Pharmacist Focus on BTK Inhibitors Moderator Shilpa Paul, PharmD, BCOP - PowerPoint Presentation

Pharmacist Focus on BTK Inhibitors Moderator Shilpa Paul, PharmD, BCOPClinical Pharmacy Specialist, LeukemiaThe University of TexasMD Anderson Cancer CenterHouston, Texas Panelist Matthew Snyder, PharmD, BCOP Clinical Pharmacist Malignant Hematology Moffitt Cancer Center Tampa, Florida

This program will include a discussion of off-label treatment and investigational agents not approved by the FDA for use in the US, and data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal.

Current BTK Inhibitors FDA Indications *Used off-label in CLL (NCCN-recommended).[c]a. Imbruvica® PI 2018. b. Calquence® PI 2017. c. NCCN guidelines: chronic lymphocytic leukemia/small lymphocytic lymphoma. V1.2019. Ibrutinib[a]CLL/SLL MCL WM MZL cGVHD [a] Acalabrutinib [b]* MCL [b]

Current BTK InhibitorsDosing Ibrutinib [a] Acalabrutinib[b]Dosing MCL and MZL: 560 mg once daily CLL/SLL, WM, and cGVHD: 420 mg once daily MCL: 100 mg every 12 hoursDose forms and strengths Capsules: 70 mg, 140 mg Tablets: 140 mg, 280 mg, 420 mg, 560 mgCapsules: 100 mg a. Imbruvica® PI 2018. b. Calquence® PI 2017.

Current BTK InhibitorsPK/PD Ibrutinib [a] Acalabrutinib[b]Occupancy > 90% up to 24 h after doses of ≥ 2.5 mg/kg/d ≥ 95% over 12 h AUC Mean steady-state AUC: MCL at 560 mg: 865 ng*h/mLMZL at 560 mg: 978 ng*h/mL CLL/SLL at 420 mg: 708 ng*h/mL Daily AUC 1111 ng*h/mL Distribution~ 10,000 L~ 34 L Metabolism Hepatic via CYP3A (major) and CYP2D6 (minor) to active metabolite PCI-45227 Hepatic, primarily via CYP3A enzymes; active metabolite ACP-5862 (mean exposure 2- to 3-fold higher than acalabrutinib, but BTK inhibition ~ 50% less potent than that of acalabrutinib)Excretion Feces: 80% (1% unchanged)Urine: < 10% as metaboliteFeces: 84% (< 1% unchanged)Urine: 12% (< 1% unchanged)t1/24 to 6 hParent: 0.9 h (range, 0.6-2.8 h); ACP-5862 (active metabolite): 6.9 h a. Imbruvica® PI 2018. b. Calquence® PI 2017.

*Kinases that contain a cysteine residue aligning with Cys-481 in Btk.Honigberg LA, et al. Proc Natl Acad Sci U S A. 2010;107:13075-13080. Ibrutinib Has Many Off-Target Effects KinaseIC50, nMBTK0.5BLK*0.5BMX* 0.8 CSK 2.3 FGR 2.3 BRK 3.3 HCK3.7 EGFR* 5.6 YES6.5ErbB2*9.4ITK* 10.7 JAK3* 16.1FRK29.2LCK33.2RET36.5FLT373TEC*78 Off-target effects may lead to toxicities

Barf T, et al. J Pharmacol Exp Ther . 2017;363:240-252. Acalabrutinib Is More Selective for BTKAcalabrutinib has less off-target kinase inhibition compared with ibrutinib in vitroThis may lead to fewer off-target effects but no head-to-head studies have been completedA phase 3 trial (ELEVATE CLL R/R) is comparing ibrutinib vs acalabrutinib in previously treated high-risk CLL Kinase Inhibition Average IC50 (nM)KinaseAcalabrutinibIbrutinib BTK 5.1 1.5 TEC 126.0 10 ITK > 1000 4.9 BMX 460.8 TXK 368 2.0EGFR> 10005.3ERBB2~ 10006.4ERBB4163.4BLK> 10000.1 JAK3 > 1000 32

Clinical Trial Data

a. Byrd JC, et al. N Engl J Med . 2014;371:213-223; b. Byrd JC, et al. J Clin Oncol. 2017;35(suppl: abstr 7510). RESONATE:Ibrutinib in Previously Treated CLLIbrutinib vs ofatumumab[a,b]ORR  42.6% vs 4.1% (P < .001) Median PFS  NR vs 8.1 mo (HR 0.133; P < .0001)12-mo OS  90% vs 81% (HR 0.43; 95% CI: 0.24, 0.79; P = .005)Active in del(17p) Key AEs: diarrhea (48%), fatigue (28%), nausea (26%), pyrexia (24%), anemia (23%)Key grade ≥ 3 AEs: neutropenia (16%), pneumonia (7%); 10 pts developed AF3-year follow-up data at ASCO® 2017  continued benefit[b] 133 patients in ofatumumab arm crossed over and received ibrutinib Phase III open-label RCT patients (N = 391) CLL/SLL with ≥ 1 prior therapy ECOG PS 0-1 R 1:1 Ibrutinib 420 mg once daily PO until progression or unacceptable toxicity Ofatumumab initial dose 300 mg followed by 2000 mg x 11 doses over 24 weeks

a. Burger JA, et al. N Engl J Med . 2015;373:2425-2437; b. Barr P, et al. Blood. 2016;128:234. RESONATE-2Ibrutinib in Previously Untreated CLLIbrutinib vs chlorambucilORR  86% vs 35% ( P < .001)Median PFS  NR vs 18.9 mo (HR 0.16; P < .001)[a]24-mo OS  95% vs 84% (HR 0.16; P = .001)[b]Sustained benefit with ibrutinib at 3 years[c] Extension Study Phase III open-label RCT patients (N = 269) treatment-naive CLL/SLL with active disease aged ≥ 65 years for patients aged 65 to 69 years, comorbidity that may preclude FCR del17p excluded R 1:1 Ibrutinib 420 mg once daily PO until progression or unacceptable toxicity Chlorambucil 0.5 mg/kg (up to 0.8 mg/kg) days 1, 15 of 28-day cycle up to 12 cycles

Barr PM, et al. Haematologica. 2018;103:1502-1510.QoL Improvements With Ibrutinib vs Chlorambucil in RESONATE-2 Greater QoL improvements with ibrutinib vs chlormabucil in FACIT-Fatigue (P = .0013)Patients in ibrutinib arm had greater improvements in disease burdenMore improvements in weight loss, fatigue, night sweats with ibrutinib ParameterIbrutinibChlorambucilLymphadenopathy ≥ 50% reduction, % 95 40 Complete resolution 42 7 Splenomegaly ≥ 50% reduction, % 95 52 Complete resolution 56 22

Safety and Extended Outcomes With Ibrutinib in RESONATE-2 Selected AE Primary Analysis [a]Follow-Up[b]Diarrhea4245 HTN 4 20 Arthralgia 16 20 AF 6 10 Major hemorrhage47a. Burger JA, et al. N Engl J Med. 2015;373:2425-2437; b. Barr PM, et al. Haematologica. 2018;103:1502-1510; c. Tedeschi A, et al. [ASH abstract 1746]. Blood. 2017;130(suppl 1). Common grade ≥ 3 AEs: neutropenia, infection [a] 3-year follow-up data at ASH 2017 reported sustained improvements with ibrutinib[c]

Ibrutinib in R/R MCL a. Wang ML, et al. N Engl J Med. 2013;369:507-516. b. Rule S, et al. Blood. 2017;130:151.Wang ML, et al[a]ORR 68% (21% CR)Median DOR 17.5 mo (95% CI: 15.8, NR) Median PFS 13.9 mo (95% CI: 7.0, NR)Nonhematologic AEs: diarrhea (50%), fatigue (41%), nausea (31%)Part of pooled analysis at ASH 2017[b]3-yr PFS 26%, 3-yr OS 45%, CR 26.5%, mOS 26.7 moPhase II open-labelpatients (N = 111)R/R MCL ECOG ≤ 2 I brutinib 560 mg once daily PO until progression or unacceptable AEs

ACE-CL-001Acalabrutinib in R/R CLL a. Byrd JC, et al. N Engl J Med. 2016;374:323-332; b. Byrd JC, et al. Blood. 2017;130:498.Updated analysis at ASH 2017[b]:ORR 85% (93% including PRL); CR 2% Median DOR NR; 18-mo DOR 85% (95% CI: 72%, 92%)Median PFS NR; 18-mo PFS 88% (95% CI: 81%, 93%)Key AEs: headache (46%), diarrhea (43%), URTI (28%), fatigue (27%), nausea (27%)Key grade ≥ 3 AEs: neutropenia (11%), pneumonia (10%); HTN (3%), AF (2%)Phase I-II uncontrolled R/R CLL patients with ≥ 1 prior treatment (N = 134) [a] Expansion phase Acalabrutinib 200 mg once dailyor100 mg twice dailyDose-escalation phase Acalabrutinib (PO, 28-day cycles) 100 mg to 400 mg once dailyor100 mg to 200 mg twice daily

ACE-LY-004Acalabrutinib in R/R MCL Wang M, et al. Lancet. 2018;391:659-667.ORR 81% (40% CR)Median DOR NR; 12-mo DOR 72% (95% CI: 62, 80%)Median PFS NR; 12-mo PFS 67% (95% CI: 58, 75%) Median OS NR; 12-mo OS 87% (95% CI: 79, 92%)Most common AEs:Any grade: headache (38%), diarrhea (31%), fatigue (27%), myalgia (21%)Grade ≥ 3: neutropenia (10%), anemia (9%), pneumonia (5%)Discontinued due to AEs in 6%Grade ≥ 3 hemorrhage: 1 case (GI hemorrhage in a patient with prior history of GI ulcers)Phase II, single-arm, open-labelpatients (N = 124)R/R MCL Acalabrutinib 100 mg twice daily until progression or unacceptable AEs

Mato AR, et al. Blood. 2016;128:3222. Ibrutinib Discontinuations in a Real-World SettingMato AR, et alRetrospective analysis of CLL patients treated with ibrutinib (N = 621)Toxicity was the most common reason for discontinuation in all settingsStarting dose (420 mg daily vs < 420 mg daily) did not impact proportion who discontinued ibrutinib due to toxicity (51% vs 50%) Previously Untreated CLL (N = 80) Drug held (30%) Dose adjusted (15%) Discontinued due to Toxicity (63%) Progression (16%) Reasons: Arthralgia (42%), AF (25%), Rash (17%) R/R CLL (N = 536) Drug held (37%) Dose adjusted (20%) Discontinued due to Toxicity (51%) Progression (21%) Reasons: AF (12%), Infection (11%), Pneumonitis (10%), Bleeding (9%), Diarrhea (7%)

Byrd JC, et al. Blood. 2017;130:4326. Acalabrutinib Pooled Safety Analysis in CLL, MCL (N = 610) TRAE Any Grade, %Grade ≥ 3, %Headache 29.2 1.3 Diarrhea 16.6 2.1 Fatigue 7.4 1.5 Nausea 9.3 1.5 Contusion 13.4 0 AF reported in 2.3% (12 of 14 patients had risk factors) Grade ≥ 3 infections: 16%

Using BTK Inhibitors in the Clinical Setting

Drug-Drug Interactions and Expert Guidance a. Imbruvica® PI 2018. b. Calquence® PI 2017. Interacting agent Suggestion CYP3A4 inhibitors and inducers [ a,b ] Diltiazem, azole antifungals, anticoagulant/ antiplatelet agents Dose-adjust according to label May be able to reduce ibrutinib to 140 mg and monitor vigilantly For acalabrutinib, only option is to reduce to 100 mg (off-label) or d/c P-gp substrates[a]Digoxin, dabigatranBe careful as ibrutinib can increase levels PPIs, H2RAs, antacids [b]Avoid PPIs with acalabrutinib (can reduce solubility/absorption)Give acalabrutinib 2 h prior to H2RAs; separate ≥ 2 h from antacidsHerbal supplements/OTC products/foods[a]Counsel patients to discuss with team; avoid strong CYP3A4 inhibitors/inducersCounsel patients to avoid grapefruit juice, Seville oranges, avoid vitamin E, green tea

Adverse Effects Ibrutinib [a] RashDiarrhea HTNArthralgias/myalgias Opportunistic InfectionsBleedingAF Acalabrutinib [b] Rash Diarrhea HTN Headache Edema/weight gain Infections a. Imbruvica® PI 2018. b. Calquence® PI 2017. Educate patients early about what to expect and how to manage AEs

a. Jones JA, et al. Br J Haematol. 2017;178:286-291; b. Caron F, et al. Blood Adv. 2017;1:772-778. Ibrutinib-Related BleedingRetrospective analysis of 327 ibrutinib-treated pts[a]:Grade 3 bleeding rate 2%Major bleeding rate 3% among patients receiving concomitant AC (11%) or AP (34%) therapyMeta-analysis: ibrutinib associated with increased risk of overall bleeding (RR, 2.72; 95% CI: 1.62, 6.58) but not major bleeding (RR 1.66; 95% CI: 0.96, 2.85)[b] Expert guidance: DOACs or LMWH are preferred if AC is neededHold ibrutinib 3 to 7 days before/after invasive procedure Avoid use of dual AC and AP therapy

Brown JR, et al. Haematologica. 2017;102:1796-1805. Risk Factors for AF in Ibrutinib RCTs Risk FactorsUnivariate HR (95% CI)Multivariate HR (95% CI)History of AF 4.868 (2.533, 9.358) 3.595 (1.703, 7.588) Ibrutinib treatment 3.489 (1.850, 6.578) 3.906 (1.889, 8.076) Age 65 to 74 3.023 (1.493, 6.119) 2.958 (1.266, 6.913) ≥ 75 3.163 (1.448, 6.909)3.538 (1.416, 8.844)HTN2.705 (1.585, 4.618)1.669 (0.893, 3.118)Hyperlipidemia2.649 (1.305, 5.377)1.942 (0.882, 4.277)

a. de Weerdt I, et al. Haematologica. 2017;102:1629-1639. IbrutinibManagement of AF CHA2DS2VASc ≤ HAS-BLED ScoreCHA2DS2VASc > HAS-BLED ScoreContinue ibrutinib at current doseRate/rhythm control Need to anticoagulate DOAC preferred [a] Avoid use of vitamin K antagonist Consider alternative therapy Minimize other medications associated with increase bleeding risk Avoid P-gp substrates (digoxin) Avoid CYP3A4 inhibitors (verapamil, diltiazem)

Practical Issues Toxicity management Asymptomatic lymphocytosisResistance to ibrutinib and acalabrutinibAdherence Missed dosesPatient counselingAccess to therapyManufacturer support programs

Please click Next below to see how your knowledge improved. The CME/CE posttest will follow. Please also take a moment to complete the program evaluation. Thank you for participating in this activity.