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

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slide1

Ibrutinib: Analysis of Pivotal Data

Richard R. Furman, MD

CLL Research Center

slide2

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

issues with novel agents
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
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.

cheson 2012 recommendations
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

evolution of responses over time kinase inhibitors
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 agents1
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
Ibrutinib: Discovery

Person

Disease

Enzyme

Drug

ibrutinib

O

NH2

N

N

N

N

N

O

Bruton’s Agammaglobulinemia,

1952

Bruton Tyrosine Kinase, 1993

Synthesized 2005

First in human 2009

1st approval 2013

Ogden Bruton (1908-2003)

ibrutinib inhibitor of bruton s tyrosine kinase
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

O

NH

2

N

N

N

N

N

O

slide14

IC50 Values of Ibrutinib and Related Kinases

Honigberg LA. PNAS 2010; 107:13075.

btk inhibition and plasma levels
BTK Inhibition and Plasma Levels

Occupancy indicates irreversible inhibition of BTK

Plasma concentration profile reflects inhibition profile of reversibly inhibited off targets

ibrutinib pivotal study resonate
Ibrutinib Pivotal Study: RESONATE

Oral ibrutinib 420 mg once daily until PD or unacceptable toxicity

n=195

1:1

R

ANDOM

I

Z

E

Crossover to ibrutinib420 mg once daily after IRC-confirmed PD (n=57)

IV ofatumumab initial dose of 300 mg followed by 2000 mg × 11 doses over 24 weeks

n=196

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
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
RESONATE: Baseline Characteristics

Byrd JC. NEJM 2014; 371:213

patient disposition
Patient Disposition

Byrd JC. NEJM 2014; 371:213

resonate progression free survival
RESONATE: Progression Free Survival

100

90

80

70

60

Progression-Free Survival (%)

50

40

30

20

10

0

0

3

6

9

12

15

Months

No. at risk

  • 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

Ibrutinib:

195

183

116

38

7

Ofatumumab:

196

161

83

15

1

0

resonate overall survival
RESONATE: Overall Survival

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100

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Ibrutinib (n=195, 16 events)

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90

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Ofatumumab (n=196, 33 events)

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80

70

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Overall Survival (%)

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3

6

9

12

15

Month

  • 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
ae bleeding
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
AE: Diarrhea

Possibily mediated by EGFR inhibition

Reversible

Only symptomatic with food in GI tract

Take medication prior to bedtime

conclusion
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!