1. Ibrutinib: Analysis of Pivotal Data
Richard R. Furman, MD
CLL Research Center

2. BCR-associated Kinases: Proven Effective Therapeutic Targets
Syk (spleen tyrosine kinase):
fostamatinib
PRT062070
GS-9973
Btk (Bruton’s tyrosine kinase):
ibrutinib
CC-292
ACP-196
ONO-4059
PI3K (phosphatidyl 3-kinase):
Idelalisib (GS-1101)
Duvelisib (IPI-145)
AMG319
Nat Rev Immunol 2:945

3. Targeting the “BCR++” Antigen Pathway:

4. 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

5. 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.

6. Lymphocytosis + Nodal Reduction with BCR Antagonists

7. Cheson 2012: Recommendations
For IMIDs: Assessment of PD should use repeat observations and incorporate indicators of PD not associated with tumor flares.
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.
Lymphocytosis is distinct from tumor flare

8. 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

9. 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

10. Bruton’s Agammaglobulinemia, Bruton Tyrosine Kinase, 1993
Ibrutinib: Discovery
Ogden Bruton ( )
Person
Bruton’s Agammaglobulinemia,
1952
Disease
Bruton Tyrosine Kinase, 1993
Enzyme
Synthesized 2005
First in human 2009
1st approval 2013
Drug N
ibrutinib O
NH2

11. BCR Kinases All Interact With Each Other

12. Ibrutinib: Inhibitor of Bruton’s Tyrosine Kinase
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 N NH 2 O

13. Phase I Study of Ibrutinib in B-Cell Malignancies
Cohort
Dose
No. of Patients CR PR I
1.25 mg/kg/d 7 2 II
2.5 mg/kg/d 9 1 3
III
5.0 mg/kg/d 6 IV
8.3 mg/kg/d 8
CD-I 10 5 V
12.5 mg/kg/d 4
CD-II
560 mg/d
Total 56
8 (14%)
22 (39%)
Advani RH. JCO 2013;31(1):88.

14. IC50 Values of Ibrutinib and Related Kinases
Irreversible
Reversible
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
Honigberg LA. PNAS 2010; 107:13075.

15. BTK Inhibition and Plasma Levels
Occupancy indicates irreversible inhibition of BTK
Plasma concentration profile reflects inhibition profile of reversibly inhibited off targets

16. Ibrutinib Pivotal Study: RESONATE
Oral ibrutinib 420 mg once daily until PD or unacceptable toxicity
n=195
1:1 R
ANDOM I Z E
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

17. 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

18. RESONATE: Baseline Characteristics
Ibrutinib (n=195)
Ofatumumab (n=196)
age (range), years
67 (30-86)
67 (37-88)
Male, % 66 70
purine analogs ref, % 45
ECOG PS 1, % 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)
≥3 Prior therapies, % 53 46
Prior therapy, %
Alkylator
Bendamustine
Purine analog
Anti-CD20
93 43 85 94
88 37 77 90
Byrd JC. NEJM 2014; 371:213

19. Study treatment disposition
Patient Disposition
Study treatment disposition
Ibrutinib %
Ofatumumab %
Did not receive study drug 3
Discontinued or completed 14 97
Completed treatment - 61
Ongoing 86 1
Median time on study, mos (range)
9.6 ( )
9.2 ( )
Primary reason for discontinuation
PD / Richter's
5 / 2
19 / 2 AE 4
Patient withdrawal
Deaths 5
Investigator decision 6
Byrd JC. NEJM 2014; 371:213

20. RESONATE: Progression Free Survival3 6 9 12
195
183
116 38 7
196
161 83 15 1 10 20 30 40 50 60 70 80 90
100
Progression-Free Survival (%)
No. at risk
Ibrutinib:
Ofatumumab:
Months
Ofatumumab
Ibrutinib
Median PFS (mo)
8.08 NR
Hazard ratio
0.215
(95% CI)
( )
Log-rank P value
<
Ibrutinib significantly prolonged PFS
78% reduction in the risk of progression or death
Investigator assessed PFS hazard ratio (95% CI: ) p value <
Richter’s transformation was confirmed in 2 patients on each arm. An additional patient on the ibrutinib arm experienced disease transformation to prolymphocytic leukemia

21. PFS By Prognostic Factor

22. RESONATE: Overall Survival40 50 60 70 80 90
100 | 10 20 30 3 6 9 12 15 18
Month
Ibrutinib (n=195, 16 events)
Ofatumumab (n=196, 33 events)
Ofatumumab
Ibrutinib
Median time (mo) NR
Hazard ratio
0.434
(95% CI)
( )
Log-rank P value
<
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

23. Resonate: Overall Response Rate

24. Adverse Events in >15%
Ibrutinib (n=195)
Ofatumumab (n=191)
Median treatment duration
8.6 months
5.3 months
Any grade
Grade 3/4
Any TEAE, % 99 51 98 39
Diarrhea 48 4 18 2
Fatigue 28 30
Nausea 26
Pyrexia 24 15 1
Anemia 23 5 17 8
Neutropenia 22 16 14
Cough 19
Thrombocytopenia 6 12
Arthralgia 7
Upper respiratory tract infection 10
Constipation 9
Infusion-related reaction 3

25. Adverse Events in >15%
Ibrutinib (n=195)
Ofatumumab (n=191)
Median treatment duration
8.6 months
5.3 months
Any grade
Grade 3/4
Any TEAE, % 99 51 98 39
Diarrhea 48 4 18 2
Fatigue 28 30
Nausea 26
Pyrexia 24 15 1
Anemia 23 5 17 8
Neutropenia 22 16 14
Cough 19
Thrombocytopenia 6 12
Arthralgia 7
Upper respiratory tract infection 10
Constipation 9
Infusion-related reaction 3

26. 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

27. AE: Diarrhea Possibily mediated by EGFR inhibition Reversible
Only symptomatic with food in GI tract
Take medication prior to bedtime

28. SAEs / Atrial Fibrillation
Adverse event, %
Ibrutinib
(n=195)
Ofatumumab (n=191)
Median treatment duration
8.6 months
5.3 months
Subjects reporting ≥1 SAE
42%
30%
Reporting ≥1 AE grade ≥3
57%
47%
Any infection grade ≥3
24%
22%
Atrial fibrillation 5% 1%
Grade ≥3 AE atrial fibrillation 3% 0%
Any hemorrhage
44%
12%
Major hemorrhage 2%

29. 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!