Abstract: Ponatinib, the only third‐generation pan‐BCR::ABL1 inhibitor with activity against all known BCR::ABL1 mutations including T315I, has demonstrated deep and durable responses in patients with chronic‐phase chronic myeloid leukemia (CP‐CML) resistant to prior second‐generation (2G) TKI treatment. We present efficacy and safety outcomes from the Ponatinib Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) and CML Evaluation (PACE) and Optimizing Ponatinib Treatment in CP‐CML (OPTIC) trials for this patient population. PACE (NCT01207440) evaluated ponatinib 45 mg/day in CML patients with resistance to prior TKI or T315I. In OPTIC (NCT02467270), patients with CP‐CML and resistance to ≥2 prior TKIs or T315I receiving 45 or 30 mg/day reduced their doses to 15 mg/day upon achieving ≤1% BCR::ABL1 IS or received 15 mg/day continuously. Efficacy and safety outcomes from patients with CP‐CML treated with ≥1 2G TKI (PACE, n  = 257) and OPTIC ( n  = 93), 45‐mg starting dose cohort, were analyzed for BCR::ABL1 IS response rates, overall survival (OS), progression‐free survival (PFS), and safety. By 24 months, the percentages of patients with ≤1% BCR::ABL1 IS response, PFS, and OS were 46%, 68%, and 85%, respectively, in PACE and 57%, 80%, and 91%, respectively, in OPTIC. Serious treatment‐emergent adverse events and serious treatment‐emergent arterial occlusive event rates were 63% and 18% in PACE and 34% and 4% in OPTIC. Ponatinib shows high response rates and robust survival outcomes in patients whose disease failed prior to 2G TKIs, including patients with T315I mutation. The response‐based dosing in OPTIC led to improved safety and similar efficacy outcomes compared with PACE.

Abstract: 7550 Background: The final 5-year analysis of the PACE trial, which evaluated use of PON in pts with refractory chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia, identified a 25% incidence of AOEs (Cortes, Blood 2018) from a search utilizing 〉 400 preferred terms (PTs) defined by MedDRA and related to vascular ischemia or thrombosis. We performed a retrospective review using an independent Endpoint Adjudication Committee (EAC) to better understand clinically relevant AOE rates in PACE. Methods: The EAC consisted of 3 cardiologists, 1 hematologist, and 1 neurologist to review AOEs (identified using 〉 500 terms) in PACE using American College of Cardiology/American Heart Association (ACC/AHA) definitions for major adverse cardiovascular events (MACE), and to review pt profiles including event, severity, concomitant medication, and hospitalization data. These results were compared with MedDRA PT search results. The EAC was blind to dose, dose modification, and investigator causality opinion. Results: The PACE review included 449 heavily pretreated pts with Ph+ leukemia (median age, 59 y; 47% female; 93% ≥2 tyrosine kinase inhibitors). With median follow-up 37.3 mo in all pts, AOEs were identified by MedDRA PT search in 25% of pts and EAC-verified in 17% (Table). In each category listed in the table, the EAC verification identified fewer AOEs and serious AOEs. Serious AOEs were identified by MedDRA PT search in 20% of pts and EAC-verified in 16%. Events that were not associated with a cardiovascular etiology or failed to meet the MACE definition set forth by the ACC/AHA were determined by the EAC not to be an AOE. Conclusions: The independent EAC review showed a lower rate of clinically relevant AOEs than was reported in PACE, suggesting an earlier possible overestimation that may not accurately reflect the risk of AOEs with PON. The ongoing PON dose-ranging OPTIC study will further evaluate the PON risk:benefit profile. Clinical trial information: NCT01207440 . [Table: see text]

Abstract: Introduction: Ponatinib is a potent oral tyrosine kinase inhibitor (TKI) approved for use in patients with refractory CML and Ph+ ALL, including patients with the resistant BCR-ABLT315I mutation. To evaluate whether patient characteristics and outcomes with ponatinib differed by extent of pretreatment with other TKIs, this post hoc analysis examines results among CP-CML patients enrolled in the phase 2 PACE trial (NCT01207440) according to the number of TKIs received prior to study entry. Updated data with 4 years of follow-up will be presented. Methods: Patients with CML or Ph+ ALL who were resistant or intolerant to dasatinib or nilotinib or who had the T315I mutation were enrolled (N=449). Ponatinib was initiated at 45 mg once daily. CP-CML patients were evaluated based on previous treatment with 1, 2, 3, or 4 prior TKIs approved for use in CP-CML (ie, imatinib, dasatinib, nilotinib, and bosutinib). Data reported in this abstract are as of February 2, 2015. Results: Overall, 270 CP-CML patients were enrolled and treated in PACE. Patient characteristics and disposition varied by number of prior TKIs (Table 1). Both median age and median time from diagnosis increased with number of prior TKIs; median dose intensity was highest in patients who had received only 1 prior TKI. The most common reasons for discontinuation across groups were adverse events (AEs) and withdrawal by patient request. Responses by number of prior TKIs are shown in Table 2. Rates of cytogenetic and molecular response to ponatinib were higher with fewer prior TKIs. While the frequency of individual AEs did not follow a consistent trend, the incidence of grade ≥3 AEs appeared to increase with the number of prior TKIs received (68%, 86%, 89%, and 100%, respectively); grade ≥3 AEs in ≥10% of CP-CML patients overall were thrombocytopenia (35%), neutropenia (17%), hypertension (13%), increased lipase (12%), and abdominal pain (10%). A similar frequency pattern was observed for serious AEs, which occurred in 58%, 53%, 62%, and 92% of patients who had previously received 1, 2, 3, and 4 approved TKIs, respectively. Serious AEs in ≥5% of CP-CML patients overall were pancreatitis (7%), angina pectoris (5%), and pneumonia (5%). The frequency of arterial occlusive events (AOEs) was 32% (6/19), 26% (25/98), 28% (39/141), and 42% (5/12) by increasing number of prior TKIs; exposure-adjusted incidence rates of new AOEs were 11.75, 10.4, 12.6, and 33.3 events per 100 patient-years, respectively. Conclusions: With 4 years of follow-up, ponatinib continues to provide benefit to ongoing CP-CML patients in the PACE trial. Analysis by treatment history indicates that patients who had received fewer TKIs prior to study entry appear to exhibit better efficacy and safety profiles. However, treatment decisions should be primarily guided by individual patient and disease factors, including mutation status, and physicians should weigh both the benefits and risks of prescribing ponatinib. Table 1. Patient Characteristics and Disposition by Number of Prior TKIs 1 TKI (n=19) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) Median age at baseline, years 52 58 63 67 Median time from diagnosis to first dose, years 2.8 5.2 7.9 12.4 Median dose intensity, mg/d 34.0 28.7 29.9 31.0 Mutations detected at baseline, % 68 51 43 75 T315I mutation detected at baseline, % 63 31 16 0 Prior TKI exposure, %, imatinib/dasatinib/nilotinib/bosutinib 68/21/5/5 97/66/36/1 100/96/96/7 100/100/100/100 Remain on study, % 53 48 40 8 Discontinued, % 47 52 60 92 Primary reason for discontinuation, % AE 16 18 17 33 Withdrawal by patient request 5 11 11 25 Disease progression 16 5 13 0 Lack of efficacy 0 2 9 8 Death 0 2 3 17 Othera 11 13 8 8 Median follow-up, months 42.3 42.9 42.1 28.2 aIncludes noncompliance, physician decision, protocol violation, and other reasons Table 2 Responses to Ponatinib by Number of Prior TKIs 1 TKI (n=16a) 2 TKIs (n=98) 3 TKIs (n=141) 4 TKIs (n=12) MCyR 12 (75) 69 (70) 69 (49) 7 (58) CCyR 12 (75) 63 (64) 63 (45) 4 (33) MMR 10 (63) 41 (42) 51 (36) 1 (8) MR4 6 (38) 30 (31) 38 (27) 1 (8) MR4.5 4 (25) 22 (22) 34 (24) 1 (8) All responses are n (%) a16/19 patients were evaluable for efficacy Disclosures Hochhaus: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Cortes:ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role, Research Funding. Pinilla-Ibarz:Novartis: Consultancy, Other: Consulting & Advisory Role, Research Funding; ARIAD Pharmaceuticals, Inc.: Consultancy, Other: Consulting & Advisory Role, Research Funding; Teva: Consultancy, Speakers Bureau; Pfizer: Consultancy, Other: Consulting & Advisory Role, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Speakers Bureau. le Coutre:Novartis: Honoraria; BMS: Honoraria; ARIAD Pharmaceuticals Inc.: Honoraria; Pfizer: Honoraria. Paquette:ARIAD Pharmaceuticals Inc.: Honoraria; BMS: Honoraria; Novartis: Honoraria. Chuah:Children International: Honoraria; Novartis: Honoraria; Bristol Meyers Squibb: Honoraria. Nicolini:Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Apperley:BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Talpaz:Pfizer: Other: CONSULTING OR ADVISORY ROLE; Novartis: Other: CONSULTING OR ADVISORY ROLE; ARIAD Pharmaceutical Inc.: Other: CONSULTING OR ADVISORY ROLE; Pfizer: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Novartis: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; ARIAD Pharmaceutical Inc.: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Incyte: Other: TRAVEL, ACCOMODATIONS, EXPENSES, Research Funding; Sanofi: Research Funding. DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Abruzzese:BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Novartis: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role. Rea:Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Baccarani:Pfizer: Other: Travel, Accommodations, Expenses; BMS: Other: Travel, Accommodations, Expenses; Novartis: Other: Travel, Accommodations, Expenses; ARAID Pharmaceutical Inc.: Other: Consulting or Advisory Role, Speakers Bureau; Pfizer: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; Novartis: Honoraria, Other: Consulting or Advisory Role, Speakers Bureau; BMS: Honoraria, Speakers Bureau; ARIAD Pharmaceutical Inc.: Other: Travel, Accommodations, Expenses. Muller:ARIAD Pharmaceuticals Inc.: Honoraria, Other: Consulting & Advisory Role, Research Funding; Novartis: Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Honoraria, Other: Consulting or Advisory Role, Research Funding. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Conlan:ARIAD Pharmaceuticals Inc.: Other: Stock. Rivera:ARIAD Pharmaceuticals Inc.: Employment, Other: Full-time Employee & Shareholder (self-managed). Guilhot:Celgene: Consultancy, Other: CONSULTING OR ADVISORY ROLE; Pfizer: Honoraria; Novartis: Honoraria, Other: TRAVEL, ACCOMODATIONS, EXPENSES. Deininger:Incyte: Consultancy, Honoraria, Other: Consulting or Advisory Role; Pfizer: Consultancy, Honoraria, Other: Consulting or Advisory Role; ARIAD Pharmaceutical Inc.: Consultancy, Honoraria, Other: Consulting or Advisory Role; Gilead: Research Funding; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Other: Consulting or Advisory Role, Research Funding; BMS: Consultancy, Honoraria, Other: Consulting & Advisory Role, Research Funding. Hughes:Bristol-Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Shah:Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Plexxikon Inc.: Research Funding. Kantarjian:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Amgen: Research Funding.

Abstract: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that has demonstrated significant clinical activity in heavily pretreated CP-CML pts. A multivariate analysis of CP-CML pts in the PACE trial found significant associations between major cytogenetic response (MCyR) and higher dose intensity; however, dose reductions and/or interruptions (DR/I) of ponatinib occur often in pts who experience adverse events (AEs). The clinical significance of such DR/I are not well known. Objectives To assess the impact of DR/I and dose intensity of ponatinib on clinical outcomes in pts with CP-CML enrolled in the PACE trial. Methods A total of 270 CP-CML pts were enrolled in this ongoing, phase 2, international, open-label clinical trial. The efficacy population (N=267) was included in this post hoc analysis. Dose reductions were defined as any reduction below the standard 45 mg daily dose; interruptions were defined as a period in which ponatinib was held for ≥3 consecutive days between non-missing doses. Up to 2 reductions (to 30 or 15 mg/day) were permitted for managing AEs. To assess the impact of dose modification on response, pts were grouped according to tertiles of average dose intensity (mg/day), calculated as the cumulative dose divided by treatment exposure. All variables were calculated within 12 mos of the first dose to correspond to the primary outcome measure of MCyR by 12 mos. Secondary efficacy endpoints included complete cytogenetic response (CCyR) and major molecular response (MMR). Responses were assessed every 3 mos. The Cochran–Armitage trend test was used to assess whether response rates increased with higher average dose intensity tertiles; all P-values were 2-sided. Data are as of 01 Apr 2013, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts still on study was 18 mos. Results A total of 209 (78%) pts required DR/I at least once within 12 mos: 172 pts (64%) had at least 1 dose reduction (median time to first dose reduction was 64 days). In pts with 〉 1 dose reduction (n=75, 28%), the median time between the first and second reduction was 91 days. Among pts with a dose reduction at any time, 35% re-escalated to 45 mg daily. Dose interruption was experienced by 199 (75%) pts (median total duration of 35 days). The most common reason for DR/I was thrombocytopenia (33%). For pts with average dose intensity ≤27 mg/day (N=89), 〉 27 to ≤42 mg/day (N=88), and 〉 42 mg/day (N=90), respectively, the median age was 62, 62, and 56 yrs; median time since initial diagnosis was 11, 7, and 6 yrs; each group had received a median of 3 prior TKIs. Among these tertiles, the best response to the most recent dasatinib- or nilotinib-containing regimen was MCyR or better in 21%, 22%, and 35%; CCyR or better in 11%, 14%, and 23%; MMR or better in 1%, 2%, and 6%, respectively. Within 12 mos of the first dose, median duration of treatment exposure was 356 (26–366), 366 (51–366) and 366 (3–366) days, respectively. Twenty-nine pts had 〈 3 mos of treatment exposure. Of those, 11 had a post-baseline cytogenetic assessment (1 had MCyR). Responses to ponatinib according to tertile are presented below (Table) for pts with ≥3 mos follow-up (N=238). MCyR, CCyR, and MMR rates increased with higher average dose intensity. Comparable response rates were seen between pts with average dose intensity 〉 27 to ≤42 mg/day and 〉 42 mg/day. Response rates were lower in pts with average dose intensity ≤27 mg/day; however, these pts still achieved MCyR, CCyR, and MMR rates that substantially exceeded those reported with the most recent dasatinib- or nilotinib-containing regimen. Conclusions Higher dose intensity of ponatinib was associated with higher response rates in this heavily pretreated CP-CML population, but lower dose intensity still led to positive clinical outcomes. It should be noted that higher responses to the most recent dasatinib- or nilotinib-containing regimen were also seen in pts with higher average dose intensity. In summary, these data indicate that although optimal responses were seen with average ponatinib dose intensity 〉 42 mg/day, pts can be effectively managed with dose reduction or interruption if clinically indicated. Disclosures: Pinilla-Ibarz: Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS, Novartis, IL-Yang: Consultancy; BMS, Novartis, Pfizer, ARIAD, IL-Yang: Research Funding; BMS, Novartis, Pfizer, IL-Yang: Honoraria; BMS, Novartis, Pfizer: Speakers Bureau; BMS, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Le Coutre:Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. Paquette:Ariad, BMS, Novartis: Consultancy; Ariad, BMS, Novartis: Honoraria; Ariad, BMS, Novartis: Speakers Bureau. Chuah:Novartis, BMS: Honoraria. Nicolini:Novartis, ARIAD, Teva: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, Teva, Pfizer, ARIAD: Honoraria; Novartis, BMS, TEva: Speakers Bureau; Novartis, ARIAD, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. DeAngelo:Araid, Novartis, BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:BMS, Novartis, Pfizer, Ariad, Teva: Honoraria. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Muller:Novartis, BMS, ARIAD: Consultancy; Novartis, BMS: Research Funding; Novartis, BMS, ARIAD: Honoraria. Gambacorti-Passerini:Pfizer: Research Funding; Pfizer, BMS: Honoraria. Lustgarten:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Rivera:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc. Other, Employment. Clackson:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Turner:ARIAD: Employment. Haluska:ARIAD: employees of and own stock/stock options in ARIAD Pharmaceuticals, Inc Other, Employment. Deininger:BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:ARIAD: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Talpaz:Ariad, BMS, Sanofi, INCYTE: Research Funding; Ariad, Novartis: Speakers Bureau; Ariad, Sanofi, Novartis: Membership on an entity’s Board of Directors or advisory committees.

Abstract: Abstract 3763 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the TKI resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), or Ph+ acute lymphoblastic leukemia (Ph+ ALL) were evaluated in a pivotal phase 2, international, open-label clinical trial (PACE). Objective: To evaluate the patterns of molecular response in patients treated with ponatinib in the PACE trial. Methods: The PACE trial enrolled 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I BCR-ABL mutation. Patients were assigned to 1 of 6 cohorts according to disease phase (CP-CML, AP-CML, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Mutation and molecular response analyses were performed at a single central laboratory. Molecular responses are reported on the International Scale (BCR-ABLIS; b2a2/b3a2 [p210] transcript only): major molecular response (MMR), ≤0.1%; MR4, ≤0.01%; MR4.5, ≤0.0032%. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 21] months). Results: The median age was 59 (18 to 94) years. The median time from initial diagnosis to start of ponatinib was 6 (0.3 to 28) years. 96% had received prior imatinib, 84% dasatinib, 65% nilotinib; 8% received 1, 39% received 2, and 53% received all 3 prior approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. BCR-ABL mutations were detected in 55% of all patients at baseline: 22.9% T315I only, 26.5% mutations other than T315I, 5.8% mutations in addition to T315I. The most common mutations were T315I (29%), F317L (8%), E255K (4%), F359V (4%), and G250E (3%). Baseline BCR-ABL transcript levels were 〉 10% in 74% (74% in CP-CML) and 〉 1% to ≤10% in 14% (20% in CP-CML). No patients entered the study in MMR. The best response to the most recent dasatinib or nilotinib containing regimen was MMR or better in 4% (3% in CP-CML). Molecular response rates by cohort are shown below for CP-CML and AP-CML. Deep molecular responses, including MR4.5, were observed in both disease phases. Of 16 BP-CML and 3 Ph+ ALL patients with the b2a2/b3a2 transcript and baseline and post-baseline bone marrow assessments, 5 BP-CML and 0 Ph+ ALL patients achieved MMR. In CP-CML, MMR rates for the most frequent mutations other than T315I were 41% F317L, 50% E255K, 31% F359V, 38% G250E. Subgroup analyses in CP-CML indicated significant differences in the MMR rate for patients with T315I only (56%; p 〈 0.001) and mutations in addition to T315I (50%; p=0.0216) vs. no mutation (21%), and for T315I only vs. mutations other than T315I (34%; p=0.0237). These differences are likely due to younger age (median 51 vs. 61 years) and exposure to fewer prior TKIs (median 2 vs. 3) in CP-CML patients with T315I vs. those without T315I. In CP-CML, 53% maintained or achieved BCR-ABLIS ≤10% by 3 months, with a trend towards higher rates in patients receiving fewer prior approved TKIs (1: 81%; 2: 61%; 3: 45%). The MMR rate (cumulative) in CP-CML improved over time: 13% by 3 months, 24% by 6 months, 28% by 9 months. The median time to MMR for CP-CML patients achieving MMR was 6 (2 to 17) months. CP-CML patients with MMR had an estimated probability of remaining in MMR at 6 months and 1 year of 87% and 84%, respectively (Kaplan-Meier). Ponatinib was generally well-tolerated. Data with a minimum follow-up of 12 months will be presented. Conclusions: Ponatinib treatment led to significant and deep molecular responses in this heavily pretreated population. In CP-CML, the MMR rate was ∼10-fold higher than that reported with the most recent dasatinib or nilotinib treatment. Disclosures: Hochhaus: ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, NOVARTIS PHARMA, BRISTOL MYERS SQUIBB, PFIZER: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy; Pfizer: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding.

Abstract: 7012 Background: The tyrosine kinase inhibitor (TKI) ponatinib has potent activity against native and mutant BCR-ABL1 and is approved for use in pts with relapsed/intolerant CML or Ph+ ALL, or with BCR-ABL1/T315I. Methods: In the pivotal PACE study (NCT01207440), ponatinib (starting dose 45 mg/d) was assessed in pts with CML or Ph+ ALL resistant/intolerant to dasatinib or nilotinib, or with T315I. In Oct ’13, dose reductions were implemented due to observed arterial occlusive events (AOEs). Efficacy and safety at 5 yrs (data as of 3 Oct ’16) for CP-CML pts are reported. Results: Of 270 CP-CML pts in the safety population, 60% received ≥3 prior TKIs. At initiation of study closure, 99 pts were ongoing; among these pts, minimum follow-up was 52 months, and most (78%) had 15 mg/d as their last dose. In all CP-CML pts (n = 267, efficacy evaluable), cumulative response rates were: MCyR, 60%; CCyR, 54%; MMR, 40%; and MR 4.5 , 24%. Among pts who achieved MCyR (n = 148) or MMR (n = 108), the Kaplan-Meier (KM) estimated probability of remaining in response at 5 yrs was 74% (95% CI, 62 – 83) and 61% (95% CI, 51 – 70), respectively. Regardless of dose reduction in Oct ’13, maintenance of response was high (Table). KM estimated 5-yr rate for PFS/OS was 49%/77%. TEAEs in ≥45% of CP-CML pts were rash 47%, abdominal pain 46%, and thrombocytopenia 46%. Most newly occurring AEs were observed within the first year. The incidence of any AOEs/serious AOEs for CP-CML pts was 29%/23%. Among CP-CML pts with no prior AOEs who had a prospective dose reduction, 17% (11/63) had a first AOE occurring after Oct ‘13. Conclusions: Long-term (5-yr) results from PACE demonstrate that ponatinib continues to show clinical benefit, irrespective of dose reductions, with deep and lasting responses in heavily pretreated CP-CML pts. Safety results were consistent with the safety profile across the ponatinib clinical program. Clinical trial information: NCT01207440. [Table: see text]

Abstract: Abstract 3749 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the uniformly TKI-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with CP-CML were evaluated in a pivotal phase 2, international, open-label clinical trial. Objectives: This prospectively defined analysis was performed to evaluate the impact that previous exposure to approved TKIs had on the efficacy and safety of ponatinib treatment among patients with CP-CML. Methods: The PACE trial enrolled 449 patients, including 270 patients with CP-CML. Enrolled patients were required to be resistant or intolerant (R/I) to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. Patients with CP-CML were assigned to 1 of 2 cohorts: R/I (N=203) or T315I (N=64). Three patients were post-imatinib and did not have T315I at baseline; they were treated but not assigned to a cohort. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 19] months). The efficacy and safety of ponatinib according to prior approved TKI therapy (imatinib, dasatinib, nilotinib) is presented for the total CP-CML (N=270) population. Results: The median age of CP-CML patients was 60 (18 to 94) years. Median time from initial diagnosis to start of ponatinib was 7 (0.5 to 27) years. Patients were heavily pretreated: 97% had received prior imatinib, 80% dasatinib, 68% nilotinib; 7% of patients had received 1 prior approved TKI, 40% 2 prior approved TKIs, 53% all 3 prior approved TKIs; 60% had received ≥3 prior approved/investigational TKIs. In patients previously treated with dasatinib or nilotinib (N=256), 84% had a history of resistance and 16% were purely intolerant to dasatinib or nilotinib. At the time of analysis, 66% of patients remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%) and progressive disease (7%). Response rates according to the number of prior approved TKIs are shown in the table below. Patients receiving fewer prior approved TKIs had higher response rates. The difference in MCyR rate was statistically significant for patients previously treated with 1 vs. 3 approved TKIs (p=0.003) and for patients previously treated with 2 vs. 3 approved TKIs (p=0.011). Differences in MMR rates were not statistically significant. Of patients achieving MCyR, 98% of patients receiving 2 prior approved TKIs and 83% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MCyR at 1 year. Of patients achieving MMR, 86% of patients receiving 2 prior approved TKIs and 80% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MMR at 1 year. Kaplan-Meier estimates were not calculable for patients receiving 1 prior TKI. The most common treatment-related AEs according to number of prior approved TKIs (1, 2, 3, respectively) were thrombocytopenia (32%, 38%, 44%), rash (37%, 37%, 39%), dry skin (37%, 36%, 39%), abdominal pain (21%, 26%, 28%), and headache (26%, 28%, 19%). Rash, dry skin, abdominal pain, and headache were generally grade 1 or 2 in severity. Thrombocytopenia was typically reported early in treatment and was manageable with or without dose reductions and/or dose interruptions. Conclusions: Ponatinib has substantial activity in patients with CP-CML, with higher response rates and improved tolerability observed in patients receiving fewer prior approved TKIs. Data with a minimum follow-up of 12 months will be presented. Disclosures: Kim: Novartis, BMS, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Pfizer: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding.