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Oncology Journal Club Addressing Imatinib-resistant CML

Oncology Journal Club Addressing Imatinib-resistant CML. Frank Giles, MD, FRCPI, FRCPath Chief, Division of Hematology and Medical Oncology Director, Institute for Drug Development Deputy Director, CTRC at University of Texas Health Science Center San Antonio, TX.

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Oncology Journal Club Addressing Imatinib-resistant CML

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  1. Oncology Journal ClubAddressing Imatinib-resistant CML Frank Giles, MD, FRCPI, FRCPath Chief, Division of Hematology and Medical Oncology Director, Institute for Drug Development Deputy Director, CTRC at University of Texas Health Science Center San Antonio, TX

  2. Historical CML Survival Curve

  3. Targets in CML Signaling Pathways VEGF PDGF Flt3 Sunitinib Surafinib PTK787 Cell membrane Dasatinib Nilotinib MK-0457 SKI606 PDK1 Dasatinib Bcr-Abl IRS MK-0457 Perifosine Triciribine PI3K Jak2 P P Hif-1a AKT TSC2 RAD001 CCI-779 AP23573 TSC1 ERK RHEB mTOR Raptor P P 4E-BP1 Translation Ribosomal proteins eIF4E S6K1 eIF4E eIF3 eIF4G PABP Cap-dependent translation Ribosome biogenesis CEP701, MLN518 PKC412

  4. Human tyrosine kinases

  5. Human Kinase Dendrogram Manning. Science; 298: 1912, 2002

  6. ASH 2007, Abstract 25 IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib Hochhaus A. et al

  7. 38 (7%) patients lost to follow-up by 5 years IRIS 6-Year Update: Overall Survival (ITT Principle) 6 year OS is 88% (95% considering only CML-related deaths) (incl. 3% after BMT, 4% non-CML related) Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007

  8. IRIS 6-Year Update: Annual Event Rates 8 7.5 7 EventLoss of CHR,Loss of MCyR, AP/BC,Death during treatment 6 4.8 5 % Annual Rates 4 AP/BC 3.3 2.8 3 1.6 2 1.5 1.5 0.9 0.8 1 0.5 0.4 0 0 1st 2nd 3rd 4th 5th 6th Year Hochhaus A. et al, Blood. 110, 11. Abstract 25. ASH 2007

  9. Incidence of CML by Age SEER 2001

  10. Patients taking recommended dose of imatinib 3500 2,921 3000 2500 2000 Patients 1500 1000 500 685 0 0–1 1–2 2–3 3–4 4–5 5–6 6–7 7–8 8–9 9–10 10–11 11–12 12–13 13+ Months Adherence to Imatinib May Decline Over Time • In this US study, persistency* was near 100% at month 4 • Persistencydeclined from 94% at month 5, to 23% at month 14 • Imatinib plasma level testing may help identify patients who become less adherent *Time on therapy without significant gaps in refills. Tsang J-P, Rudychev I, Pescatore SL. Poster presented at ASCO 2006.

  11. Genes Associated with CML Progression Radich. PNAS 103: 2794, 2006

  12. Dasatinib in Blast Phase CMLOverall Survival 1.0 0.8 0.6 0.4 0.2 0 Proportion alive 0 3 6 9 12 15 18 21 Months Martinelli. ASH 2006. Abs 745

  13. Clinical Resistance to Imatinib Mechanisms • Primary resistance • Insufficient inhibition of BCR-ABL • Low plasma levels of imatinib • Activity of drug pumps • Secondary resistance • Imatinib-resistant BCR-ABL kinase-domain mutations • Overproduction of BCR-ABL • BCR-ABL-independent mechanisms • ? Activation of other kinases • ? Other molecular events Giles. Hematol Am Soc Hematol Educ Program:2005:183-187; von Bubnoff. Leukemia. 203;17:829.

  14. IC50 < 10 nM 10-50 nM 50-250 nM 250-1000 nM Kinase Selectivity Profiles Of Nilotinib And Dasatinib Nilotinib 4 targets Imatinib 4 targets Dasatinib 15 targets After Fabian et al. Nature Biotech. 2005;23:329

  15. Dasatinib: SRC/ABL Kinase Inhibitor Shah. Science 305: 399, 2004

  16. Major cytogeneticresponse Complete hematologicresponse CHR PCyR 80 91 CCyR 5 75 59 % 52 11 13 49 40 Total Total Imatinibintolerant Imatinibresistant Dasatinib 70 mg BID in CP-CML Efficacy at 15.2 month Median Follow-up Baccarani. Blood. 2006;108: Abstr 164.

  17. 0 2 4 6 8 10 12 14 16 18 20 Months Progression-Free Survivalwith Dasatinib 70 mg BID in CP CML 1.0 0.8 0.6 0.4 0.2 0 Proportion progression-free * 70 mg BID †Progression defined as confirmed AP / BC, loss of CHR / MCyR, ↑ WBC count, or death Baccarani. Blood 2006; 108: Abstract 164.

  18. Dasatinib 70 mg BID in CP-CML Dose Adjustment

  19. Dasatinib 70 mg BID in CP-CML Fluid Retention/Cardiac AEs Baccarani. Blood 2006; 108: abst# 164

  20. ASCO 2007, Abstract 7004 Dasatinib 50 Mg Or 70 Mg BID Compared To 100 Mg Or 140 Mg QD In Patients With CML In Chronic Phase (CP) Who Are Resistant Or Intolerant To Imatinib: One-year Results Of CA180034 Shah NP. et al.

  21. 100 mg QD (N = 165) 100 mg Imatinib-resistant or -intolerant CP-CML 50 mg BID (N = 167) 140 mg QD (N = 163) 140 mg 70 mg BID (N = 167) Dasatinib in CP-CMLStudy Design International, 139-center, Randomized, Open-label, Phase III 662 treated 670 randomized • Accrual period: July 2005–March 2006: Total 662 pts • Minimum follow-up: 6 months • Median treatment duration, months (range): 8 (<1–15) Shah et al .JCO 25; 2007 Abstract # 7004.

  22. Dasatinib Phase III in CP-CML Failing Imatinib (N = 662) + 100 QD vs 70 BID Shah, JCO. 2007;25: Abstract 7004

  23. Dasatinib Phase III in CP-CML Failing ImatinibProgression-free Survival 1.0 0.8 0.6 0.4 0.2 0 Proportion progression free 0 2 4 6 8 10 12 14 16 18 20 Months Kantarjiran. Blood. 2006;108: Abstr 746

  24. Dasatinib: Pleural Effusions in CML • 138 patients: Phase I (50); Phase II (88) • Pleural effusion: 48 patients (35%; grade 3/4 in 23 [17%]). 29% in CP, 50% in AP, 33% in BP • MVA risk factors: History of cardiac disease, hypertension, twice-daily schedule • Exudative in 78% of assessable cases • Increased RV systolic pressure documented • Management included: • Drug interruption - 83% • Diuretics - 71% • Corticosteroids - 27% • Thoracentesis - 19% Quintás-Cardama. JCO 25: 3908, 2007

  25. ABL Binding Surfaces Nilotinib Imatinib Weisberg. Ca Cell 7:129, 2005 Manley. Biochem Bio Acta 1754:3, 2005

  26. Nilotinib / Imatinib: Potency and Selectivity Nilotinib has no significant effect on other kinases evaluated, including Src, FLT3, VEGFR, EGFR, InsR, RET, MET , IGFR at concentrations <3000 nM. Mestan. Blood 104 546a: Abs 1978, 2004 Weisberg. Cancer Cell 7:129, 2005

  27. Nilotinib: Pre-clinical Activity • More potent, more selective, inhibitor of Bcr-Abl auto, substrate phosphorylation than imatinib • Selectively induces apoptosis, inhibits proliferation of Bcr-Abl transfected and primary leukemia cells • Increases survival in murine Bcr-Abl MPD models including imatinib-resistant models • Inhibits PDGFRα,ß and KIT ~ Imatinib • STAT, CRKL inhibitor Verstovsek et al. Cancer. 2005;104:1230 Golemovic et al. Clin Ca Res. 2005;11:4941 Griffin et al. Blood. 2004;104:160a Abs# 551 Le Coutre et al. Blood. 2004;104:218a Abs# 76Mahon et al. Blood. 2004;104:251b Abs# 4670 Martinelli et al. Blood. 2004;104:255b Abs# 4687 Weisberg et al. Br. J. Cancer 2006, 94, 1765O’Hare et al. Cancer Res. 2005;65(11):4500-5 Manley et al. Biochim Biophys Acta. 2005 1754(1-2) Scuto et al. Blood. 2004;104:546a Abs# 1977 Weisberg et al. Cancer Cell. 2005;7(2):129-41

  28. Nilotinib Phase I Study CML Hematologic Responses Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006 * Indicates co-first author.

  29. Nilotinib Phase I Study: PK Twice daily 60,000 Daily 40,000 AUC (ng/ml/hr) 20,000 0 50 100 200 400 600 800 1200 400 600 Dose (mg) • Median time to peak concentrations 3 hours post dose • Mean apparent half-life = 15 hours • Steady state by day 8 in both QD and BID regimens • All trough levels > IC50 for cellular Bcr-Abl phosphorylation • PK parameters dose proportional to 400 mg QD • Exposure is greatest in the 600 mg BID group Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006. *Indicates co-first author.

  30. Clinical Resistance to Imatinib Mechanisms • Primary resistance • Insufficient inhibition of BCR-ABL • Low plasma levels of imatinib • Activity of drug pumps • Secondary resistance • Imatinib-resistant BCR-ABL kinase-domain mutations • Overproduction of BCR-ABL • BCR-ABL-independent mechanisms • ? Activation of other kinases • ? Other molecular events Giles. Hematol Am Soc Hematol Educ Program:2005:183-187; von Bubnoff. Leukemia. 203;17:829.

  31. T315I** F382L F311L/I/V F317L G383D V299L L324Q L298V L248V L387F/M M343T E292V M388L E453G/K/A/V G250E/A/F A344V V289A/I S348L A397P Q252H/R E450G/Q/K A350V M472I Y253F/H G236E Q447R H396R/P K357R F486S S417Y E255K/V P-loop Activation loop E275K M351T/L V379I E459K/Q I418V S438C M244V D276G E355G/D T277A/N L364I D241G E279K F359V/C/D/I E281A M237I K285N BCR-ABL Mutations Associated With Imatinib Resistance

  32. Nilotinib Inhibits 32 of 33 Imatinib-resistant BCR-ABL Mutant Phenotypes With IC50 < 1 Um T315I 10,000 Nilotinib resistant: >10,000 nM 1,500 Nilotinib sensitive: Range 19–791 nM 1,000 IC50 Cell Proliferation (nM) 500 P-loop 0 T315I M237I L387F F317L S348L F317V F486S L248V F311V F359V F317C F359C E355A A380S E255V E255D E275K H396R E281K E255R E292K E255K Y253H G250V M388L M351T E355G K285N G250E G250A Q252H D276G M244V

  33. Nilotinib: Phase I StudyGrade 3/4 Possibly Related Laboratory AEs Overall (N=119) 400 BID (N=32) 3% Bilirubin 3% 600 BID (N=18) 11% 5% Lipase 9% 11% 3% ALT/AST 3% 0% 5% Amylase 5% 0% Kantarjian*, Giles* et al. N Engl J Med. 354:2542, 2006 * Indicates co-first author

  34. ASH 2007, Abstract 471 and 735 Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance Le Coutre P. et al. (471) Kantarjian HM. et al. (735)

  35. Nilotinib: Phase II Baseline Demographics and Disease Characteristics Kantarjian HM et al. ASH abstract 735, Blood 2007: 110 (11). Le Coutre P et al. ASH abstract 471, Blood 2007: 110 (11).

  36. Nilotinib Phase II Studies: Dose Intensity (mg/day) 800 797 787 Planned Delivered Delivered (CP) N = 316 (AP) N = 64 le Coutre et al. ASH 2006; Abst #165 Kantarjian et al. ASH 2006; Abst #2169

  37. Hematologic Response Cytogenetic Response Nilotinib Phase II CML-CP Study Response Rates

  38. Hematologic Response Cytogenetic Response Nilotinib Phase II CML-AP Study:Response Rates

  39. 95% 91% Alive, % Total = 321 Failed = 25 lll = Censored observations Months Since Start of Treatment Nilotinib Phase II Study: CML-CP Overall Survival Post Imatinib Failure Kantarjian et al. ASH 2007 abstract 735

  40. 92% 81% Alive, % Patients = 129 Number deaths = 27 Months Since Start of Treatment Phase II CML-AP StudyOverall Survival Post Imatinib Failure Le Coutre et al. ASH 2007 abstract 471

  41. Phase II CML-CP StudyGrades 3/4 Biochemical Laboratory Abnormalities Kantarjian et al. ASH 2007 abstract 735

  42. Phase II CML-CP StudyPossibly Related Non-hematologic AEs (frequency >10%) Kantarjian et al, ASH 2007 abstract 735

  43. Cross-intolerance Between Imatinib and Nilotinib Patients enrolled in nilotinib study 2101 with grade 3/4 imatinib intolerance CML-CP (N=94) / CML-AP (N=23) Patients with cross-intolerance (grade 3/4) after switching to nilotinib Rash / skin toxicity Fluid retention GI intolerance Liver toxicity Myalgias / Arthralgias Cortes et al. ASH abstract 29, Blood 2007:110 (11)

  44. Nilotinib Cross Intolerance in Patients with Imatinib Intolerance Nonhematologic AEs

  45. Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality Nilotinib Phase II Study CML-CP Myelosuppresion

  46. Most Frequent Newly Occurring or Worsening Hematologic Lab Abnormalities Regardless of Causality Nilotinib Phase II Study CML-AP Myelosuppresion

  47. Nilotinib: CML CP After Dasatinib and Imatinib • Giles F et al. Presented at: 43rd ASCO Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 7038. • Giles F et al. Presented at: 12th Congress of the EHA; June 7-10, 2007; Vienna, Austria. Abstract 554.

  48. Cautions With Dasatinib / Nilotinib • QTc prolongation: Both – Baseline EKG, Close K and Mg monitoring • Past pancreatitis:Nilotinib C/I • Hypertension, COPD, CCF, Chest wall injury, Asthma, Pneumonia, GI bleeding, Auto-immune disorders, aspirin:Dasatinib C/I

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