Dr Jenny Byrne Nottingham Second and Third Generation Tyrosine Kinase Inhibitors: How do we Choose? Dr Jenny Byrne Nottingham

Imatinib is a wonderful drug!

IRIS 8-Year Update Overall Survival (Intent-to-Treat) – Imatinib Arm Es t i m imaa e d o v r a l s u ivaa 8 y w 5 % (93%, considering only CML related deaths) 1 2 3 4 6 7 9 M n h S c R z : C L O % Alive 3

IRIS 8 year Results BUT Imatinib is a great drug …… Not all patients respond well to Imatinib IRIS data excludes patients who discontinued ‘study’ Imatinib

Outcome for Patients Discontinuing IRIS Trial All randomized to imatinib (n= 553; 100%) Still receiving study imatinib (n = 332; 60%) Discontinued study imatinib* (n = 221; 40%) In CCR (n = 317; 57%) No CCR (n = 15; 3%) Safety (n = 43; 8%) Efficacy (n = 82; 15%) Other (n = 96; 17%) Still on drug 317 in CCyR (298 never lost CCyR, 19 had re-gained after initial loss CCyR) 15 not in CCyR (6 had lost CCyR but are still in MCyR, 9 never achieved CCyR, mostly not documented BMA) Discontinuations Safety = 26 discontinuations + 4 cross-over for intolerance + 13 deaths (all CML unrelated on study treatment, except the 1 case in CMR with UNK reason suspected to be CML) Efficacy = 72 discontinuatios + 10 cross-over (including progressions to AP/BC, loss of responses but also Unsatisfactory Therapeutic Effect, e.g. Lack of response) Other = 16 BMT + 80 Other (incl. Withdrew consent, Lost to follow-up, PV etc) Alive (n = 17; 40%) Dead** (n = 26; 60%) Alive (n = 52; 63%) Dead (n = 30; 37%) Alive (n = 81; 84%) Dead (n = 15; 16%) **Including primary discontinuation reason ‘Death’ (n=13) *Patients may have continued imatinib off study. 5

Up to 40% of patients may ‘fail’ Imatinib

Imatinib Resistance and Intolerance Some patients do not do well on imatinib... Imatinib resistance may be defined as: Lack/loss of satisfactory response during imatinib therapy or progression from chronic to accelerated phase or from chronic or accelerated to blast phase Imatinib intolerance may be defined as: Side effects requiring either a dose reduction of imatinib to ≤400 mg/day or discontinuation of imatinib due to drug-related toxicity (Poor adherence / missed doses may also be an issue)

Primary resistance Acquired resistance Resistance has been defined as primary or acquired (also known as secondary) Failure to achieve a response Loss of a confirmed response Primary haematological resistance failure to achieve a CHR In chronic phase failure to return to CP In advanced disease Primary cytogenetic resistance failure to achieve a CCyR or MCyR Haematological resistance confirmed loss of a CHR Cytogenetic resistance confirmed loss of a MCyR or CCyR Molecular resistance increase in BCR-ABL transcripts of more than 1 log Often assoc with emergence of a bcr-abl mutation Resistance can be defined as decreased effectiveness of a drug in treating a disease.1 Imatinib resistance can be categorized as primary or secondary. Primary resistance is also known as intrinsic resistance, and secondary resistance is also known as acquired resistance. Molecular resistance can also be indicated as a trend (at least three points). Primary resistance is defined as failure to achieve and/or sustain a significant haematological response (i.e complete haematological response [CHR]) or cytogenetic response (i.e. complete cytogenetic response [CHR]) Secondary resistance is defined as the progressive reappearance of the leukaemic clone after an intial response to the drug. This includes: Haematological resistance (loss of normalisation of peripheral blood counts and spleen size) Cytogenetic resistance (loss of a major cytogenitc response [MCR]) Molecular resistance (loss of a complete or major molecular response [MMR]). Baccarani and the Leukaemia Net recent guidance would class all of these patients as Imatinib failures (see next slide). 1. Melo JV, Chuah C. Cancer Lett 2006 (in press). Hochhaus et al., Hematol Oncol Clin N Am 2004;18:641–56

BCR/ABL mutations are the most frequently reported mechanism of acquired resistance F486S P B C A Q252H/R E255K/V Y253H/F G250E/A/F L248V D241G M237I M244V E279K E281A T277A E276G K285N E275K E355G/D F359V/C/D/I V379I L3641 M351T/L F382L G383D L384M L387F/M M388L H396R/P A397P E453G/K/A/V E450G/Q/K Q447R S438C E459K/Q A350V T315I/A/D A344V M343T F317L S348L L324Q G321E F311L/I/V C305S V299L E292V L298V V289A/I P296H Adapted from Melo et al (2006) K357R 5417Y Acquired point mutations in the ABL kinase domain are the most frequently reported mechanism for acquired resistance.1 These mutations shift the loop into the ‘active’ or ‘open’ conformation of the BCR-ABL protein, as well as interrupt critical contact points necessary for imatinib to bind. Imatinib binds to BCR-ABL in the ‘inactive’ or ‘closed’ conformation of the kinase only. Mutations are grouped into four main sites/types: -Imatinib binding site (B) -P-loop (P; ATP binding site) -A-loop (A; activation loop) -Catalytic site (C) 1. Deininger M, Buchdunger E, Druker BJ. Blood. 2005;105:2640–53. Kinase domain mutations occur in 50-90% of cases of acquired resistance Resistance manifests itself through different mechanisms causing Changes to the stability of the Bcr-Abl conformation Reduction in binding efficiency of imatinib Branford et al., Blood 2003;102:276–83; Shah et al., Hematol 2005;183–7; Melo et al., Cancer Lett 2006 (in press)

There is a Clear Need to Monitor Response to Therapy Carefully: ELN Guidelines 2013 Time Optimal Response Warning Failure Baseline n/a High risk or CCA/Ph+, major route 3 months BCR-ABL1 ≤ 10% and/or Ph+ ≤ 35% BCR-ABL1 >10% and/or Ph+ 36-95% No CHR and/or Ph+ >95% 6 months BCR-ABL1 <1% and/or Ph+ 0 (CCyR) BCR-ABL1 1-10% and/or Ph+ 1-35% and/or Ph+ >35% 12 months BCR-ABL1 ≤ 0.1% (MMR) BCR-ABL1 >0.1-1% BCR-ABL1 >1% and/or Ph+ >0 Anytime Stable or improving MMR ACA/Ph- (-7 or 7q-) Loss of CHR, loss of CCyR, confirmed loss of MMR, mutations, ACA in Ph+ cells Baccarani M, et al. Blood 2013: 122: 872–884

Importance of achieving optimal response of ≤ 10% BCR-ABLIS at 3 months Early response is predictive of survival Significant difference in 8-year overall survival (OS) rates in a real-world s P < 0.001 Achieving ≤ 10% BCR-ABL at 3 months correlates with significantly higher rates of improved PFS and OS1 7 Marin et al. 2012

Achievement of MMR at 12 months (ITT) Important to ‘Get the Drugs in’ to Achieve Optimal responses: Missed Doses Do Matter! Imatinib Dasatinib Dosing in 1st 12 months Achievement of MMR at 12 months (ITT) 100% 125/227 (55.1%) 129/187 (69.0%) 95-99.9% 14/27 (51.9%) 20/29 (69.0%) 80-95% 3/10 (30.0%) 17/37 (45.9%) <80% 6/18 (33.3%) 13/29 (44.8%) Chance of achievement of RQ-PCR <0.1% at 12 months decreases with decreased average dosing

Which 2nd line drug should we choose for our patients? Up to 40% of patients may ‘fail’ 1st line Imatinib Up to 20% may ‘fail’ Nilotinib / dasatinib 1st line

TKIs in CML Imatinib CDF Dasatinib Nilotinib Bosutinib Ponatinib 2000 Off patent 2016 Imatinib Development License NICE approved CDF Dasatinib -1st and 2nd line Nilotinib - 1st and 2nd line Bosutinib - 2nd/3rd line if other TKIs not appropriate Ponatinib - T315I or if no other TKI indicated 2000 2005 2010 2015

Licensed Drugs in CML Dasatinib More potent 100 mg once daily - 400 mg twice a day Bosutinib - 500 mg once a day Ponatinib Most potent 30 mg once daily

Treating CML is Not Easy! PATIENT FACTORS Patients are not all the same! Different ages, comorbidities, sensitivity to side effects Compliance DISEASE FACTORS CML is not a homogeneous disease! Different biological properties affecting sensitivity to different drugs Different mutations DRUG FACTORS The different drugs are not all equal! Different toxicities Varying efficacy against different mutations

Aim is to match the correct patient with the correct drug for their CML! Not that easy as in the UK we are not able to access all the drugs freely

What do the Guidelines Say? ELN Guidelines 2013 – 2nd Line Treatment A change of therapy is mandatory for resistance or toxicity If there is intolerance, any other available TKI can be used, including imatinib second-line after a second-generation TKI first-line. For resistance, the logic sequence is: [1] from imatinib to any other available and approved TKI (dasatinib, nilotinib, bosutinib, ponatinib), [2] from nilotinib to other TKIs (dasatinib, bosutinib, ponatinib), and [3] from dasatinib to other TKIs (nilotinib, bosutinib, ponatinib). Regrettably, there are no studies comparing different TKIs in second-line. Therefore, the choice of the second-line TKI is guided by some patient characteristics, mainly age and comorbidities, by the type of side effects with the first TKI, and by the presence of BCR-ABL1 kinase mutations, and also by drug availability and cost, and by doctor experience.

No Clear Winner with Respect to Efficacy No trials have directly compared the drugs

Factors that need to be borne in mind when choosing 2nd line treatments Any known mutations Known toxicities of the drugs Patient related comorbidities What drugs are funded by the NHS!

Efficacy against Different Mutations

Efficacy against Double Mutations Even more difficult when there are 2 mutations

Side Effects due to the TKIs are caused by their ‘Off-Target’ Effects Most of the drugs have unwanted effects on other cellular proteins leading to their side effects Imatinib (Phos. IC50) PDGFR 72 nM > Kit 99 nM BcrAbl 221 nM Src >1000 nM Nilotinib 20 nM 75 nM 209 nM Dasatinib 0.1 nM 1.8 nM 2.9 nM 18 nM Bosutinib 3 nM 85 nM >3000 >10000 nM 1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48:772. 2. Weisberg E, et al. Cancer Cell 2005;7:1129. 3. Remsing Rix LL, et al. Leukemia 2009;23:477. 4. O’Hare T. et al (2009) Cancer Cell. 16: 401-412

Choice of Drug: Relative Toxicities Imatinib Nilotinib Dasatinib Bosutinib Oedema ++ + - Diarrhoea +++(transient) Rash Headache Glucose Lipase QT prolongation Hepatotoxicity Haem toxicity Pleural effusions ++ (20%) + (3%) Pulm hypertension + (0.5%) ?+ PAOD and IHD + (6%)

Need to balance risk benefit

Choice of Drug - Comorbidities Try to Avoid in Nilotinib Worsens blood glucose levels Cardiovascular risk factors Diabetics Patients with history of cardiovascular problems eg angina, stroke Dasatinib Pleural effusions Pulmonary hypertension Chronic lung diseases

NICE & the CDF Difficult times… We may not be able to use the drugs we want to due to funding issues NICE & the CDF - Recent changes

Currently approved 2nd Line Treatments NICE SMC Second-line therapy for adults with CP/AP Ph+ CML who are resistant to treatment with standard-dose imatinib or who have imatinib intolerance2 Nilotinib* Second-line therapy for adults with CP Ph+ CML who are resistant to or intolerant of at least one prior treatment including imatinib Nilotinib5 NICE. Technology appraisal 251. Dasatinib, nilotinib and standard-dose imatinib for the first-line treatment of chronic myeloid leukaemia (part review of technology appraisal guidance 70). 2012. NICE. Technology appraisal 241: Leukaemia (chronic myeloid) – dasatinib, nilotinib, imatinib (intolerant, resistant). 2012. Scottish Medicines Consortium. Nilotinib 150 mg hard capsules (Tasigna®) no. 709/11. 2011. Scottish Medicines Consortium. Imatinib Mesylate (Glivec®) no. 01/02. 2002. Scottish Medicines Consortium. Nilotinib, 200 mg capsules (Tasigna®) no. 440/08. 2008 *If the manufacturer makes nilotinib available with the discount agreed as part of the patient access scheme Dasatinib and high dose Imatinib not approved (2012) NB: Can still get other drugs for certain patients via the Cancer Drugs Fund 1. NICE. Technology appraisal 251. 2. NICE. Technology appraisal 241. 3. SMC. No. 709/11. 4. SMC. No. 01/02. 5. SMC. No. 440/08.

Cancer Drugs Fund (CDF) New drugs have to prove their safety, quality and efficacy NICE: clinical effectiveness – how well does something work in comparison with what we already use? AND cost effectiveness – how much more life or quality of life do we get for the extra money spent? A positive NICE appraisal has to be funded by the NHS: as the budget is fixed, something else has to be axed or delayed Main issue with NICE - too slow, so in 2007 government set up CDF to improve access to cancer drugs in the UK Each drug is scored for impact on survival, quality of life, toxicity and ‘unmet need’ (is it the only systemic therapy for that disease?) 14/15 expenditure on November list £390m and £420m in 15/16 84 separate drug indications in the CDF in November 14 and as overspent the lowest scoring 45 indications assessed in this recent prioritisation process and 18 removed (including CML drugs) Due to finish April 2016 – not quite sure what next!

Available TKIs: NICE and National CDF 1st Line CP 2nd Line CP 3rd / 4th Line CP Imatinib  (NICE)  (after IFN) X Nilotinib Dasatinib x  If IM intol / ref AND NIL intol (but not refractory) Bosutinib If NIL AND DAS intol (but not refractory) Ponatinib Unless T315I

Not all patients will respond to 2nd line drugs CHR MCyR CCyR Nilotinib 2nd Line Responses 40- 50% of patients requiring a 2nd line treatment will ‘fail’ There is some evidence for 3rd line treatment using an alternative drug but funding is an issue Other option is a stem cell transplant (which is funded)

Bosutinib 3rd Line Results Response, n (%) IM + D Resistant (n = 36) Intolerant (n = 51) IM + NI (n = 27) Median follow-up (range), mo 14.8 (2.7–47.3) 28.7 (0.3–49.7) 12.2 (2.0–48.0) Hematologic response Evaluable patients 36 50 27 Complete 22 (61) 40 (80) 21 (78) Cytogenetic response 34 38 24 Major 10 (29) 14 (37) 7 (29) 3 (9) 13 (34) 4 (17) Partial 7 (21) 1 (3) 3 (13) Molecular response 25 47 16 2 (8) 17 (36) 1 (6) IM, imatinib; D, dasatinib; NI, nilotinib. aEvaluable patients had a baseline and 1 post-baseline disease assessment for the corresponding endpoint or had died or discontinued the study due to disease progression. bOf the 13 patients in this cohort excluded from the analyses, 6 had no post-baseline assessment, 5 had no baseline assessment, and 2 had no valid assessments at baseline or post-baseline. [20 metaphases] Khoury et al. Oral presentation 892, ASH 2010. 32

Ponatinib Results Licensed post 1st line if other drugs not suitable

Efficacy of 3rd Line Drugs Evidence suggests ponatinib more effective than bostunib Lipton et al (Ariad sponsored)

What do the Guidelines Say re 3rd Line? There are no evidence-based, reliable, specific recommendations for the patients who fail two or even three TKIs. These patients form a heterogeneous group Can try any of the remaining TKIs Consider SCT in eligible patients. Ponatinib is likely to be more efficient than any other TKI, but there are no comparative studies

Summary The second generation drugs are effective for many patients who are resistant to or intolerant of Imatinib Not clear which one is the best Responses may be durable Side effect profiles of the drugs differ and rarely overlap Generally safer than transplants Should be offered to patients who fail / can’t take Imatinib Choice of drug should depend on mutation analysis, side effects & patient comorbidities BUT not all drugs are funded Not a cure all! Some patients won’t respond Limited choice for 3rd line treatment in the UK Transplantation remains an alternative option