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 PI3K (phosphatidyl 3-kinase): Idelalisib (GS-1101) Duvelisib (IPI-145) 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 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 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

Bruton’s Agammaglobulinemia, Bruton Tyrosine Kinase, 1993 Ibrutinib: Discovery Ogden Bruton (1908-2003) 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

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 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

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.

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.

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 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

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) 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

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 (0.33-16.62) 9.2 (0.07-16.49) 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

RESONATE: Progression Free Survival 3 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) (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 40 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) (0.238-0.789) Log-rank P value < 0.0049 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) 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

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

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 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%

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!