New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida Phase III RESONATE-2: Frontline Ibrutinib vs Chlorambucil in Elderly Patients With CLL *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

RESONATE-2: Background  CLL primarily seen in older pts who often have comorbidities [1] –Chlorambucil standard frontline therapy for older pts; fludarabine may be too toxic for older or frail pts  Ibrutinib: first-in-class oral BTK inhibitor –FDA- and EMA-approved for pts with previously treated CML, including those with del(17p) and by EMA for those with mutated TP53  Phase III RESONATE trial of ibrutinib in relapsed/refractory CLL showed 78% reduction in risk of progression and 57% reduction in risk of death vs ofatumumab [2]  Phase II PCYC-1102 trial in treatment-naive pts with CLL showed 84% ORR and 96% 30-mo PFS and 97% 30-mo OS with 81% of pts continuing ibrutinib at 3 yrs [3]  Current RESONATE-2 trial evaluated ibrutinib in older pts with treatment-naive CLL or SLL 1. Thurmes P, et al. Leuk Lymphoma. 2008;49: Byrd JC, et al. N Engl J Med. 2014;37: Byrd JC, et al. Blood. 2015;124: Slide credit: clinicaloptions.comclinicaloptions.com

Phase III RESONATE-2: Study Design  Open-label, randomized trial  Primary endpoint: IRC-evaluated PFS  Secondary endpoints: OS, ORR, hematologic improvement, safety Treatment-naive CLL pts 65 yrs of age or older; for pts yrs, comorbidity that precludes FCR; no warfarin use; no del(17p) (N = 269) Ibrutinib 420 mg QD until PD or unacceptable toxicity (n = 136) Chlorambucil 0.5 mg/kg* Days 1 and 15 of 28-d cycle up to 12 cycles (n = 133) PCYC-1116 extension study after IRC- confirmed progression Stratified by ECOG PS 0-1 vs 2 Rai stage III-IV vs ≤ II Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com Crossover upon PD (n = 43) *Up to 0.8 mg/kg maximum.

RESONATE-2: Baseline Characteristics Characteristic Ibrutinib (n = 136) Chlorambucil (n = 133) Median age, yrs (range)  70 yrs or older, % 73 (65-89) (65-90) 70 ECOG PS 2, %89 Rai stage III or IV, %4447 CIRS score > 6, %3133 Creatinine clearance < 60 mL/min, %4450 Bulky disease ≥ 5 cm, %4030 β 2 -microglobulin > 3.5 mg/L, %6367 Hemoglobin ≤ 11 g/dL, %3841 Platelet count ≤ 100,000/mm³, %2621 del(11q), %2119 Unmutated IGVH, %4345 Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: PFS (Primary Endpoint)  At median follow-up of 18.4 mos, 84% vs 91% reduction in risk of disease progression or death with ibrutinib by independent vs investigator assessment  PFS results not dependent on age, Rai stage, ECOG PS, or bulky disease  1 Richter’s transformation in chlorambucil arm; none on ibrutinib arm Outcome Ibrutinib (n = 136) Chlorambucil (n = 133) HR (95% CI) P Value Independent Assessment Median PFS, mosNE ( ) < mo PFS rate, %9052 Investigator Assessment Median PFS, mosNE ( ) < mo PFS rate, %9445 Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: PFS in High-Risk Subgroups by Investigator Assessment  In ibrutinib arm, 92% 18-mo PFS rate in IGHV-mutated subgroup vs 95% in unmutated subgroup Median PFS, Mos Ibrutinib (n = 136) Chlorambucil (n = 133) HR P Value del(11q) subgroupNR90.02 <.0001 Unmutated IGHV subgroup NR90.06 <.0001 Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: OS  84% reduction in risk of death with ibrutinib Outcome Ibrutinib (n = 136) Chlorambucil (n = 133) HR (95% CI) P Value Median OS, mosNE 0.16 ( ) mo OS rate, %9884 Deaths, n317 Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: Best Response by Investigator Assessment  90% of pts responded to ibrutinib vs 35% to chlorambucil (P <.0001)  ORR at 8 mos: 82% with ibrutinib vs 30% with chlorambucil Response, % Ibrutinib (n = 136) Chlorambucil (n = 133) CR/CRi105 nPR12 PR7629 PR-L30 SD640 PD120 Sustained improvement in Hb in pts with anemia* 8445 Sustained improvement in platelets in pts with thrombocytopenia † 7743 Tedeschi A, et al. ASH Abstract 495. *P <.0001; † P =.0054 Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: Exposure to Study Treatment Parameter Ibrutinib (n = 136) Chlorambucil (n = 133) Median duration of study treatment, mos (range) 17.4 ( )7.1 ( ) Dose reduction, n (%)13 (10)25 (19) Continuing treatment at end of study, n (%)118 (87)0 Completing maximum of 12 cycles of chlorambucil, n (%) NA53 (40) Mean chlorambucil dose, mg/kg (range)NA0.6 ( ) Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: Discontinuation of Ibrutinib  13 of 14 who discontinued ibrutinib due to AEs or progression remained alive at median follow-up of 10 mos after discontinuation Outcome, n Ibrutinib (n = 136) Discontinued ibrutinib due to AEs12  Died1  Progression of disease after discontinuation3  Subsequent therapy without progression3  Progression free without additional therapy5 Discontinued therapy due to progression on therapy 2 Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: Adverse Events Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com  Pts with grade 3 HTN (n = 6) managed with anti-HTN drugs, did not require dose reduction of ibrutinib; 4 had history of HTN  Among pts with atrial fibrillation (n = 8), 2 discontinued ibrutinib –7 of 8 with history of HTN, CAD, and/or myocardial ischemia  Among pts with major bleeding (n = 6), 3 discontinued ibrutinib –3 of 6 on concomitant aspirin, vitamin E, or low-molecular-weight heparin Parameter Ibrutinib (n = 136) Chlorambucil (n = 133) Median duration of study treatment, mos (range) 17.4 ( )7.1 ( ) Selected AEs, %  Hypertension140  Atrial fibrillation61  Major hemorrhage42

RESONATE-2: Adverse Events  Majority of AEs on ibrutinib arm were grade 1; did not result in treatment discontinuation  Fatigue, nausea, vomiting, cytopenias occurred more frequently with chlorambucil  Grade 3 maculopapular rash in 3% of pts on ibrutinib and 2% of those on chlorambucil Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

RESONATE-2: Conclusions  Phase III trial of ibrutinib vs chlorambucil in elderly treatment-naive pts with CLL –84% reduction in risk of progression by independent assessment and 84% reduction in risk of death with ibrutinib –Improved bone marrow function (↑ Hb, platelets) with ibrutinib –Most pts (87%) continued ibrutinib with a median follow-up of 1.5 yrs  Ibrutinib shows favorable benefit/risk profile vs traditional chemotherapy in elderly pts with CLL/SLL Tedeschi A, et al. ASH Abstract 495. Slide credit: clinicaloptions.comclinicaloptions.com

Go Online for More CCO Coverage of ASH 2015! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in:  Acute leukemias/chronic leukemias  Myeloma/plasma cell disorders  Lymphomas  MDS and myeloproliferative neoplasms clinicaloptions.com/oncology