1 / 36

Second and Third Generation Tyrosine Kinase Inhibitors: How do we Choose?

Second and Third Generation Tyrosine Kinase Inhibitors: How do we Choose?. Dr Jenny Byrne Nottingham. Imatinib is a wonderful drug !. 1. 0. 0. 9. 0. 8. 0. 7. 0. i. Es. t. imaa. t. e. d. o. v. e. r. a. l. l. s. u. r. ivaa. i. l. m. l. 6. 0. a. t. 8. y. e.

morriss
Download Presentation

Second and Third Generation Tyrosine Kinase Inhibitors: How do we Choose?

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

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

  2. Imatinib is a wonderful drug!

  3. 1 0 0 9 0 8 0 7 0 i Es t imaa t e d o v e r a l l s u r ivaa i l m l 6 0 a t 8 y e a r s w a s 8 5 % E (93%, considering onlyCML related deaths) 5 0 4 0 3 0 2 0 S u r v i v a l : d e a t h s a s s o c i a t e d w i t h C M L 1 0 O v e r a l l S u r v i v a l 0 0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6 1 0 8 M o n t h s S i n c e R a n d o m i z a t i o n IRIS 8-Year UpdateOverall Survival (Intent-to-Treat) –Imatinib Arm % Alive

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

  5. Outcome for Patients Discontinuing IRIS Trial Efficacy (n = 82;15%) Still receiving study imatinib (n = 332; 60%) In CCR (n = 317; 57%) No CCR (n = 15; 3%) Safety(n = 43; 8%) Alive(n = 17; 40%) Other (n = 96; 17%) Alive(n = 52; 63%) Dead(n = 30; 37%) Alive(n = 81; 84%) Dead(n = 15; 16%) Dead**(n = 26; 60%) All randomized to imatinib(n= 553; 100%) Discontinued study imatinib* (n = 221; 40%) **Including primary discontinuation reason ‘Death’ (n=13) *Patients may have continued imatinib off study.

  6. Up to 40% of patients may ‘fail’ Imatinib

  7. 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)

  8. 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 Hochhaus et al., Hematol Oncol Clin N Am 2004;18:641–56

  9. T315I/A/D F311L/I/V F317L C305S G321E F382L V299L L324Q G383D L298V M343T K357R L384M P296H A344V L387F/M E292V S348L M388L A350V M351T/L V379I V289A/I E355G/D L3641 F359V/C/D/I K285N Adapted from Melo et al (2006) E281A E279K T277A E276G E275K L248V G250E/A/F Q252H/R P B C A Y253H/F E255K/V A397P M244V H396R/P D241G M237I E453G/K/A/V F486S E450G/Q/K Q447R E459K/Q S438C BCR/ABL mutations are the most frequently reported mechanism of acquired resistance 5417Y • 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., Blood2003;102:276–83; Shah et al., Hematol2005;183–7; Melo et al., Cancer Lett 2006 (in press)

  10. There is a Clear Need to Monitor Response to Therapy Carefully: ELN Guidelines 2013 Baccarani M, et al. Blood 2013: 122: 872–884

  11. 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

  12. Important to ‘Get the Drugs in’ to Achieve Optimal responses: Missed Doses Do Matter! Chance of achievement of RQ-PCR <0.1% at 12 months decreases with decreased average dosing

  13. 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

  14. TKIs in CML Off patent 2016 Imatinib Development NICE approved License 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 CDF 2000 2005 2010 2015

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

  16. 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

  17. 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

  18. 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.

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

  20. 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!

  21. Efficacy against Different Mutations

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

  23. 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 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

  24. Choice of Drug: Relative Toxicities

  25. Need to balance risk benefit

  26. Choice of Drug - Comorbidities

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

  28. 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 orwho 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 *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.

  29. 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!

  30. Available TKIs: NICE and National CDF

  31. 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) Not all patients will respond to 2nd line drugs Nilotinib 2nd Line Responses CCyR CHR MCyR

  32. Bosutinib 3rd Line Results Khoury et al. Oral presentation 892, ASH 2010.

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

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

  35. 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

  36. 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

More Related