BL missing or BL = 0 and Wk 24 = 0 not included in TSS response rate analysis.
Subjects with BL > 0 but Wk 24 missing or BL = 0 but Wk 24 missing or > 0 considered nonresponders.
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract Reproduced with permission.

7. Simplify 1: Secondary Efficacy Outcomes
Transfusion-Related Endpoints at Wk 24
Transfusion Independence Rate P < .001
Transfusion Dependence Rate P = .019
RBC Transfusion Rate Through Wk 24 P < .001
100
100 2
MMB (n = 215)
RUX (n = 217) 80 80
1.5
68.4
70.0
66.5 60 60
49.3
Pts (%)
Pts (%)
Median no. of units/mo 1
40.1 40 40
30.2
24.7
24.0
0.5
0.4 20 20
MMB, momelotinib; RBC, red blood cell; RUX, ruxolitinib.
0.0
0.0
0.0
Baseline
Wk 24
Baseline
Wk 24
Baseline
Wk 24
All P-values are nominal.
Superiority of momelotinib established for all RBC transfusion endpoints
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract Reproduced with permission.

8. Simplify 1: Disposition, Drug Exposure at Wk 24
Pts, n (%)
Momelotinib
(n = 215)
Ruxolitinib
(n = 217)
Completed
175 (81)
201 (93)
Discontinued
40 (19)
16 (7) AE
19 (9)
9 (4)
Death
5 (2)
Investigator/pt decision
6 (3)
3 (1)
DP/symptomatic spleen growth
4 (2)
2 (< 1)
Insufficient efficacy
1 (< 1)
Protocol violation/non-compliance
Never dosed
Total duration of exposure, wks
(n = 214)
(n = 216)
Mean (SD)
21.3 (6.37)
23.3 (3.13)
AE, adverse event; DP, disease progression; SD, standard deviation.
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract 7000.

9. Simplify 1: TEAEs TEAE, n (%) Momelotinib (n = 214)
Ruxolitinib (n = 216)
Any TEAE
Grade ≥ 3
197 (92)
76 (36)
206 (95)
94 (44)
Serious TEAE
49 (23)
39 (18)
TEAE leading to treatment discontinuation
28 (13)
12 (6)
TEAE leading to death
GI disorders
Death NOS
Infections
Renal and urinary disorders
Vascular disorders
Injury
Neoplasm
Nervous system disorders
7 (3)
2 (< 1)
1 (< 1)
2 (< 1)*
AML, acute myeloid leukemia; GI, gastrointestinal; NOS, not otherwise specified; TEAE, treatment-emergent adverse event.
*n = 1 AML; n =1 mantle cell lymphoma.
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract 7000.

10. Simplify 1: AEs Occurring in ≥ 10% in Either Arm
AEs Occurring in ≥ 10% in Either Arm, n (%)
Any Grade
Grade ≥ 3
Momelotinib (n = 214)
Ruxolitinib (n = 216)
Any
197 (92)
206 (95)
73 (34)
94 (44)
Thrombocytopenia
40 (19)
63 (29)
15 (7)
10 (5)
Diarrhea
38 (18)
43 (20)
6 (3)
3 (1)
Headache
37 (17)
1 (< 1)
Dizziness
34 (16)
25 (12)
Nausea
8 (4)
2 (< 1)
Fatigue
31 (14)
26 (12)
Anemia
29 (14)
82 (38)
12 (6)
50 (23)
Abdominal pain
22 (10)
24 (11)
Peripheral neuropathy
1 (<1)
AEs, adverse events.
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract 7000.

11. Simplify 1: Conclusions
In JAK-inhibitor-naive MF pts, momelotinib achieved noninferior SRR vs ruxolitinib
SRR: 26.5% vs 29.0%; P = .011
However, momelotinib failed to achieve noninferiority vs ruxolitinib for key secondary endpoint of TSS improvement rate
Momelotinib significantly improved transfusion requirements and anemia vs ruxolitinib
No new safety signals with momelotinib detected
Peripheral neuropathy with momelotinib vs ruxolitinib: 10% vs 5%
MF, myelofibrosis; SRR, spleen response rate; TSS, total symptom score.
Slide credit: clinicaloptions.com
Mesa RA, et al. ASCO Abstract 7000.

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