PACE trial: Ponatinib dose-ranging study in chronic-phase chronic myeloid leukemia: a randomized, open-label phase 2 clinical trial.pptx

PACE trial

1. Original Article A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias J.E. Cortes, D.-W. Kim, J. Pinilla- Ibarz , P. le Coutre , R. Paquette, C. Chuah , F.E. Nicolini , J.F. Apperley, H.J. Khoury, M. Talpaz , J. DiPersio , D.J. DeAngelo, E. Abruzzese , D. Rea, M. Baccarani , M.C. Müller, C. Gambacorti-Passerini , S. Wong, S. Lustgarten , V.M. Rivera, T. Clackson, C.D. Turner, F.G. Haluska , F. Guilhot , M.W. Deininger, A . Hochhaus , T. Hughes, J.M. Goldman, N.P. Shah, and H. Kantarjian , for the PACE Investigators NEJM vol. 369 no. 19 November 7, 2013

2. Study Overview Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonine to isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph-positive ALL).

3. Study Design Phase II trial Multicenter Open Label . 6 Cohorts. Randomized 2013. NEJM.

4. Methods 449 patients. Patients were eligible if they were at least 18 years of age and had CML or Ph-positive ALL (30% lymphoid blasts in blood or bone marrow at diagnosis and no history of CML). Resistance to Dasatinib or Nilotinib. Development of the T315I mutation after any tyrosine kinase inhibitor therapy. Patients received an initial dose of 45 mg of ponatinib orally once daily. The median follow-up was 15 months.

5. End Points Primary endpoint: Major cytogenetic response at any time within the first 12 months (in patients with chronic-phase CML) Major hematologic response at any time within the first 6 months (in patients with accelerated-phase CML, blast-phase CML, or Ph-positive ALL)

6. End Points Secondary endpoints: Chronic Phase CML included a complete hematologic response accelerated- and blast-phase CML and Ph-positive ALL included a complete or partial cytogenetic response and a confirmed major cytogenetic response. Major molecular response. Time to the response. Duration of the response. Progression-Free Survival (OS). Overall Survival (OS). Safety.

7. PACE : Baseline Characteristics

8. Study Results

9. Primary End Point

10. Primary End Point

11. Primary End Point

12. Primary End Point

13. Secondary End Points

14. Secondary End Point

15. Secondary End Point

16. Secondary End Point

17. Secondary End Point

18. Secondary End Point

19. Secondary End Point (Safety)

20. Secondary End Point (Safety)

21. PACE: Conclusions In conclusion, ponatinib showed clinically significant activity in patients with CML and those with Ph-positive ALL.

22. Original Article Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: final 5-year results of the phase 2 PACE trial J.E. Cortes, D.-W. Kim, J. Pinilla- Ibarz , P. le Coutre , R. Paquette, C. Chuah , F.E. Nicolini , J.F. Apperley, H.J. Khoury, M. Talpaz , J. DiPersio , D.J. DeAngelo, E. Abruzzese , D. Rea, M. Baccarani , M.C. Müller, C. Gambacorti-Passerini , S. Wong, S. Lustgarten , V.M. Rivera, T. Clackson, C.D. Turner, F.G. Haluska , F. Guilhot , M.W. Deininger, A . Hochhaus , T. Hughes, J.M. Goldman, N.P. Shah, and H. Kantarjian , for the PACE Investigators The American Society of Hematology Blood VOLUME 132, NUMBER 4 26 JULY 2018

23. Study Overview This analysis focuses on chronic-phase CML (CP-CML) patients (n=270) with 56.8-month median follow-up.

24. Study Design Phase II trial Multicenter Open Label . Randomized 2018. Blood.

25. End Points Primary endpoint: Major cytogenetic response ( MCyR ) by 12 months for patients with CP-CML. Major hematologic response ( MaHR ) by 6 months for patients with AP-CML, BP-CML, or Ph+ ALL.

26. End Points Secondary endpoints: major molecular response (MMR). Time to and duration of response. Progression-Free Survival (OS). Overall Survival (OS). Safety.

27. Study Results

28. Primary End Point CP-CML

29. Primary End Point CP-CML

30. Primary End Point CP-CML

31. Primary End Point

32. Primary End Point

33. Primary End Point

34. Secondary End Point CP-CML

35. Secondary End Point CP-CML

36. Secondary End Point (OS) CP-CML

37. Secondary End Point AP-CML

38. Secondary End Point BP-CML

39. Secondary End Point Ph + ALL

40. Secondary End Point (PFS) CP-CML

41. Secondary End Point AP-CML

42. Secondary End Point BP-CML

43. Secondary End Point Ph + ALL

44. Secondary End Point (Safety)

45. Secondary End Point (Safety)

46. Secondary End Point (Safety)

47. Secondary End Point (Safety)

48. PACE-5 years follow up: Conclusions These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients.

49. PACE-5 years follow up: Conclusions These final PACE results demonstrate ponatinib provides durable and clinically meaningful responses, irrespective of dose reductions, in this population of heavily pretreated CP-CML patients.

50. Original Article Ponatinib long-term follow-up of efficacy and safety in CP-CML patients in real world settings in France: The POST-PACE study Gabriel Etienne, Delphine Rea, Valerie Coiteux , Agnès Guerci-Bresler , Françoise Huguet , Laurence Legros , Philippe Rousselot , Franck-Emmanuel Nicolini Leukemia Research 104 (2021) 106541

51. POST-PACE : Conclusions In summary, data obtained in POST-PACE confirm a long-term sustained PON clinical benefit even for patients with heavily pre-treated CML. Adapted dosing schedules are key management issues to maintain PON efficacy while controlling tolerability in heavily pre-treated long-term responders CP-CML patients.

52. Original Article Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee James L. Januzzi , Joseph M. Garasic , Scott E. Kasner , Vickie McDonald, Mark C. Petrie, Jonathan Seltzer, Michael Mauro, Kevin Croce, Ellin Berman, Michael Deininger, Andreas Hochhaus9, Javier Pinilla‑ Ibarz , Franck Nicolini , Dong‑ Wook Kim, Daniel J. DeAngelo, Hagop Kantarjian , Jing Xu, Tracey Hall, Shouryadeep Srivastava, Daniel Naranjo and Jorge Cortes Journal of Hematology & Oncology 2022, 15(1):1

53. Study Overview The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used.

54. Study Results

55. Arterial occlusive event (AOE) rates with ponatinib Rates of non-adjudicated and adjudicated AOEs.

56. Arterial occlusive event (AOE) rates with ponatinib Exposure-adjusted incidence of newly occurring arterial occlusive events (AOEs) by year (all patients)

57. Arterial occlusive event (AOE) rates with ponatinib

58. Arterial occlusive event (AOE) rates with ponatinib Overall survival (OS) in chronic-phase chronic myeloid leukemia (CP-CML) patients with and without AOEs

59. Conclusions Independent reconsideration of AOEs by an expert adjudication committee showed lower rates of clinically relevant AOEs overall (17% vs. 25%) and serious AOEs (16% vs. 20%) than were originally reported in the PACE trial, suggesting an earlier possible overestimation that may not accurately reflect the AOE risk with ponatinib. The incidence of exposure-adjusted newly occurring AOEs decreased over time during ponatinib treatment.