Dose reduction. What do we know and how we do it in clinical practice. Andreas Hochhaus

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1 Dose reduction. What do we know and how we do it in clinical practice. Andreas Hochhaus Hadera I Oct 2018

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3 Front-line Randomized Trials in CML-CP Trial Drugs References IRIS IM 400 vs IFN/AraC TOPS IM 400 vs IM 800 Cortes JCO 2010 O Brien NEJM 2003; Druker NEJM 2006; Hochhaus NEJM 2017 GIMEMA IM 400 vs IM 800 Baccarani Blood 2009 SWOG IM 400 vs IM 800 Deininger Br J Haem 2014 DASISION IM 400 vs DAS 100 Kantarjian NEJM 2010; Cortes JCO 2016 SWOG 0325 IM 400 vs DAS 100 Radich Blood 2012 SPIRIT IM 400+/-AraC or +/- PegIFN vs IM 600 Preudhomme NEJM 2010 CML IV IM 400+/-IFN vs IFN vs IM 800 ENESTnd IM 400 vs NIL 600 vs NIL 800 BELA BFORE IM 400 vs BOS 500 IM 400 vs BOS 400 Hehlmann JCO 2014; Kalmanti Leukemia 2015 Saglio NEJM 2010; Hughes Blood 2014; Hochhaus Leukemia 2016 Brümmendorf Br J Haem 2015 Cortes ASCO 2017 SPIRIT 2 IM 400 vs DAS 100 O Brien ASH 2014, EHA 2015 EPIC Radotinib IM 400 vs Ponatinib 45 IM 400 vs. Radotinib 600 vs. Radotinib 800 Lipton Lancet Oncol 2016 Kwak ASH 2015

4 Target profile of 1 st and 2 nd generation TKIs Imatinib PDGFR > Kit > Bcr-Abl > Src (Phos. IC 50 ) 72 nm 99 nm 192 nm >1000 nm Nilotinib Bcr-Abl > PDGFR > Kit > Src (Phos. IC 50 ) 19 nm 75 nm 209 nm >1000 nm Dasatinib Src > Bcr-Abl > PDGFR > Kit (Phos. IC 50 ) 0.1 nm 1.8 nm 2.9 nm 18 nm Bosutinib Bcr-Abl > Src > Kit > PDGFRa (Phos. IC 50 ) 0.5 nm 1.0 nm 6300 nm >10 µm

5 TKI off-target effects?

6 Apperley, Lancet 2007

7 Sensitivity Drug dosage / concentration Leukemia cells

8 Sensitivity Drug dosage / concentration Most resistant cells will be selected and create relapse Leukemia cells

9 TKI drug interactions Drugs inhibiting CYP3A4 may increase TKI exposure ketoconazole, itraconazole, voriconazole erythromycin, clarithromycin, telithromycin ritonavir, atazanavir, indinavir, nelfinavir, saquinavir, nefazodon, CYP3A4 inducers may decrease TKI exposure dexamethasone, rifampicin, rifabutin, phenytoin, carbamazepin, phenobarbital Concomitant use of TKI and CYP3A4 substrate may increase substrate exposure (narrow therapeutic index!) fentanyl, alfentanil astemizole, terfenadine cyclosporine, sirolimus, tacrolimus quinidin, ergot alkaloids, pimozide, cisapride simvastatin Grapefruit juice may increase TKI plasma concentration

10 Adherance measure by MEMS (microelectronic monitoring system) Adherence Young age Dose increase Adverse effects Marin et al., J Clin Oncol 2010

11 Relative toxicities of TKIs in independent second-line trials after imatinib failure % Severe toxicity Imatinib* (Druker et al. 2006) Nilotinib (Nicolini et al. 2009; Dasatinib (Shah et al., 2008) Bosutinib (Cortes et al., 2010) Myelosuppression Fluid retention Diarrhea Glucose / Lipase Druker et al. N Engl J Med. 2006; 355: Nicolini et al. Haematologica (EHA Meeting Abstracts) 2009; 94(s2): Abstract 0630 Shah et al. Blood (ASH Annual Meeting Abstracts), Nov 2008; 112: Cortes et al. JCO. 2010; ASCO Ann. Meeting Proc. 28, 15S: 6502 * first line

12 Nilotinib in Newly Diagnosed CML-CP (ENESTnd) Study Design N = centers 35 countries R A N D O M I Z E D * Nilotinib 300 mg BID (n = 282) Nilotinib 400 mg BID (n = 281) Imatinib 400 mg QD (n = 283) *Stratification by Sokal risk score Follow-up 5 years Primary endpoint: Key secondary endpoint: Other endpoints: MMR at 12 months Durable MMR at 24 months CCyR, time to MMR and CCyR, EFS, PFS, time to AP/BC, OS Saglio G, et al. N Engl J Med. 2010;362(24): Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207].

13 % With MMR Nilotinib in Newly Diagnosed CML-CP (ENESTnd): 24 Month Data Cumulative Incidence of MMR* Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD n By 12 months 55%, P <.0001 By 24 months 71%, P < %, P < %, P <.0001 Δ 24%-28% Δ 23%-27% 44% % 10 0 *ITT population. Data cut-off: 20 Aug BID, twice daily; QD, once daily Time Since Randomization (Months) Hughes TP, et al. Blood. 2010;116(21):94-95 [abstract 207].

14 Cardiovascular events on nilotinib vs. imatinib Hochhaus et al. ENESTnd, Leukemia 2016

15 DASISION: Cumulative incidence of BCR-ABL IS % (MR 4.5 ) 100 Dasatinib 100 mg QD Imatinib 400 mg QD % 20 By 24 months 17% 10 P= % Months Kantarjian et al., ASCO 2011

16 Adverse events Dasatinib vs. Imatinib Cortes et al. J Clin Oncol 2016

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18 Half live of various TKIs van Erp et al., Cancer Treatment Reviews 2009; 35:

19 Dasatinib: Transient inhibition of BCR-ABL Shah et al., Cancer Cell 2008

20 CML Tx naive Dasatinib Holiday for Improved Tolerability (DasaHIT) 4 weeks HU, Imatinib or Dasatinib CML TKI resistant CML TKI intolerant R 5 *100mg + 2 * 0mg (5+2) 7 *100mg Non-Inferiority N = trial centers 5 Jahre TS = n * G (CTCAE v.4.03) Screening monthly molecular monitoring BCR-ABL IS 24 months cum. MR 24 ms SA-1 SA-2 SA: Safety analysis (DMC) TS: Toxicity Score cum. MR 24 ms: cumulative molecular response by 24 ms.

21 PACE: Response to ponatinib in patients with CP-CML after failure to previous TKIs 100 Resistant/intolerant (n=203) T315I (n=64) All CP-CML (n=267) MCyR CCyR MMR MR 4 MR 4.5 Cortes, et al. Blood. 2018;132:

22 Ponatinib:Estimated duration of MMR (response at any time) for CP-CML patients Cortes, et al. Blood. 2018;132:

23 Ponatinib: arterial occlusive events and venous thromboembolism Venous: (5%)* Arterial: (29%)* VTE (AE 5%/SAE 4%) CARDIAC (AE CARDIAC 14%/SAE 11%) CEREBRAL (AE 12%/SAE 10%) PERIPHERAL (AE 11%/SAE 9%) Examples of AE terms included in category Examples of AE terms included in category Examples of AE terms included in category Examples of AE terms included in category -Deep vein thrombosis -Pulmonary embolism -Retinal vein occlusion -Angina pectoris -Myocardial infarction -Coronary artery disease -Cerebrovascular accident -Cerebral infarction -Carotid artery stenosis -Peripheral arterial occlusive disease -Peripheral artery stenosis -Peripheral ischemia No. of events (%) Median time to onset, days (range) Median AE duration, days Discontinuation due to AE, n (%) Dose modification, n (%) *Events occurring in patients with CP-CML; 4-year follow-up. Dose reduction and/or interruption. 39 (14) 33 (12) 31 (11) 394 ( ) 681 ( ) 505 (8 1300) (10) 6 (18) 2 (6) 21 (53) 9 (27) 8 (26) SOURCE: Cortes, et al. Am Soc Clin Oncol 2016:Abstr ARIAD Pharmaceuticals, Inc. Data on file as of Aug 2015.

24 No. of patients with events per 100 patient-years PACE: exposure-adjusted incidence of new AOEs over time Summary of Exposure-Adjusted Incidence Rates for Newly Occurring AOEs * in All Patients mg/d mg/d mg/d mg/d Dose intensity (mg/d) to <1 year 1 to <2 years 2 to <3 years 3 to <4 years **In the safety population Later intervals exclude patients with prior events; ongoing patients may have a different risk than those at study start SOURCE: Cortes, et al. Am Soc Clin Oncol 2016:Abstr Interval

25 PACE: Relative Risk of Serious AOEs by Risk Category PACE safety population RR (95% CI) Risk factor Hypertension * (n=240) 2.6 ( ) Ischemic cardiac disease (n=101) 2.4 ( ) Diabetes (n=72) 2.1 ( ) Hypercholesterolemia (n=229) 2.0 ( ) Age 65 years (n=155) 1.8 ( ) Male (n=238) 1.6 ( ) Non-ischemic cardiac disease (n=193) 1.4 ( ) Obesity (n=109) 1.2 ( ) NOTE: Node size in graph represents patient numbers; line signifies derived 95% CI. RR (95% CI) This univariate analysis of the PACE population shows that the relative risk for serious AOEs differs by risk category; some conditions are associated with higher risk Before starting treatment with ponatinib, a patient s CV status should be assessed, including history and physical examination, and CV risk factors should be actively managed * Includes medical history, prior concomitant medication, and/or baseline blood pressure gr 2. Includes medical history and/or prior concomitant medication. Includes medical history, prior concomitant medication, and/or baseline glucose gr 2. Includes medical history, prior concomitant medication, and/or baseline triglycerides gr 1. Includes medical history and/or baseline BMI 30 kg/m 2. SOURCE: ARIAD Pharmaceuticals, Inc. Data on file as of Aug Previously presented by Cortes, et al. Eur Hematology Assoc Ann Mtg 2015:Abstr P234

26 Estimated probability Multivariate analysis of arterial occlusive events by dose intensity Probability of arterial occlusive events vs dose intensity in subset of PACE* patients (n=446) Fit 95% CI Dose intensity mg/day 30 mg/day 45 mg/day Each 15 mg/day reduction in average daily dose intensity is predicted to lead to approximately a 33% reduction in the risk of arterial occlusive events Multivariate analyses suggested that dose reduction/interruption may be a strategy for reducing risk 0.0 *Post hoc retrospective analysis; estimation by reduced multivariate model. The optimal dose has not yet been identified. SOURCE: Hochhaus, et al. J Clin Oncol 2014;32(5s):abstr 7084.

27 Company-sponsored trial: OPTIC (a dose-ranging study) An international randomized phase 2 trial to characterize the efficacy and safety of three starting doses of ponatinib Adult patients with CP-CML resistant to 2 TKIs and without significant CV history Primary endpoint: MCyR by 12 months; N=450 1:1:1 randomization Ponatinib 45 mg once daily * Ponatinib 30 mg once daily * Ponatinib 15 mg once daily * Dose reduction to 15 mg once daily upon achievement of MCyR or MR2 at 3, 6, 9, or 12 months Discontinue from study if no MCyR by 12 months OR Continue treatment up to 2 years or until loss of response or intolerance All compounds are either investigational or being studied for potential new use. Efficacy and safety have not been established. This information is presented only for purposes of providing an overview of clinical trials and should not be construed as a recommendation for use. * Dose reductions due to AEs permitted.

28 Optimal TKI-Dose? Salvage therapy Frontline Drug Initial approval Current Should be Initial attempt Approved Should be Imatinib 400 mg QD 400 mg QD mg QD 400 mg QD mg QD Dasatinib 70 mg BID 100 mg QD mg QD? 100 mg QD 100 mg QD 70 mg QD? 100 mg 5x/w.? Nilotinib 400 mg BID 400 mg BID mg QD? mg BID 300 mg BID 300 mg BID Bosutinib 500 mg QD 500 mg QD 400 mg QD? 500 mg QD 400 mg QD 400 mg QD Ponatinib 45 mg QD 45 mg QD 30 mg QD? 45 mg QD -- --

29 Dose reduction Standard dose Regular initial reduction Minimum dose to avoid resistance Imatinib 400 mg/d 300 mg/d 300 mg/d Nilotinib 2x300 mg/d 450 mg/d 400 mg/d Dasatinib 100 mg/d 80 mg/d 70 mg 5*/week Bosutinib 400 mg/d 300 mg/d 300 mg/d Ponatinib 30 mg/d 15 mg/d 15 mg/d

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