Nilotinib: a selective choice for resistant and intolerant patients - PowerPoint PPT Presentation

Nilotinib: a selective choice for resistant and intolerant patients to imatinib Massimo Breccia Azienda Policlinico Umberto I° Università Sapienza Roma

Introduction • Nilotinib is a rationally designed novel tyrosine kinase inhibitor (TKI); it is highly potent and the most selective of the TKIs used to treat chronic myeloid leukemia (CML) • Nilotinib binds to ABL with greater affinity and improved topological fit than imatinib; it inhibits most imatinib-resistant BCR-ABL 1 mutants (except T315I) • Nilotinib is approved for the treatment of patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CML-CP) or accelerated phase (CML-AP) resistant to or intolerant of prior therapy, including imatinib

2101 STUDY

Study Design • Phase 2, open-label, single-treatment arm • Patient population: adults with imatinib-resistant or -intolerant Ph+ CML-CP  Standard eligibility criteria  QTc > 450 msec not eligible • Nilotinib was given 400 mg orally twice daily (2 hours following meals) • Primary endpoint: Major cytogenetic response (MCyR) • Secondary endpoints  Complete cytogenetic response (CCyR)  Complete hematologic response (CHR)  Duration of MCyR  Progression-free Survival (PFS); progression defined as: − Progress to AP/BC − Loss of CHR − Loss of MCyR  OS  Safety  MMR: BCR-ABL1 transcript levels ≤ 0.1% according to the international scale

Definition of Imatinib Resistance and Intolerance Imatinib resistance: either treatment with imatinib ≥ 600 mg/day with disease progression (≥ 50% increase in white blood cell, blast, basophil, or platelet counts), no hematologic response in bone marrow after 4 weeks, or patients receiving < 600 mg/d with any mutations at the following amino acids: L248, G250, Q252, Y253, E255, T315, F317, H396 • Primary resistance  No CHR at or after 3 months  No minimal cytogenetic response (minCyR) at or after 6 months  No MCyR at or after 12 months • Secondary resistance  Loss of CHR  Loss of minCyR, loss of MCyR, loss of CCyR, or cytogenetic relapse  Development of clonal evolution Imatinib intolerance with resistance • Patients without an MCyR* who discontinued for: • Persistent grade 3/4 imatinib-related adverse event (AE), despite optimal supportive care • Persistent grade 2 imatinib-related AE, despite optimal supportive care  Persisting ≥ 1 month, or  Recurring > 3 times with imatinib dose reduction * Patients without MCyR were chosen because they were fully and appropriately assessable for the primary study endpoints. Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Results Table 1. Baseline Demographics (N = 321) Median age, years (range) 58 (21-85) Median duration of CML, months (range) 58 (5-275) Median duration of prior imatinib therapy, months (range) 32 (< 1-94) Active disease prior to therapy, n (%) 206 (64) Imatinib resistant/intolerant (%)* 70/30 Prior highest imatinib dose ≥ 600 mg/day, n (%) 232 (72) Patients with baseline CHR, n (%) 114 (36) Patients ≥ 65 years, n (%) 98 (31) Other prior therapy Hydroxyurea, n (%) 266 (83) Interferon-α, n (%) 134 (42) Cytarabine, n (%) 78 (24) CHR, complete hematologic response; CML, chronic myeloid leukemia; MCyR, major cytogenetic response. *Intolerant patients were also resistant and were not allowed to have prior MCyR at study entry. • Median duration of CML was nearly 5 years • 72% of patients received prior doses of imatinib ≥ 600 mg/day Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Patients disposition Table 2. Patient Disposition (N = 321) n (%) Ongoing treatment 124 (39) Discontinued treatment 197 (61) Disease progression 88 (27) Adverse event(s) 61 (19) Drug related 50 (16) Non-drug related 11 (3) Abnormal test/laboratory value 6 (2) Other* 39 (12) Death † 3 (< 1) * Includes protocol violation, patient withdrawal of consent, lost to follow-up, reason not stated, and administrative problems. † Includes only those patients for whom death was reported as primary reason for discontinuation of therapy. Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Median dose intensity Table 3. Nilotinib Exposure (N = 321) Median duration of nilotinib, days (range) 561 (1-1096) Median dose intensity, mg/day (range) 789 (151-1110) Patients with dose interruption*, n (%) 185 (58) Median cumulative duration of dose interruption, days 20 (1-345) (range) Median percent of dose interruption, % days (range) 4 (< 1-62) Patients with dose reduction, n (%) 125 (39) *Dose interruptions defined conservatively as > 1 day of interruption regardless of reason. • Median dose delivered was close to the planned dose of 800 mg/day • Median duration of exposure was long (561 days) • 62% of patients had nilotinib therapy ≥ 12 months and 42% ≥ 24 months at the time of data cutoff • The median duration of dose interruptions was short • 73% of patients who required treatment interruptions resumed treatment after interruption at the planned dose Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Hematologic and Cytogenetic Response in Patients With a Minimum Follow-Up of 24 Months (N = 321) 1 00 90% 85% 90 80 72% 66% 70 59% 56% 51% 60 44% 41% 50 40 Pa 30 20 1 0 0 n 321 155 321 226 95 321 226 95 I matinib O verall I matinib I matinib I matinib I matinib O verall* I matinib O verall I ntolerantw/ R esistant † I ntolerantw/ R esistant R esistant I ntolerantw/ R esistance †,‡ R esistance ‡ R esistance ‡ CH CH CH R R R M M M CyR CyR CyR CCyR CCyR CCyR CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response. * Patients who achieved (without baseline CHR) or maintained CHR (had CHR at study entry). † Patients with no CHR at baseline. ‡ See definition of imatinib-intolerant with resistance in the Methods sections. • Median time to CHR was 1.0 month in patients without CHR at baseline • Median time to MCyR was 2.8 months (range, 0.9-28) • Median time to CCyR was 3.3 months (range, 0.9-27) • MCyR was achieved in 59% of patients, 74% of whom were CCyR Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Cytogenetic Response in Patients With and Without CHR at Baseline 1 00 80 73% Patients, % 59% 58% 60 52% 44% 40 36% 20 0 n 321 114 207 A ll Baseline CH R NoBaseline CH R CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response. • Patients entering the study with CHR at baseline had higher response rates (MCyR, CCyR, and MMR) than those without baseline CHR Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update MMR in Patients With and Without Cytogenetic Response and With and Without CHR at Baseline A llpatients 1 00 W ith M C yR 80 W ith C C yR 60 58% 56% 53% 51% Patie 40 44% 38% 39% 28% 20 22% 0 n 294 1 83 1 35 1 05 78 62 1 89 1 05 73 A ll Baseline CH R No Baseline CH R CCyR, complete cytogenetic response; CHR, complete hematologic response; MCyR, major cytogenetic response; MMR, major molecular response. • 44% of patients achieving MCyR achieved MMR • 56% of patients achieving CCyR achieved MMR Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Duration of CCyR 1 00 Pts Without Loss of Response, % eath, % 90 80 ithout ProgressionorD 70 60 50 40 30 20 P t E vt C en P atients with C C yR : 1 41 1 8 1 23 1 0 W C ensored observations 0 0 3 6 9 1 2 1 5 1 8 21 24 27 30 33 M onths Since Complete Cytogenetic R A t-R isk : E vents 1 41 : 0 1 27 : 4 1 1 2 : 9 92 : 1 3 53 : 1 8 0 : 1 8 CCyR, complete cytogenetic response. Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Progression-Free Survival 100 BC, % 90 P/ 80 ithout Progressionto A 70 60 50 40 30 Patients W 20 P t E vt C en 10 A llpatients: 321 94 227 C ensored 0 0 3 6 9 1 2 1 5 1 8 21 24 27 30 33 36 M onths Since Start of Treatment AP, accelerated phase; BC, blast crisis; Cen, censored; Evt, event; Pt, patient. • Median PFS has not yet been reached for patients with CHR at baseline • For all patients, median estimated PFS was 33.6 months • Estimated PFS rate at 24 months was higher for patients with baseline CHR (75%) compared with patients without CHR at study entry (48%) • Only 9 patients (3%) progressed to AP/BC based on actual laboratory values Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.

2101 Study 24-Month Update Overall Survival 1 00 90 80 live, % 70 60 Patients A 50 40 30 20 P t E vt C en A ll patients: 321 44 277 1 0 C ensored obse 0 0 3 6 9 1 2 1 5 1 8 21 24 27 30 33 36 M onths Since Start of Treatment A t-R isk : E vents 321 : 0 31 4 : 3 294 : 1 5 274 : 27 223 : 39 0 : 44 Cen, censored; Evt, event; Pt, patient. • Estimated OS rate at 24 months was 87% Kantarjian HM, et al. Blood . 2009;114(22):464. Abstract # 1129.