Ibrutinib: Analysis of Pivotal Data
Richard R. Furman, MD
CLL Research Center
BCR-associated Kinases:
Proven Effective Therapeutic Targets
• Syk (spleen tyrosine kinase):
1. fostamatinib
2. PRT062070
3. GS-9973
• Btk (Bruton’s tyrosine kinase):
1. ibrutinib
2. CC-292
3. ACP-196
4. ONO-4059
• PI3K (phosphatidyl 3-kinase):
1. Idelalisib (GS-1101)
2. Duvelisib (IPI-145)
3. AMG319
Nat Rev Immunol 2:945
Targeting the “BCR++” Antigen Pathway:
Issues with Novel Agents
• Response Criteria
– Redefine clinical endpoints
– Evolution of response over time
• Dosing:
– No more MTD dosing
– Threshold dosing
– Fixed dosing / wide therapeutic window
• Re-evaluation of Prognostic Markers
• Re-evaluation of MRD
Redefining Clinical End Points
“Cheson 2012”
• Standard response criteria: measure of treatment efficacy
• Need to provide means for determining need for treatment
discontinuation
• For novel agents, response criteria don’t measure effect:
– Thalidomide / lenalidomide: tumor flare
– BCR Antagonists: lymphocytosis (Not tumor flare)
Cheson BD. JCO 2012;30:2820.
Lymphocytosis + Nodal Reduction
with BCR Antagonists
Cheson 2012: Recommendations
1. For IMIDs: Assessment of PD should use repeat
observations and incorporate indicators of PD not
associated with tumor flares.
2. For BCR-targeted agents: lymphocytosis alone should not
be considered an indicator of PD. Need to demonstrate
other CLL-related signs or symptoms of PD.
3. Lymphocytosis is distinct from tumor flare
Evolution of Responses Over Time:
Kinase Inhibitors
• Achievement of best response
was time dependent
• Proportion with CR/PR increased
during follow-up
• Proportion with PR+L diminished
as the lymphocyte count
declined over time
Issues with Novel Agents
• Response Criteria
– Redefine clinical endpoints
– Evolution of response over time
• Dosing:
– No more MTD dosing
– Threshold dosing
– Fixed dosing / wide therapeutic window
• Re-evaluation of Prognostic Markers
• Re-evaluation of MRD
Ibrutinib: Discovery
Person
Disease
Enzyme
Drug
ibrutinib
O
NH2
N
N
N
N
N
O
Ogden Bruton
(1908-2003)
Bruton’s
Agammaglobulinemia,
1952
Bruton
Tyrosine
Kinase, 1993
Synthesized 2005
First in human 2009
1st approval 2013
BCR Kinases All Interact With Each Other
Ibrutinib: Inhibitor of Bruton’s Tyrosine Kinase
•
O
•
NH 2
N
•
•
N
N
N
N
O
•
•
Forms an irreversible bond with
cysteine-481 in Btk
Potent Btk inhibition
IC50=0.5 nM
Orally bioavailable
Daily dosing resulting in 24-hr target
inhibition
Possible impact on T-cells
Possible impact upon Tec, Bmx, Blk,
Itk, and platelets
Phase I Study of Ibrutinib in
B-Cell Malignancies
Cohort
Dose
No. of Patients
CR
PR
I
1.25 mg/kg/d
7
0
2
II
2.5 mg/kg/d
9
1
3
III
5.0 mg/kg/d
6
2
1
IV
8.3 mg/kg/d
8
3
1
CD-I
8.3 mg/kg/d
10
1
5
V
12.5 mg/kg/d
7
0
4
CD-II
560 mg/d
9
1
6
56
8 (14%)
22 (39%)
Total
Advani RH. JCO 2013;31(1):88.
IC50 Values of Ibrutinib and Related Kinases
Irreversible
Reversible
Kinase
Ibrutinib
IC50 (nM)
Kinase
Ibrutinib
IC50 (nM)
BTK
0.46
FGR
2.31
BLK
0.52
CSK
2.30
BMX/ETK
0.76
Brk
3.34
EGFR
5.55
HCK
3.67
ErbB2
9.40
LCK
33.24
ITK
10.70
ABL
86.12
JAK3
16.13
Syk
>10,000
TEC
77.76
JAK2
>10,000
Honigberg LA. PNAS 2010; 107:13075.
BTK Inhibition and Plasma Levels
70
100%
Plasma Concentration
(ng/mL)
Occupancy indicates
irreversible inhibition of
BTK
50
40
80%
70%
Plasma Conc
60%
% Active-Site Occupancy
50%
30
40%
Plasma concentration profile
reflects inhibition profile of
reversibly inhibited off targets
20
30%
20%
10
10%
0
0%
0
4
8
12
16
Time Post-dose (h)
20
24
28
BTK Active-Site Occupancy
90%
60
Ibrutinib Pivotal Study: RESONATE
R
A
N
D
O
M
I
Z
E
Oral ibrutinib 420 mg once
daily until PD or unacceptable
toxicity
n=195
1:1
IV ofatumumab initial dose of
300 mg followed by 2000 mg
× 11 doses over 24 weeks
n=196
Crossover to ibrutinib
420 mg once daily after
IRC-confirmed PD (n=57)
Eligibility: Relapsed and not appropriate for purine analog therapy:
Disease progression < 3 years from prior purine analog
Age >70 or age>65 with comorbidities
Relapsed and deletion 17p
purine analog associated AIHA / ITP
Byrd JC. NEJM 2014; 371:213
RESONATE: Study Objectives
• Primary Objective
– PFS as assessed by the IRC per 2008 IWCLL criteria with the
2012 clarification for treatment-related lymphocytosis
 Secondary Objectives
– Overall survival
– IRC-assessed overall response rate
– Safety and tolerability
 Exploratory Objective
– Investigator assessed progression free survival and overall
response rate
RESONATE: Baseline Characteristics
Ibrutinib (n=195)
Ofatumumab (n=196)
67 (30-86)
67 (37-88)
Male, %
66
70
purine analogs ref, %
45
45
ECOG PS 1, %
59
59
Rai stage III/IV, %
56
58
Bulky disease ≥5 cm, %
64
52
Del11q / 17p, %
32 / 32
30 / 33
# prior Rx, n
3 (1-12)
2 (1-13)
53
46
93
43
85
94
88
37
77
90
age (range), years
≥3 Prior therapies, %
Prior therapy, %
Alkylator
Bendamustine
Purine analog
Anti-CD20
Byrd JC. NEJM 2014; 371:213
Patient Disposition
Study treatment disposition
Ibrutinib %
Ofatumumab %
Did not receive study drug
Discontinued or completed
Completed treatment
Ongoing
Median time on study, mos (range)
0
14
86
9.6 (0.33-16.62)
3
97
61
1
9.2 (0.07-16.49)
Primary reason for discontinuation
PD / Richter's
AE
Patient withdrawal
Deaths
Investigator decision
5/2
4
1
4
1
19 / 2
4
3
5
6
Byrd JC. NEJM 2014; 371:213
RESONATE: Progression Free Survival
Progression-Free Survival (%)
100
90
80
70
60
Ofatumumab Ibrutinib
Median PFS (mo)
8.08
NR
Hazard ratio
0.215
(95% CI)
(0.146-0.317)
Log-rank P value
< 0.0001
50
40
30
20
10
0
0
No. at risk
Ibrutinib: 195
Ofatumumab: 196




3
6
9
12
15
38
15
7
1
0
Months
183
161
116
83
Ibrutinib significantly prolonged PFS
78% reduction in the risk of progression or death
Investigator assessed PFS hazard ratio 0.133 (95% CI: 0.085-0.209) p value < 0.0001
Richter’s transformation was confirmed in 2 patients on each arm. An additional patient on
the ibrutinib arm experienced disease transformation to prolymphocytic leukemia
PFS By Prognostic Factor
RESONATE: Overall Survival
100| | | | |
90
Overall Survival (%)
Ibrutinib (n=195, 16 events)
Ofatumumab (n=196, 33 events)
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80
70
Ofatumumab Ibrutinib
Median time (mo)
NR
NR
Hazard ratio
0.434
(95% CI)
(0.238-0.789)
Log-rank P value
< 0.0049
60
50
40
30
20
10
0



0
3
6
9
Month
12
15
18
Ibrutinib significantly prolonged OS compared with ofatumumab
This represents a 57% reduction in the risk of death for the ibrutinib arm
At the time of this analysis, 57 patients initially randomized to ofatumumab
were crossed over to receive ibrutinib following IRC-confirmed PD
Resonate: Overall Response Rate
Adverse Events in >15%
Ibrutinib (n=195)
Median treatment duration
Any TEAE, %
Diarrhea
Fatigue
Nausea
Pyrexia
Anemia
Neutropenia
Cough
Thrombocytopenia
Arthralgia
Upper respiratory tract infection
Constipation
Infusion-related reaction
Ofatumumab (n=191)
8.6 months
5.3 months
Any grade Grade 3/4 Any grade Grade 3/4
99
48
28
26
24
23
22
19
17
17
16
15
0
51
4
2
2
2
5
16
0
6
1
1
0
0
98
18
30
18
15
17
15
23
12
7
10
9
28
39
2
2
0
1
8
14
1
4
0
2
0
3
Adverse Events in >15%
Ibrutinib (n=195)
Median treatment duration
Any TEAE, %
Diarrhea
Fatigue
Nausea
Pyrexia
Anemia
Neutropenia
Cough
Thrombocytopenia
Arthralgia
Upper respiratory tract infection
Constipation
Infusion-related reaction
Ofatumumab (n=191)
8.6 months
5.3 months
Any grade Grade 3/4 Any grade Grade 3/4
99
48
28
26
24
23
22
19
17
17
16
15
0
51
4
2
2
2
5
16
0
6
1
1
0
0
98
18
30
18
15
17
15
23
12
7
10
9
28
39
2
2
0
1
8
14
1
4
0
2
0
3
AE: Bleeding
• Resonate: all grades: 44% vs 12%
grade 3-4: 1% vs 2%
• BTK and TEK modulate glycoprotein VI signaling following
binding of collagen
• Three Studies:
– Farooqui: PFA-100: epinephrine / ADP normal
– Rushworth: aggregometry: collagen and ADP abnormal
no explanation for ADP findings
– Kamel: aggregometry: collagen abnormal
AE: Diarrhea
• Possibily mediated by EGFR inhibition
• Reversible
• Only symptomatic with food in GI tract
• Take medication prior to bedtime
SAEs / Atrial Fibrillation
Ibrutinib
(n=195)
Ofatumumab
(n=191)
8.6 months
5.3 months
Subjects reporting ≥1 SAE
42%
30%
Reporting ≥1 AE grade ≥3
57%
47%
24%
22%
5%
1%
3%
0%
44%
12%
1%
2%
Adverse event, %
Median treatment duration
Any infection grade ≥3
Atrial fibrillation
Grade ≥3 AE atrial fibrillation
Any hemorrhage
Major hemorrhage
Conclusion
• Ibrutinib initially approved based upon phase II data for relapsed CLL
patients who have received at least one prior therapy
• Based upon the RESONATE data, ibrutinib’s approval updated to include
deletion 17p at any line of therapy
• Phase III data provided new insights into adverse events: atrial
fibrillation
• Responses will evolve over time: STAY TUNED!