Second generation JAK inhibitors: Targeting the JAK-STAT ...splenomegaly and fatigue. –Main side...
Transcript of Second generation JAK inhibitors: Targeting the JAK-STAT ...splenomegaly and fatigue. –Main side...
Rami S. Komrokji, MD Clinical Director, Associate Professor Malignant Hematology Department
H. Lee Moffitt Cancer Center Tampa, Florida
Second-generation JAK inhibitors: Targeting the JAK-STAT pathway
Disclosures for Rami S. Komrokji, MD Royalty N/A
Receipt of intellectual property/ Patent holder
N/A
Consulting fee Incyte
Speakers bureau Incyte
Fees for non-CME services N/A
Contracted research Incyte
Ownership interest (stocks, stock options)
N/A
Other N/A
N/A = Not Applicable (no conflicts listed) Presentation includes discussion of investigational JAK inhibitors that are not yet FDA approved
Case presentation
69 year old Caucasian male with past medical history of hypertension: • 1986: Diagnosed with polycythemia rubra vera and treated
with periodic phlebotomy until 2008 when his counts stabilized.
• 2012: He developed progressive splenomegaly, leukocytosis, anemia, and thrombocytopenia (WBC 17 K, Hgb 10.2 g/dL, platelets 150). – A bone marrow was consistent with post PV-myelofibrosis (post
PV-MF). Normal male karyotype – PCR was positive for JAK2V617F mutation
• No suitable donor could be identified for consideration of allogeneic stem cell transplantation.
Case presentation
69 year old Caucasian male with past medical history of hypertension diagnosed with post PV-MF: • July 2012: He was started on ruxolitinib 15 mg po BID
with excellent clinical response in terms of splenomegaly and fatigue. – Main side effect was anemia with Hgb decreased to the
range of 8-9 g/dL when procrit was administered by local oncologist maintaining Hgb between 9-10 g/dL with no transfusion.
• May 2014: Progressive splenomegaly, ruxolitinib dose increased up to 25 mg po BID but with worsening of his anemia requiring red blood cell transfusion and only modest further clinical response.
Case presentation questions
• Could a 2nd generation JAK inhibitor offer an advantage over ruxolitinib as first-line therapy in patients with cytopenia?
• Can we consider treatment with a 2nd generation JAK inhibitor after ruxolitinib failure?
Outline
• Overview of JAK inhibitors highlighting the targets, differences, and stage of development.
• What can a 2nd generation JAK2 inhibitor offer beyond ruxolitinib as an upfront treatment? – Pacritinib – Momelotinib
• Is there a role for a 2nd JAK2 inhibitor after ruxolitinib failure? – Fedratinib data as 2nd line
• Novel approaches targeting JAK/Stat pathway
JAK2 inhibitors Drug Other target Phase Status
Ruxolitinib JAK-1 III Approved
Pacritinib FLT-3 III ongoing
Momelotinib JAK1, JNK1, TYK2, CDK2, RICJ2 III ongoing
Fedratinib FLT-3, RET III withdrawn
AZD1480 JAK1, JAK3, FLT4, FGFR1, TRKA II
Gandotinib (LY2784544)
I withdrawn
NS-018 SRC, FLT3, ABL I/II
XL019 I withdrawn
BMS-911543 I/II withdrawn
Cervantes F. How I treat myelofibrosis. Blood. 2014;124(17):2635-2642.
What can a 2nd generation JAK2 inhibitor offer beyond ruxolitinib as
an upfront treatment?
Pacritinib: A Selective JAK2/FLT3 Inhibitor
William AD, et al. J Med Chem 2011; 54:4638 Hart S, et al. Leukemia 2011; 25:1751
Kinase IC50 (nM)
JAK1 1280
JAK2wt 23
JAK2V617F 19
JAK3 520
TYK2 50
FLT3 22
FLT3-D835Y 6
• Pacritinib (SB1518): oral,
selective, dual JAK2/FLT3
inhibitor
• Potent inhibition of JAK2-STAT3
-STAT5 pathway without
myelosuppression in preclinical
studies
• Did not appear to be associated
with clinically significant
treatment-emergent anemia or
thrombocytopenia in early clinical
studies
Analysis of 2 Phase II Trials of Pacritinib in Patients with Baseline Platelet Counts of ≤100,000/µL
• International phase II studies (001, 003) conducted between 2010-2012 (n=65) – Pacritinib dosed 400 mg oral once daily
– Spleen size assessed by physical exam (PE) and MRI
– Patient-reported outcomes assessed using the Myelofibrosis Symptom Assessment Form (MF-SAF)1
– Standard adverse event (AE) reporting and central laboratory testing
• Databases were integrated to evaluate safety and efficacy in patients with baseline platelet counts of ≤100,000/µL or >100,000/µL
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
Demographics
Baseline Platelets
≤100,000/µL
(n=28)*
Baseline Platelets
>100,000/µL
(n=37)*
All
(n=65)
Age, Median (range) 69 (46-85) 68 (44-85) 68 (44-85)
Male, N (%) 19 (68%) 28 (76%) 47 (72%)
MF Diagnosis, N (%)
Primary MF 21 (75%) 19 (51%) 40 (62%)
Post-PV MF 5 (18%) 11 (30%) 16 (25%)
Post-ET MF 2 (7%) 7 (19%) 9 (14%)
DIPSS Risk Category, N (%)**
Intermediate-1 3 (11%) 11 (30%) 14 (22%)
Intermediate-2 11 (39%) 9 (24%) 20 (31%)
High 4 (14%) 10 (27%) 14 (22%)
JAK2V617F positive, N (%) 23 (82%) 29 (78%) 52 (80%)
** DIPSS was calculated post-hoc and was indeterminate on the remainder of the patients: 10 (36%), 7 (19%)
and 17 (26%), respectively Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
* No significant differences were observed between the two groups
Baseline hematologic parameters
Baseline Platelets
≤100,000/µL
(n=28)*
Baseline Platelets
>100,000/µL
(n=37)*
All
(n=65)
Platelet Count (x103/mL)
Mean (SD) 56 (± 23) 261 (± 147) 173 (± 151)
Median (IQR) 59
(34-70)
227
(163-315)
121
(60-238)
Range 15-97 104-859 15-859
Platelet transfusions
within 180 days prior to
study screening, N (%) 3 (11%) 0 (0%) 3 (5%)
Hemoglobin (g/dL),
Median (range) 8.8 (3.7-14) 10.7 (7.4-14.4) 9.7 (3.7-14.4)
RBC transfusions within
180 days prior to study
screening, N (%) 13 (46%) 13 (35%) 26 (40%)
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
* No significant differences were observed between the two groups
Endpoint Time Period
Baseline Platelets
≤100,000/µL
(n=28)*
Baseline Platelets
>100,000/µL
(n=37)*
All
(n=65)
≥ 50%
Reduction in
spleen size by
PE
Up to 24
weeks 12 / 28 (43%) 14 / 34 (41%) 26 / 62 (42%)
Up to last
visit on
treatment
13 / 28 (46%) 14 / 35 (40%) 27 / 63 (43%)
≥ 35%
Reduction in
spleen volume
by MRI
Up to 24
weeks 7 / 23 (30%) 6 / 26 (23%) 13 / 49 (27%)
Up to last
visit on
treatment
10 / 23 (44%) 8 / 26 (31%) 18 / 49 (37%)
Spleen response
* No significant differences were observed between the two groups
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
Baseline Platelets
≤100,000/µL
(n=28)**
Baseline Platelets
>100,000/µL
(n=37)**
All
(n=65)
Up to 24
weeks 11 / 28 (39%) 16 / 34 (47%) 27 / 62 (44%)
Up to last
visit on
treatment
13 / 28 (46%) 17 / 34 (50%) 30 / 62 (48%)
≥50% reduction in patient-reported symptom score*
* The symptom score is the sum of the individual scores for worst fatigue, early satiety,
abdominal pain or discomfort, night sweats, itching, and bone pain reported on the MF-
SAF (Mesa RA, Schwager S, Radia D ,et al. The Myelofibrosis Symptom Assessment Form (MFSAF): An evidence-
based brief inventory to measure quality of life and symptomatic response to treatment in myelofibrosis. Leuk Res.
2009; 33(9): 1199-203).
* No significant differences were observed between the two groups
Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
Platelet count change over time
Baseline platelets ≤100,000/µL Baseline platelets >100,000/µL
Baseline platelets >350,000/µL
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Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
Hemoglobin change over time
Baseline platelets ≤100,000/µL Baseline platelets >100,000/µL
Me
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Verstovesk S, . . . Komrokji RS, et al. Blood 2013;122(21): abstr 395
Pacritinib: Conclusions
• Demonstrated encouraging spleen size and patient-reported symptom score reduction regardless of baseline platelet counts
• Duration of exposure and daily dose were unaffected by starting platelet counts
• There was no apparent association with clinically significant treatment emergent anemia or thrombocytopenia
• A phase III trial, PERSIST-2, will evaluate pacritinib in MF patients with platelet counts ≤ 100,000/µL vs. BAT, including ruxolitinib
• The PERSIST-1 phase III trial, which compares pacritinib to BAT, not including a JAK2 inhibitor, is currently enrolling, has no upper or lower limit for platelet counts
Small-molecule, ATP-competitive, JAK1 and JAK2 inhibitor
Has good selectivity over other JAK family kinases (JAK3, TYK2) and excellent selectivity over other tyrosine and serine/threonine kinases
Inhibits STAT phosphorylation downstream of constitutively active JAK2 or cytokine-stimulated JAK1 or JAK2
Orally active
Update on the long-term efficacy and safety of momelotinib, a
JAK1 and JAK2 inhibitor, for the treatment of myelofibrosis
Pardanani A, et al. Blood 2013;122(21): abstr 108
Dose Groups
100 mg QD (n=3)
150 mg QD* (n=52)
200 mg QD (n=3)
300 mg QD* (n=60)
400 mg QD (n=6)
150 mg BID* (n=42)
Continues long-term dosing of momelotinib
48 subjects remain on study as of Oct, 2013
Data collection and analysis ongoing
Median duration of treatment (days): 627 (range 23 1294)
Core Study CCL09101 (n=166)
Treatment Duration: 9 months
Extension Study CCL09101E
(n=120)
*Dose level targeted for expansion
MTD
Dose-limiting toxicities: Grade 3
hyperlipasemia, Grade 3 headache
Studies CCL09101 and CCL09101E
Pardanani A, et al. Blood 2013;122(21): abstr 108
Key eligibility criteria for study CCL09101
Diagnosis of PMF or Post-PV/ET MF
IPSS high risk or Int-2 risk, or Int-1 risk with
symptoms and/or unresponsive to available
therapy
AST or ALT ≤ 2.5 x ULN, or ≤ 5 x ULN if due to
extramedullary hematopoiesis
Bilirubin ≤ 2 x ULN or direct bilirubin < 1.0
Creatinine ≤ 2.5 x ULN
ANC ≥ 500/µL, platelet ≥ 50,000/µL
4-weeks wash out for prior radiation
therapy
14-days wash out for prior systemic
therapy
Presence of peripheral neuropathy is not
allowed (amendment 3/2011)
Clinically active hepatitis B or C is not
allowed
Known positive HIV is not allowed
Pardanani A, et al. Blood 2013;122(21): abstr 108
Baseline characteristics Characteristic Value
Number of subjects 166
Age (years)
Median (range) 68 (34-89)
Sex
Male/Female 58%/42%
Myelofibrosis
Primary 63%
Post-PV 22%
Post-ET 15%
JAK2V617F positive 77%
Prior therapy
JAK inhibitor 13%
Characteristic Value
Splenomegaly > 10 cm 79%
Palpable spleen size (cm)
Mean 18.3
Median 18
RBC transfusion dependent 43%
Median hemoglobin level (g/dL) 9.4
Transfusion independent
(n=93) 10.3
Transfusion dependent
(n=72) 8.7
Median platelet count (109/L) 182
Pardanani A, et al. Blood 2013;122(21): abstr 108
Spleen response
Spleen Response Number of
Subjects (%)
Total enrollment 166 (100%)
Baseline spleen size > 5 cm at baseline 148 (89%)
≥ 50% reduction in splenomegaly that lasts
≥ 8 weeks for splenomegaly ≥ 10 cm at
baseline: A (A/148)
52 (35%)
Resolution of splenomegaly that lasts ≥ 8
weeks for splenomegaly > 5 and < 10 cm:
B (B/148)
6 (4%)
Spleen Response: A + B 58 (39%)
Pardanani A, et al. Blood 2013;122(21): abstr 108
Anemia response
Anemia Response Number of
Subjects (%)
Transfusion dependent at baseline 72 (43%)
Achieved transfusion independence on study
that lasts ≥ 12 weeks: C (C/72) 49 (68%)
Transfusion independent with Hgb < 10 g/dL at
baseline 39 (24%)
Rise in Hgb ≥ 2 g/dL on study that lasts ≥ 12
weeks: D (D/39) 10 (26%)
Anemia Response: C + D 59 (53%)
Transfusion dependence at baseline is defined as ≥ 2 units of RBC transfusions in the 30 days prior to C1/D1 and/or identified as transfusion dependent in medical history
Pardanani A, et al. Blood 2013;122(21): abstr 108
Duration of anemia response
Number of events (%): 18 (30.5)
Number of censored (%): 41 (69.5)
Median (days) (95% CI): 1,042 (514, NE)
Event Censored
Duration of anemia response (days)
Pro
ba
bili
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0 200 400 600 800 1000
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pardanani A, et al. Blood 2013;122(21): abstr 108
Treatment-related adverse events (> 10% of subjects)
Total number of subjects enrolled 166
All Grades ≥ Grade 3
Thrombocytopenia 77 (46.4%) 49 (30%)
Neuropathy peripheral 73 (44.0%) 0 (0%)
Diarrhoea 42 (25.3%) 0 (0%)
Dizziness 40 (24.1%) 0 (0%)
Nausea 37 (22.3%) 0 (0%)
Headache 26 (15.7%) 2 (1%)
Alanine aminotransferase increased 25 (15.1%) 4 (2%)
Aspartate aminotransferase increased 20 (12.0%) 2(1%)
Lipase increased 24 (14.5%) 8 (5%)
Hyperamylasaemia 17 (10.2%) 0 (0%)
• Thrombocytopenia includes platelet count decreased, thrombocytopenia
• Neuropathy peripheral includes formication, hypoaesthesia, paraesthesia, peripheral sensory neuropathy, neuropathy
peripheral
• Lipase increased includes hyperlipasaemia, lipase increased
• Hyperamylasaemia includes amylase increased, hyperamylasaemia
• Treatment-relatedness assessed by investigator
Pardanani A, et al. Blood 2013;122(21): abstr 108
First dose effect of momelotinib
Number (%)
Total subjects enrolled 166
Adverse event of dizziness* on C1/D1 23 (14%)
Related to study drug 16 (10%)
Unrelated to study drug 5 (3%)
Relatedness not reported 2 (1%)
Adverse event of hypotension* on C1/D1 11 (7%)
Related to study drug 8 (5%)
Unrelated to study drug 3 (2%)
• *Dizziness includes dizziness, lightheadedness
• *Hypotension includes low blood pressure, decreased blood pressure, hypotension
• 3 subjects with dizziness also reported hypotension
• Treatment-relatedness assessed by investigator
Pardanani A, et al. Blood 2013;122(21): abstr 108
Platelet count and momelotinib starting dose
Month
525
150 mg QD
300 mg QD
150 mg BID
Doses at C1D1
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1 2 3 4 6 5 7 8
0
25
50
75
25
100
125
150
175
200
225
250
275
300
325
350
375
400
425
450
475
500
Me
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25
50
75
100
125
150
175
200
225
250
275
300
325
350
375
400
425
450
475
500
525
Time (Months)
1 2 3 4 5 6 7 8
Dose at C1D1: 150 mg QD 300 mg QD 150 mg BID
Pardanani A, et al. Blood 2013;122(21): abstr 108
N=420
1:1 randomization
Screening (≤ 35 days)
Double-blind Treatment Phase Open-label Phase Long-term Follow-up
Momelotinib + placebo
Ruxolitinib + placebo
Week 24
Momelotinib QD Momelotinib
Momelotinib
Week 192
Year 4 Year 5 Day 1
Within 5 days of randomization
Phase 3 study design (GS-US-352-0101)
Is there a role for a 2nd JAK2 inhibitor after ruxolitinib failure?
Efficacy and safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with
ruxolitinib: A phase II study (JAKARTA-2)
• Patients ≥18 yrs with splenomegaly and platelet count ≥50 ×109/L received fedratinib 400 mg orally, once daily for consecutive 4-wk cycles.
• Eligible patients had received ≥14 d RUX treatment, and had discontinued RUX for ≥14 d prior to starting fedratinib.
• No consensus definition of RUX resistance/intolerance, (investigator assessment) as resistant (lack or loss of response) or intolerant to RUX.
• Primary endpoint : spleen response rate (RR) (≥35% reduction in spleen volume from baseline at Wk 12 [MRI/CT blinded central review]
Harrison CN, et al. Blood. 2013;122(21):abstr 661
Efficacy and safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with
ruxolitinib: A phase II study (JAKARTA-2)
• 27 patients received fedratinib treatment (median RUX exposure 10.7 months [range 1.9–34.4])
• Baseline Characteristics: – The median age was 69 yrs – 56% male – 67% primary MF – 63% high-risk MF – 67% JAK2V617F positive – 41% platelet count <100 × 109/L – median spleen volume 3190 mL [1072–7815].
• Eighteen patients were considered resistant by the treating physician (8 lack of response, 3 disease progression, 7 loss of response) and 9 intolerant (6 hematologic, 3 non-hematologic toxicity)
• Median fedratinib exposure : 4 cycles (range 1–10); 19 patients remain on treatment.
Harrison CN, et al. Blood. 2013;122(21):abstr 661
Efficacy and safety of fedratinib in patients with intermediate- or high-risk myelofibrosis (MF) previously treated with
ruxolitinib: A phase II study (JAKARTA-2)
RUX resistant (n=18)
RUX intolerant (n=9)
Overall (n=27)
Spleen response at Wk 12a, n/N (%)
6/14 (43)
2/6 (33)
8/20 (40)
Symptom response to Wk 12b, n/N (%
3/18 (17)
2/8 (25)
5/26 (19)
a7 patients not evaluable: no post-baseline MRI/CT scan (n=5); no baseline MRI/CT scan (n=1); MRI/CT scan outside time window for Wk 12 assessment (n=1). b1 patient not evaluable: no baseline and at least one post-baseline assessment of TSS.
Harrison CN, et al. Blood. 2013;122(21):abstr 661
Momelotinib: Response rates of JAK inhibitor-treated subjects
Number
Previously treated with JAK inhibitor 22
Ruxolitinib 14
TG101348 5
“JAK inhibitor study” 3
Spleen evaluable1 20
Spleen response2: A (A/20) 2 (10%)
Transfusion independence evaluable3 13
Transfusion independence response4: B (B/13) 7 (54%)
(1) Spleen evaluable: baseline palpable splenomegaly > 5 cm and had completed ≥ 8 weeks of treatment
(2) Spleen response: ≥ 50% decrease from baseline in palpable spleen length for baseline splenomegaly ≥
10 cm or resolution of palpable splenomegaly for baseline splenomegaly > 5 and < 10 cm
(3) Transfusion independence evaluable: transfusion dependent at baseline and had completed ≥ 12
weeks of treatment
(4) Transfusion independence response: For those who are transfusion dependent at baseline,
achievement of transfusion independence that lasts ≥ 12 weeks
Pardanani A, et al. Blood 2013;122(21): abstr 108
Novel approaches targeting JAK/Stat pathway
Targets of intervention by putative small-molecule inhibitors around the cytokine receptor,
JAK-STAT, MAPK, and PI3K-mTOR pathways.
Constantinescu S N , and Vainchenker W. Hematology Am Soc
Hematol Educ Program 2012;2012:553-560
Copyrighted Figure
Searching for “mutant”-specific JAK2 inhibitors by targeting a predicted mechanism of
activation of JAK2 kinase domain (JH1) by the V617F pseudokinase (JH2) mutation.
Constantinescu S N , and Vainchenker W. Hematology Am Soc
Hematol Educ Program 2012;2012:553-560
Copyrighted Figure
Conclusions
• 2nd generation JAK2 inhibitors may offer advantages as first-line therapy in term of efficacy or toxicity based on different 2ndry targets.
• Responses to 2nd generation JAK2 inhibitors may be observed after failure of ruxolitinib and should be further pursued in clinical trials.
• Novel approaches targeting JAK-STAT pathway include search for mutant specific inhibitors, non-competitive inhibitors, and targeting downstream signaling.
Thank You