Ibrutinib: Analysis of Pivotal Data

Richard R. Furman, MDCLL Research Center

BCR-associated Kinases:Proven Effective Therapeutic Targets

Nat Rev Immunol 2:945

• Syk (spleen tyrosine kinase):1. fostamatinib2. PRT0620703. GS-9973

• Btk (Bruton’s tyrosine kinase):1. ibrutinib 2. CC-2923. ACP-1964. ONO-4059

• PI3K (phosphatidyl 3-kinase):1. Idelalisib (GS-1101)2. Duvelisib (IPI-145)3. AMG319

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 Reductionwith 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

Ogden Bruton (1908-2003)

Person

Bruton’s Agammaglobulinemia,

1952

Disease

Bruton Tyrosine

Kinase, 1993

Enzyme

Synthesized 2005First in human 2009

1st approval 2013

Drug

N

ibrutinib

NO

N

N N

NH2

O

BCR Kinases All Interact With Each Other

Ibrutinib: Inhibitor of Bruton’s Tyrosine Kinase

• Forms an irreversible bond with cysteine-481 in Btk

• Potent Btk inhibitionIC50=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

N

NN

NH2

O

N

O

Phase I Study of Ibrutinib inB-Cell Malignancies

Advani RH. JCO 2013;31(1):88.

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

Total 56 8 (14%) 22 (39%)

Honigberg LA. PNAS 2010; 107:13075.

IC50 Values of Ibrutinib and Related KinasesIrreversible Reversible

Kinase IbrutinibIC50 (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

0 4 8 12 16 20 24 280

10

20

30

40

50

60

70

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Plasma Conc

% Active-Site Occupancy

Time Post-dose (h)

Pla

sm

a C

on

ce

ntr

ati

on

(ng

/mL

)

BT

K A

cti

ve

-Sit

e O

cc

up

an

cy

BTK Inhibition and Plasma Levels

Plasma concentration profile reflects inhibition profile of reversibly inhibited off targets

Occupancy indicates irreversible inhibition of BTK

Ibrutinib Pivotal Study: RESONATE

Byrd JC. NEJM 2014; 371:213

RANDOMIZE

Oral ibrutinib 420 mg once daily until PD or unacceptable

toxicityn=195

IV ofatumumab initial dose of 300 mg followed by 2000 mg

× 11 doses over 24 weeksn=196

1:1

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 analogAge >70 or age>65 with comorbiditiesRelapsed and deletion 17ppurine analog associated AIHA / ITP

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

Byrd JC. NEJM 2014; 371:213

Ibrutinib (n=195) Ofatumumab (n=196)age (range), years 67 (30-86) 67 (37-88)

Male, % 66 70purine analogs ref, % 45 45

ECOG PS 1, % 59 59Rai 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

93438594

88377790

Patient Disposition

Byrd JC. NEJM 2014; 371:213

Study treatment disposition Ibrutinib % Ofatumumab % Did not receive study drug 0 3Discontinued or completed 14 97

Completed treatment - 61Ongoing 86 1 Median time on study, mos (range) 9.6 (0.33-16.62) 9.2 (0.07-16.49)

Primary reason for discontinuation    PD / Richter's 5 / 2 19 / 2AE 4 4Patient withdrawal 1 3Deaths 4 5Investigator decision 1 6

RESONATE: Progression Free Survival

0 3 6 9 12

195 183 116 38 7196 161 83 15 1 0

150

10

20

30

40

50

60

70

80

90

100

Prog

ress

ion-

Free

Sur

viva

l (%

)

No. at riskIbrutinib:

Ofatumumab:

Months

Ofatumumab IbrutinibMedian PFS (mo) 8.08 NRHazard ratio 0.215(95% CI) (0.146-0.317)Log-rank P value < 0.0001

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

Ofatumumab IbrutinibMedian time (mo) NR NRHazard ratio 0.434(95% CI) (0.238-0.789)Log-rank P value < 0.0049

Ibrutinib (n=195, 16 events)Ofatumumab (n=196, 33 events)

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

Ove

rall

Sur

viva

l (%

)

40

50

60

70

80

90

100

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0

10

20

30

0 3 6 9 12 15 18Month

Resonate: Overall Response Rate

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 grade Grade 3/4 Any TEAE, % 99 51 98 39    Diarrhea 48 4 18 2    Fatigue 28 2 30 2    Nausea 26 2 18 0    Pyrexia 24 2 15 1    Anemia 23 5 17 8    Neutropenia 22 16 15 14    Cough 19 0 23 1    Thrombocytopenia 17 6 12 4    Arthralgia 17 1 7 0    Upper respiratory tract infection 16 1 10 2    Constipation 15 0 9 0

Infusion-related reaction 0 0 28 3

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 grade Grade 3/4 Any TEAE, % 99 51 98 39    Diarrhea 48 4 18 2    Fatigue 28 2 30 2    Nausea 26 2 18 0    Pyrexia 24 2 15 1    Anemia 23 5 17 8    Neutropenia 22 16 15 14    Cough 19 0 23 1    Thrombocytopenia 17 6 12 4    Arthralgia 17 1 7 0    Upper respiratory tract infection 16 1 10 2    Constipation 15 0 9 0

Infusion-related reaction 0 0 28 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

Adverse event, % Ibrutinib (n=195)

Ofatumumab (n=191)

Median treatment duration 8.6 months 5.3 monthsSubjects 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 1% 2%

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!