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Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. 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. This trial was registered at www.clinicaltrials.gov as #NCT01207440.

Ponatinib has potent activity against native and mutant BCR-ABL1, including BCR-ABL1T315I. The pivotal phase 2 Ponatinib Ph+ALL and CML Evaluation (PACE) trial evaluated efficacy and safety of ponatinib at a starting dose of 45 mg once daily in 449 patients with chronic myeloid leukemia (CML) or Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) resistant/intolerant to dasatinib or nilotinib, or with BCR-ABL1T315I. This analysis focuses on chronic-phase CML (CP-CML) patients (n = 270) with 56.8-month median follow-up. Among 267 evaluable patients, 60%, 40%, and 24% achieved major cytogenetic response (MCyR), major molecular response (MMR), and 4.5-log molecular response, respectively. The probability of maintaining MCyR for 5 years was 82% among responders. Dose reductions were implemented in October 2013 to decrease the risk of arterial occlusive events (AOEs); ≥90% of CP-CML patients who had achieved MCyR or MMR maintained response 40 months after elective dose reductions. Estimated 5-year overall survival was 73%. In CP-CML patients, the most common treatment-emergent adverse events were rash (47%), abdominal pain (46%), thrombocytopenia (46%), headache (43%), dry skin (42%), and constipation (41%). The cumulative incidence of AOEs in CP-CML patients increased over time to 31%, while the exposure-adjusted incidence of new AOEs (15.8 and 4.9 per 100 patient-years in years 1 and 5, respectively) did not increase over time. 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. This trial was registered at www.clinicaltrials.govas #NCT01207440.

BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ∼20% of total alleles (referred to as “low-level mutations”), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status.

BCR-ABL1 kinase domain mutations can confer resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). In preclinical studies, clinically achievable concentrations of the third-generation BCR-ABL1 TKI ponatinib inhibit T315I and all other single BCR-ABL1 mutants except T315M, which generates a single amino acid exchange, but requires 2 sequential nucleotide exchanges. In addition, certain compound mutants (containing ≥2 mutations in cis) confer resistance. Initial analyses based largely on conventional Sanger sequencing (SS) have suggested that the preclinical relationship between BCR-ABL1 mutation status and ponatinib efficacy is generally recapitulated in patients receiving therapy. Thus far, however, such analyses have been limited by the inability of SS to definitively identify compound mutations or mutations representing less than ∼20% of total alleles (referred to as “low-level mutations”), as well as limited patient follow-up. Here we used next-generation sequencing (NGS) to define the baseline BCR-ABL1 mutation status of 267 heavily pretreated chronic phase (CP)-CML patients from the PACE trial, and used SS to identify clonally dominant mutants that may have developed on ponatinib therapy (30.1 months median follow-up). Durable cytogenetic and molecular responses were observed irrespective of baseline mutation status and included patients with compound mutations. No single or compound mutation was identified that consistently conferred primary and/or secondary resistance to ponatinib in CP-CML patients. Ponatinib is effective in CP-CML irrespective of baseline mutation status.

Background: Chronic-phase chronic myeloid leukemia (CP-CML) patients treated with tyrosine kinase inhibitors (TKIs) can expect to achieve high response rates with 1st-line therapy. In 2nd line, however, as many as one-third of patients will not achieve optimal response, and over time, up to one-half of responders will lose response. For patients who require a 3rd line (3L) of therapy, ponatinib and bosutinib provide new treatment options. Relative efficacy and safety are considerations in selecting 3L treatment, and some physicians may reserve ponatinib for patients who fail 3L bosutinib. However, reserving ponatinib for 4th line (4L) after bosutinib may be associated with a decrease in efficacy. We used data from the PACE Phase 2 registrational trial of ponatinib to estimate the efficacy difference associated with reserving ponatinib for 4L after bosutinib failure versus using ponatinib as 3L therapy.

Levy: ARIAD Pharmaceuticals, Inc: Other: abstract publication value, advisory board speaking engagement, advisory board participation. McGarry:ARIAD: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc.: Employment, Equity Ownership, Other: Stock. Yang:ARIAD Pharmaceuticals, Inc: Employment. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership.

Talpaz: ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Cortes:ARIAD Pharmaceuticals, Inc., BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Shah:ARIAD, BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Hu:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Turner:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Druker:BMS: Research Funding; ARIAD Pharmaceuticals, Inc.: PI and co-investigator on clinical trials, PI and co-investigator on clinical trials Other; MolecularMD: Consultancy, Equity Ownership. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Mauro:ARIAD Pharmaceuticals, Inc.: Consultancy.

Mauro: ARIAD Pharmaceuticals, Inc.: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

Knickerbocker: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Dorer:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Talpaz:ARIAD, BMS, Sanofi. Incyte, Pfizer: Research Funding.

Mueller: ARIAD, Novartis, BMS: Consultancy, Honoraria, Research Funding. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Honoraria, Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding.

Levy: ARIAD Pharmaceuticals, Inc.: Consultancy, This ASH abstract publication value, advisory board speaking engagement, advisory board participation Other. McGarry:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Huang:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals Inc: Employment, Equity Ownership. Nieset:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership.

Lipton: Novartis, BMS, Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis, BMS, Pfizer, Teva: Consultancy. Off Label Use: Ponatinib is a BCR-ABL kinase inhibitor that has been approved by the US FDA for the treatment of adult patients with CML (all phases) or Ph+ ALL that is T315I-positive or for whom no other TKI therapy is indicated.. Chuah:Novartis, BMS: Honoraria. Assouline:Pfizer, Novartis: Honoraria, Research Funding. Etienne:Novartis, BMS,Pfizer, ARIAD Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nicolini:Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Le Coutre:ARIAD Pharmaceuticals, Inc., Novartis, BMS, Pfizer: Honoraria. Clark:Novartis, Sanofi Aventis: Speakers Bureau; Novartis, Pfizer, Sanofi Aventis: Honoraria; Novartis, BMS, Pfizer, Sanofi Aventis: Research Funding. Stenke:ARIAD Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Oehler:ARIAD Pharmaceuticals, Inc.: Advisory board Other. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani:ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria, Speakers Bureau; ARIAD, Novartis, BMS: Consultancy. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Kantarjian:ARIAD, Pfizer, Amgen: Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Deininger:BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy; BMA, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding.

Cortes: ARIAD Pharmaceuticals, Inc., BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Kim:ARIAD Pharmaceuticals, Inc.: Research Funding. Pinilla-Ibarz:Novartis, ARIAD, BMS, Pfizer: Speakers Bureau; Novartis, ARIAD: Research Funding. Le Coutre:ARIAD Pharmaceuticals, Inc., Novartis, BMS, Pfizer: Honoraria. Paquette:Novartis, BMS, ARIAD: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, BMS: Honoraria. Nicolini:Novartis, BMS, ARIAD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Apperley:ARIAD Pharmaceuticals, Inc., BMS, Novartis, Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Khoury:ARIAD Pharmaceuticals, Inc.: Honoraria, Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. DeAngelo:ARIAD, Novartis, BMS: Consultancy. Abruzzese:Novartis, BMS, ARIAD, Pfizer: Consultancy. Rea:Novartis, BMS, Pfizer, ARIAD: Honoraria. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, Novartis, BMS, Pfizer, Teva: Honoraria; ARIAD, Novartis, BMS, Pfizer, Teva: Speakers Bureau. Müller:Novartis, BMS, ARIAD: Consultancy, Honoraria, Research Funding. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Turner:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Kantarjian:ARIAD Pharmaceuticals, Inc., Pfizer, Amgen: Research Funding.

Pritchard: ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Hodgson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Baccarani:ARIAD, Novartis, BMS: Consultancy; ARIAD, BMS, Novartis, Pfizer, Teva: Honoraria, Speakers Bureau. Cortes:ARIAD, BMS, Novartis, Pfizer, Teva: Consultancy, Research Funding. Deininger:BMS, Novartis, Celgene, Genzyme, Gilead: Research Funding; BMS, ARIAD, Novartis, Incyte, Pfizer: Advisory Board, Advisory Board Other; BMS, ARIAD, Novartis, Incyte, Pfizer: Consultancy. Guilhot:ARIAD Pharmaceuticals, Inc.: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Hughes:Novartis, BMS, ARIAD Pharmaceuticals, Inc.: Honoraria, Research Funding. Shah:ARIAD Pharmaceuticals, Inc., BMS: Research Funding. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding. Clackson:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Haluska:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Knickerbocker:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership.

Background:Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) active against native and mutated forms of BCR-ABL, and is approved for patients with refractory CML and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia and those with the T315I mutant. Long-term follow-up of the anti-leukemic activity and safety of ponatinib in patients with CML or Ph+ ALL in this phase 1 clinical trial is reported.

Prior to the introduction of bosutinib and ponatinib, CP-CML patients who had failed 2 prior lines of TKI had limited treatment options with generally poor treatment response and outcomes. These newer TKIs are important additions to the treatment armamentarium, but the optimal choice of 3rd-line (3L) treatment has not been established. Clinical trials in patients who have failed 2 previous lines of TKI suggest ponatinib is more efficacious than bosutinib, but with a less favorable side-effect profile, requiring a potential benefit-risk tradeoff in treatment choice. Comparison of overall benefit-risk from available clinical trial data is challenging due to single- arm designs, low overall mortality, disparate impact of characteristic side-effects, and the likely crossover/sequential use of alternative TKIs among patients discontinuing therapy. We therefore examined efficacy outcomes previously validated as predictors of long-term survival, as well as treatment duration and reason for study drug discontinuation, as surrogates for overall benefit-risk in 3L CP-CML patients treated with ponatinib vs. bosutinib.

Background:

Background: Ponatinib is an approved potent oral tyrosine kinase inhibitor active against native and mutated forms of BCR-ABL, including T315I. The phase 2 PACE study demonstrated that ponatinib is highly active in heavily pretreated Philadelphia chromosome‒positive leukemia patients. Ponatinib efficacy and safety were evaluated in newly diagnosed CP-CML patients in the EPIC trial.

The efficacy and safety of subsequent TKIs in pts who have experienced failure of dasatinib is not fully known. Ponatinib, a pan-BCR-ABL inhibitor, was evaluated in a phase 2, international, open-label clinical trial (PACE). This post-hoc analysis explored the efficacy and safety of ponatinib following failure of dasatinib in CP-CML pts in the PACE trial.The PACE trial enrolled 449 pts, including 270 with CP-CML. Pts had to be resistant or intolerant to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. The primary endpoint in CP-CML was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 1 April 2013 are reported, with a minimum follow-up of 18 months for pts remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 107 CP-CML pts following failure of dasatinib as the most recent prior therapy, irrespective of other TKI therapy, is presented (Group D). Eighteen pts who experienced failure of dasatinib but received ≥1 anticancer therapy, other than hydroxyurea or anagrelide, prior to ponatinib treatment were excluded from the analyses. Data are also presented for 2 subsets of Group D: 52 pts whose only TKI therapy was imatinib followed by dasatinib (Group I-D), and 46 pts whose only TKI therapy was imatinib, then nilotinib, and then dasatinib (Group I-N-D). An analysis of cross-intolerance was also conducted in 69 pts with prior dasatinib treatment at any time who discontinued dasatinib due to intolerance.Baseline characteristics are shown in the table. Group I-D tended to be younger, with less time since diagnosis versus Group I-N-D. At the time of analysis, 60%, 65%, and 54% of pts in Groups D, I-D, and I-N-D remained on study. The most common reasons for discontinuation were adverse events (AEs; 16%, 15%, 17%) and progressive disease (9%, 6%, 11%) in Groups D, I-D, and I-N-D. Efficacy end points are shown in the table. In Group D, MCyR was seen in pts with the following dasatinib-resistant mutations at baseline: V299L, 3/4 (75%); T315I, 17/23 (74%); F317L, 3/10 (30%). The most common treatment-related AEs were thrombocytopenia (44%, 37%, 57%), rash (39%, 39%, 39%), and dry skin (39%, 29%, 52%) in Groups D, I-D, and I-N-D. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 3% of pts in Group D (treatment-related: 3%, 1%, 0%). Seventy-three of 217 pts receiving prior dasatinib at any time discontinued dasatinib due to intolerance. Of these 73 pts, 27 experienced the same AE(s) with ponatinib that led to dasatinib intolerance; 12 pts had grade 3/4 thrombocytopenia, 6 pts had other grade 3/4 AEs (3 with neutropenia, 1 each with pleural effusion, dyspnea, pulmonary hypertension), 8 pts had grade 1/2 AEs. Six of these 27 pts discontinued ponatinib due to the same AE that led to dasatinib intolerance. Thrombocytopenia was the primary AE involved in cross-intolerance (4 pts); congestive cardiac failure (grade 5) and pleural effusion each occurred once.Ponatinib has substantial activity in pts with CP-CML following failure of dasatinib, with a safety profile reflective of this heavily pretreated population. Cross-intolerance between dasatinib and ponatinib was infrequent.Hochhaus: Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. 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. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad and Teva: Consultancy; Novartis & Bristol Myers Squibb: 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. 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. 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, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. 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: 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. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. Kantarjian:RIAD, Novartis, BMS, Pfizer: Research Funding.

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.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.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.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.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.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.

In CML, the presence of BCR-ABL kinase domain (KD) mutations, including low-level mutations, can predict clinical responses to 2nd line BCR-ABL tyrosine kinase inhibitors (TKIs). In addition, sequential treatment with TKIs can lead to development of compound mutations (≥2 mutations in the same BCR-ABL allele) that can be highly TKI-resistant. Ponatinib is a potent BCR-ABL TKI that, preclinically, has demonstrated activity against all BCR-ABL mutations tested and suppresses the emergence of any single mutation at clinically achievable concentrations (40 nM with ≥30 mg/d). In vitro, higher ponatinib concentrations were required to suppress emergence of certain compound mutations on a background of T315I or E255V single mutations. We evaluated the impact of single, low-level, and compound mutations at BL on responses to ponatinib and EOT mutations in CP-CML pts in the phase 2 PACE trial.Pts with CP-CML (93% received ≥2 prior TKIs, 60% ≥3) resistant or intolerant to dasatinib and/or nilotinib (N=203) or with T315I confirmed at BL (N=64) were enrolled. The primary endpt was major cytogenetic response (MCyR) by 12 mos. Median follow-up at analysis (1 Apr 2013) was 20 (0.1-28) mos, with a minimum follow-up of 18 mos for pts remaining on study. Next generation sequencing (NGS) and Sanger sequencing (SS) were done at a central laboratory. NGS was conducted on all BL samples (N=267) with the Ion Torrent PGM using chemistry that enabled read lengths up to 400 bp for detection of compound mutations; mutations observed at a frequency ≥1% are reported. SS was conducted on both BL and EOT samples.By NGS at BL, 267 mutations (amino acid substitutions in the ABL KD [M237-E507]) were detected among 163 (61%) pts; 106 (40%) mutations were low level mutations not detected by SS. 75 unique single mutations were observed: 27 were detected by SS and NGS, all 27 have been associated with resistance to TKIs other than ponatinib; 48 were low level mutations detected only by NGS, 5 have been associated with resistance to TKIs other than ponatinib. 12% of pts had only low level mutations. Overall, no mutations were detected in 39% of pts, 1 mutation in 37%, and ≥2 mutations in 24%. Compound mutations were detected in 65% of pts who had ≥2 mutations, representing 15% of pts overall (10% with 1, 5% with 2 to 4 compound mutations). 48 unique compound mutations were observed; T315I, F317L, and F359C/I/V were the most commonly observed mutations within compound mutations.Responses were seen in pts with each of the 20 unique single mutations present in >1 pt at BL by NGS, including Y253H, E255V/K, T315I, M351T, F359V. Responses were observed regardless of overall NGS BL mutation status (table). The high response rates and durability of response in pts with compound mutations suggest that, in general, the presence of compound mutations at BL did not adversely affect the activity of ponatinib.Of the 109 pts who discontinued, 84 had successful mutation assessments by SS at or near the EOT visit. 4 pts had mutations at EOT that were not detected by NGS at BL; all 4 involved compound mutations (T315I/F359V [100%/90%], T315I/M351T [100%/40%], Y253H/F359V [100%/100%; n=2]), with one or both of the involved mutations detected individually at BL or by history. Overall, 12 pts lost MCyR (none with T315I at BL); 6 of the 12 discontinued and had EOT mutations assessed, no changes from BL were observed.Responses to ponatinib were observed regardless of BL mutation status. Interestingly, responses tended to be lower in pts without mutations, suggesting that BCR-ABL independent mechanisms may be involved. No single mutation conferring resistance to ponatinib in CP-CML has been observed to date. In general, ponatinib activity was not adversely affected by the presence of compound mutations at BL. Rarely, the development of compound mutations was observed at EOT in pts with one of the involved mutations at BL or by history. Early introduction of ponatinib may suppress the emergence of single BCR-ABL mutations, and, as a result, the development of compound mutations. NCT01207440Deininger: BMS, ARIAD, NOVARTIS: Consultancy; BMS, NOVARTIS, CELGENE, GILEAD: Research Funding; ARIAD, NOVARTIS: Advisory Boards, Advisory Boards Other. Shah:Ariad, Bristol-Myers Squibb: Consultancy, Research Funding. 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. 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. 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. 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. Lustgarten: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. Hodgson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Goldman:ARIAD: Honoraria. Kantarjian:ARIAD, Novartis, BMS, Phizer: Research Funding. Soverini:Novartis, BMS, ARIAD: Consultancy. Hochhaus:Ariad, Novartis, BMS, MSD, Pfizer: Research Funding; Novartis, BMS, Pfizer: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Branford:Novartis, BMS, ARIAD: Research Funding; Novartis, BMS, ARIAD: Honoraria.

Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in the phase 2, international, open-label clinical trial (PACE) in pts with CML or Ph+ ALL.449 pts resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled. Five pts (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses only. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos for CP-CML, major hematologic response (MaHR) at any time within 6 mos for advanced Ph+ leukemia. Data are as of 1 April 2013, with a median follow-up of 19 (0.1-30) mos, and 18 mos minimum follow-up for pts remaining on study.Median age was 59 (18-94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3-28) yrs. Pts were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib, 7% bosutinib; 58% received ≥3 TKIs. In pts previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance, 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, 23% MaHR or better in advanced Ph+ leukemia. The most common BCR-ABL mutations at baseline were 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44% of pts (Sanger sequencing). At the time of analysis, 46% of pts remained on study (60% CP-CML). The most common reasons for discontinuation: progressive disease (20%), adverse events (AEs; 13%; most common was thrombocytopenia, 4%). Response rates are shown in the table. Response rates were higher in CP-CML T315I vs R/I cohorts, however, a post-hoc multivariate analysis previously showed that T315I was not an independent predictor of MCyR. Other features, especially higher dose intensity and younger age in T315I pts, may explain the higher response rates. In CP-CML, responses were deep and durable; 91%, 91%, and 75% of pts with MCyR, CCyR, or MMR, respectively, were estimated to remain in response at 12 mos; progression-free survival (PFS) and overall survival (OS) were estimated to be 80% (median 27 mos) and 94% at 12 mos, respectively; progression to AP/BP occurred in 3 CP-CML pts , 2 other pts with a history of AP re-entered AP. 49% of AP-CML pts with MaHR were estimated to remain in response at 12 mos (median 12 mos); PFS and OS were estimated to be 56% (median 14 mos) and 84% at 12 mos. 36% of BP-CML pts with MaHR were estimated to remain in response at 12 mos (median 5 mos); PFS and OS were estimated to be 18% (median 4 mos) and 30% (median 7 mos) at 12 mos. 8% of Ph+ ALL pts with MaHR were estimated to remain in MaHR at 12 mos (median 3 mos); PFS and OS were estimated to be 7% (median 3 mos) and 39% (median 8 mos) at 12 mos. The most common drug-related AEs (>30%) were thrombocytopenia (37%), rash (34%), and dry skin (32%). Pancreatitis was the most common drug-related serious AE (5%); it occurred early and was primarily managed with dose modification, 1 pt discontinued. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 3%, and 2% of pts (drug-related: 2%, 1%, 1%).Ponatinib has substantial activity in these heavily pretreated Ph+ leukemia pts who have limited available treatment options, with a safety profile reflective of the population. Updated data with a minimum follow-up of 2 yrs will be presented.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. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD, BMS, Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Ariad, Teva, Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis, BMS, Teva: Speakers Bureau; Novartis, BMS, Teva, Pfizer, Ariad: Honoraria; Novartis & Bristol Myers Squibb: Research Funding; Novartis, Ariad and Teva: Consultancy. Apperley:Novartis: Research Funding; Ariad, Bristol Myers Squibb, Novartis, Pfizer, Teva: Honoraria. 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. 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, Speakers Bureau. Müller:Novartis, BMS, Ariad: Consultancy, Honoraria; Novartis, BMS: Research Funding. 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: 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.

Information is generally lacking regarding the efficacy and safety of subsequent TKIs after failure of nilotinib. This post-hoc analysis explored the efficacy and safety of ponatinib, a potent oral pan-BCR-ABL inhibitor, following failure of nilotinib in CP-CML patients in the phase 2 PACE trial.

Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) with activity against native and mutant BCR-ABL. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial.To review the management of treatment-related AEs (TRAEs) that emerged during therapy with ponatinib in the PACE trial.A total of 270 CP-CML pts (267 in efficacy population) resistant or intolerant to dasatinib or nilotinib or with the T315I mutation were enrolled in this ongoing, phase 2, international, open-label clinical trial. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 mos. Safety monitoring included collection of AEs, and the following variables were evaluated: incidence, severity, time to onset, duration, and management. Select TRAEs are discussed. Data as of 01 Apr 2013 are reported, with a median follow-up of 20 (0.1–28) mos. Minimum follow-up for pts remaining on study was 18 mos.Median age was 60 (18-94) yrs; median time from diagnosis to first dose was 7 (0.5-27) yrs; 93% had =2 prior TKIs, 60% =3. Ponatinib demonstrated significant activity in CP-CML pts: 56% MCyR, 46% CCyR, and 36% MMR. At the time of analysis, 60% of pts remained on study. The most frequent reasons for discontinuation were AEs (14%) and progression (8%).The most common hematologic TRAE was thrombocytopenia (41% any grade, 32% grade 3/4). The incidence by time to initial onset is shown below (Figure). Pts experienced thrombocytopenia for a median total duration of 166 days (64% of whom had >1 event) and typically required dose modification: 13% drug withdrawn, 40% dose reduced, 29% dose interrupted only, 17% no dose modification. Among pts with thrombocytopenia, 27% required a platelet transfusion. Thirteen percent of CP-CML pts experienced treatment-related neutropenia and thrombocytopenia.The most common nonhematologic TRAE was rash (39% any grade, 4% grade 3/4), which includes erythematous, macular, and papular rash. Pts experienced rash for a median total duration of 65 days (46% of whom had >1 event) and most did not require dose modification: 0% drug withdrawn, 15% dose reduced, 11% dose interrupted only, 73% no dose modification. One additional pt discontinued due to grade 2 treatment-related exfoliative rash.Pancreatitis was observed (7% any grade, 6% grade 3/4). Median duration was 5 days. Pts were typically managed with dose modification: 5% drug withdrawn, 58% dose reduced, 32% dose interrupted only, 5% no dose modification.Treatment-emergent cardiovascular events were observed in 8% of pts and treatment-emergent cerebrovascular or peripheral vascular events in 11%. Cardiovascular events were considered treatment-related in 4%; cerebrovascular or peripheral vascular events were also considered treatment-related in 4%. The median time to initial onset was 9 mos for cardiovascular and 11 mos for cerebrovascular or peripheral vascular events. The median duration was 6 and 97 days, respectively. Management of pts with cardiovascular AEs: 20% drug withdrawn, 10% dose reduced, 40% dose interrupted only, 30% no dose modification. Management of pts with cerebrovascular or peripheral vascular AEs: 8% drug withdrawn; 8% dose reduced; 17% dose interrupted only; 67% no dose modification.Ponatinib has robust antileukemic activity in heavily pretreated CP-CML pts (93% of whom received =2 prior TKIs). Treatment-related thrombocytopenia and pancreatitis generally occurred early in therapy and were manageable with dose modification. Treatment-related rash generally occurred early in therapy, was mild-to-moderate in severity, managed without the need for dose modification, and rarely led to discontinuation. Management of treatment-related arterial thrombotic events varied; pts with predisposing cardiovascular risk factors should be monitored closely and managed accordingly. ClinicalTrials.gov ID: NCT01207440 aIncidence = (number of pts with initial onset during time interval) / (number of pts dosed during time interval [N] excluding those who previously experienced the event) X 100Le Coutre: Novartis: Research Funding; Novartis, BMS, Pfizer: Honoraria. 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. Pinilla-Ibarz:Novartis, Ariad: Research Funding; Novartis, Ariad, BMS and Pfizer: Speakers Bureau. 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. 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. DeAngelo:Ariad, 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. Yanase: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. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding.

The efficacy and safety of subsequent TKIs in pts who have experienced failure of dasatinib is not fully known. Ponatinib, a pan-BCR-ABL inhibitor, was evaluated in a phase 2, international, open-label clinical trial (PACE). This post-hoc analysis explored the efficacy and safety of ponatinib following failure of dasatinib in CP-CML pts in the PACE trial.

Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) with activity against native and mutant BCR-ABL. The efficacy and safety of ponatinib (45 mg once daily) in pts with CP-CML were evaluated in the phase 2 PACE trial.

Information is generally lacking regarding the efficacy and safety of subsequent TKIs after failure of nilotinib. This post-hoc analysis explored the efficacy and safety of ponatinib, a potent oral pan-BCR-ABL inhibitor, following failure of nilotinib in CP-CML patients in the phase 2 PACE trial.The PACE trial enrolled 449 patients, including 270 with CP-CML. Patients had to be resistant or intolerant to dasatinib or nilotinib, or have the T315I mutation at baseline. The primary end point in CP-CML was MCyR at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 1 April 2013 are reported, with a minimum follow-up of 18 months for patients remaining on study. The efficacy and safety of ponatinib (45 mg QD) in 106 CP-CML patients following failure of nilotinib as the most recent prior anticancer therapy, irrespective of other TKI therapy, is presented (Group N). Eleven patients who experienced failure of nilotinib but received ≥1 anticancer therapy, other than hydroxyurea or anagrelide, prior to ponatinib treatment were excluded from the analyses. Data are also presented for 2 subsets of Group N: 33 patients whose only TKI therapy was imatinib followed by nilotinib (Group I-N), and 68 patients whose only TKI therapy was imatinib, then dasatinib, and then nilotinib (Group I-D-N). An analysis of cross-intolerance was also conducted in 43 patients with prior nilotinib treatment at any time who discontinued nilotinib due to intolerance.Baseline characteristics are shown in the table. Group I-N tended to be younger, with less time since diagnosis versus Group I-D-N. At the time of analysis, 59%, 64%, and 56% of patients in Groups N, I-N, and I-D-N remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%, 12%, 13%) and progressive disease (9%, 6%, 9%) in Groups N, I-N, and I-D-N. Efficacy endpoints are shown in the table. In Group N, MCyR was observed in patients with the following nilotinib-resistant mutations at baseline: Y253H, 1/2 (50%); E255K, 5/6 (83%); T315I, 12/22 (55%); F359V, 3/7 (43%); F359C, 1/2 (50%); F359I, 2/3 (67%). The most common treatment-related AEs were thrombocytopenia (38%, 33%, 40%), rash (35%, 30%, 37%), and dry skin (35%, 42%, 31%) in Groups N, I-N, and I-D-N. Serious cardiovascular, cerebrovascular, and peripheral vascular AEs occurred in 6%, 4%, and 2% of patients in Group N (treatment-related: 3%, 1%, 2%). Forty-four of 184 patients discontinued prior nilotinib at any time due to intolerance. Of these 44 patients, 24 experienced the same AE(s) with ponatinib that led to nilotinib intolerance; 12 patients had grade 3/4 thrombocytopenia, 6 patients had other grade 3 AEs (2 with dyspnea, 1 each with atrial fibrillation, musculoskeletal pain, abdominal pain, pain in extremity), 6 patients had grade 1/2 AEs. 7 of the 24 patients discontinued ponatinib due to the same AE that led to nilotinib intolerance. Thrombocytopenia (5 patients) was the primary AE involved in cross-intolerance; atrial fibrillation and pain in extremity each occurred once.Ponatinib has substantial activity in patients with CP-CML following failure of nilotinib, with a safety profile reflective of this heavily pretreated population. Cross-intolerance between nilotinib and ponatinib was infrequent.Kantarjian: ARIAD: Research Funding; Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding. Cortes:Ariad, Pfizer, Teva: Consultancy; Ariad, BMS, Novartis, Pfizer, Teva: Research Funding. Kim:BMS: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; IL-Yang: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Research Funding. Pinilla-Ibarz:Novartis: Research Funding, Speakers Bureau; ARIAD: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Pfizer: Speakers Bureau. le Coutre:Novartis: Research Funding; Novatis, BMS, Pfizer: Honoraria. Paquette:ARIAD: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Chuah:Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Nicolini:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; ARIAD: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Teva: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Apperley:Novartis: Honoraria, Research Funding; ARIAD: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Teva: Honoraria. 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. DeAngelo:ARIAD: Consultancy; Novartis: Consultancy; BMS: Consultancy. Abruzzese:BMS, Novartis: Consultancy. Rea:Pfizer: Honoraria; ARIAD: Honoraria; Teva: Honoraria; Novartis: Honoraria; BMS: Honoraria. Baccarani:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Teva: Honoraria, Speakers Bureau. Müller:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; ARIAD: Consultancy, Honoraria. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; BMS: Honoraria. ARIAD: Employment. Rivera:ARIAD: 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: Consultancy, Research Funding; ARIAD: advisory board, advisory board Other, Consultancy; Novartis: advisory board, advisory board Other, Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding. Hochhaus:Pfizer: Honoraria, Research Funding; ARIAD: Research Funding; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; MSD: Research Funding. Hughes:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding. Goldman:Ariad: Honoraria. Shah:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding.

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.

In CML, the presence of BCR-ABL kinase domain (KD) mutations, including low-level mutations, can predict clinical responses to 2ndline BCR-ABL tyrosine kinase inhibitors (TKIs). In addition, sequential treatment with TKIs can lead to development of compound mutations (≥2 mutations in the same BCR-ABL allele) that can be highly TKI-resistant. Ponatinib is a potent BCR-ABL TKI that, preclinically, has demonstrated activity against all BCR-ABL mutations tested and suppresses the emergence of any single mutation at clinically achievable concentrations (40 nM with ≥30 mg/d). In vitro, higher ponatinib concentrations were required to suppress emergence of certain compound mutations on a background of T315I or E255V single mutations. We evaluated the impact of single, low-level, and compound mutations at BL on responses to ponatinib and EOT mutations in CP-CML pts in the phase 2 PACE trial.

Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in the phase 2, international, open-label clinical trial (PACE) in pts with CML or Ph+ ALL.

Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial.449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months.Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 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. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis).Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented.Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, 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, 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:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: 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, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, 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; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

Many patients (pts) with advanced Ph+ leukemias experience failure of all currently available tyrosine kinase inhibitors (TKIs) targeting BCR-ABL and have limited treatment options. 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 pts with AP-CML, BP-CML, or Ph+ ALL were evaluated in a phase 2, international, open-label clinical trial.The PACE trial enrolled 449 pts, including 85 AP-CML, 62 BP-CML, and 32 Ph+ ALL. Pts were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I mutation at baseline. AP-CML, BP-CML, and Ph+ ALL pts were assigned to 1 of 4 cohorts: AP-CML R/I, AP-CML T315I, BP-CML/Ph+ ALL R/I, BP-CML/Ph+ ALL T315I. Two AP-CML pts were not assigned to a cohort (post-imatinib, did not have T315I at baseline) and were excluded from efficacy analyses and included in safety analyses. The primary endpoint was major hematologic response (MaHR) at any time within 6 mos after treatment initiation. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 mos (median 13 [4 to 21], 6 [0.1 to 18], and 6 [0.1 to 16] mos for AP-CML, BP-CML, and Ph+ ALL, respectively).The median age for AP-CML, BP-CML, and Ph+ ALL pts was 60, 53, and 62 yrs, respectively. Median time from initial disease diagnosis to start of ponatinib was 7, 4, and 1.5 yrs, respectively. Pts were heavily pretreated: 94% received prior imatinib, 88% dasatinib, 61% nilotinib; 8% received 1 prior approved TKI, 39% received 2, and 53% received 3. Sixteen percent had undergone prior stem cell transplant. In pts previously treated with dasatinib or nilotinib (N=171), 94% had a history of resistance to dasatinib or nilotinib, 6% were purely intolerant. Reported MaHR rates with the most recent dasatinib or nilotinib therapy were 35% AP-CML, 16% BP-CML, 43% Ph+ ALL.At the time of analysis, 59% of AP-CML, 8% of BP-CML, and 9% of Ph+ ALL pts remained on study. Overall, the most common reasons for discontinuation were progressive disease (19%, 50%, and 53%, respectively) and adverse events (AEs; 11%, 16%, and 6%, respectively). Hematologic and cytogenetic response rates are shown in the table; MaHR and MCyR were observed across cohorts. MMR was achieved by 14% of AP-CML pts (14% R/I, 17% T315I). There was a trend for higher response rates among pts who received fewer prior approved TKIs. In AP-CML pts, the differences in MaHR rates by number of prior approved TKIs (1: 3/4 [75%]; 2: 20/33 [61%]; 3: 24/46 [52%]) were not significant (Fisher's Exact); differences in MCyR rates (1: 4/4 [100%]); 2: 13/33 [39%]; 3: 15/46 [33%]) were significant for pts treated with 1 vs 2 (p=0.0360) and 1 vs 3 prior approved TKIs (p=0.0168).Of pts achieving MaHR, 42% of AP-CML and 35% of BP-CML/Ph+ ALL pts were projected (Kaplan-Meier) to remain in MaHR at 1 yr. In AP-CML, the median progression-free survival (PFS) was estimated (Kaplan-Meier) as 80 (range 6 to 88) wks; the probability of maintaining PFS at 6 mos and 1 yr was estimated as 80% and 57%, respectively. Median overall survival (OS) had not yet been reached; the probability of OS at 6 mos and 1 yr was estimated (Kaplan-Meier) as 96% and 85%, respectively. In BP-CML/Ph+ ALL, median PFS was estimated as 18 (range 0.1 to 74) wks; the probability of maintaining PFS at 6 mos and 1 yr was estimated as 34% and 20%, respectively. Median OS was estimated as 30 (range 0.4 to 77) wks; the probability of OS at 6 mos and 1 yr was estimated as 54% and 34%, respectively. Ponatinib was generally well-tolerated; the most common treatment-related AEs were thrombocytopenia (29%), rash (25%), and neutropenia (22%). The most common serious treatment-related AEs were thrombocytopenia (3%) and pancreatitis (3%). Rash was generally grade 1 or 2 in severity. Thrombocytopenia, neutropenia, and pancreatitis were typically reported early in treatment and were manageable with dose modification.Ponatinib was generally well-tolerated and had substantial activity in pts with AP-CML, BP-CML, or Ph+ ALL, regardless of mutation status or prior therapy. Data with a minimum follow-up of 12 mos will be presentedKantarjian: Novartis: Consultancy; Pfizer: Research Funding; BMS: Research Funding; Novartis: Research Funding; ARIAD: Research Funding. Off Label Use: ponatinib. 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: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, Amgen: Honoraria. Shah:ARIAD Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding.

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).To evaluate the patterns of molecular response in patients treated with ponatinib in the PACE trial.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).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.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.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.

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.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.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.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.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.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.

Ponatinib is a potent, oral, pan-BCR-ABL inhibitor with activity against native and mutant forms of BCR-ABL, including the tyrosine kinase inhibitor (TKI)-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally QD) were evaluated in a phase 2, international, open-label clinical trial (PACE). These multivariate analyses explored the impact of dose intensity and several prognostic and predictive factors on clinical responses, adverse events (AEs), and laboratory changes.Enrolled patients were resistant or intolerant (R/I) to dasatinib or nilotinib, or had the T315I BCR-ABL mutation at baseline. A total of 267 chronic phase (CP), 83 accelerated phase (AP), and 94 blast phase (BP) CML/Ph+ ALL patients were assigned to 1 of 6 cohorts according to disease phase (CP-, AP-, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Three CP-CML and 2 AP-CML patients were treated, but not assigned to a cohort (post-imatinib, did not have T315I at baseline); these patients were excluded from efficacy analyses and included in safety analyses. For the purposes of the efficacy multivariate analyses, AP-CML, BP-CML, and Ph+ ALL patients were combined. The baseline covariates analyzed were age, time since diagnosis, number of prior TKIs, presence or absence of the T315I mutation, neutrophil and platelet counts, and weight. The primary efficacy outcome analyzed was major cytogenetic response (MCyR) in CP-CML and major hematologic response (MaHR) for all other patients. The safety outcomes analyzed were the following AEs: pancreatitis, elevated lipase, alanine aminotransferase (ALT) increase, aspartate aminotransferase (AST) increase, rash, neutropenia, thrombocytopenia, arthralgia, and hypertriglyceridemia. The impact on neutrophils, platelets, bilirubin, ALT, AST, creatinine, lipase, and triglycerides was also examined. Binary event outcomes were analyzed using logistic regression models. Data values over time were analyzed using linear mixed effects models. Laboratory values were log-transformed. Data as of 27 April 2012 were used in these analyses.Median baseline characteristics of the CP-CML R/I and T315I cohorts, respectively, were: 61 vs 51 yrs of age, 8 vs 5 yrs since initial diagnosis, 3 vs 2 prior TKIs. The median dose intensity for the CP-CML R/I and T315I cohorts was 30 and 39 mg/day, respectively. In general, other baseline characteristics were balanced between these 2 cohorts. Multivariate analysis found statistically significant associations between MCyR and increasing dose intensity (mg/day) (p<0.0001) and decreasing age (p=0.046) in CP-CML. Despite the finding that CP-CML patients with the T315I mutation had a higher response rate than those without the T315I mutation (MCyR 70% vs 49%), presence of T315I was not a significant prognostic factor for response after adjusting for other covariates (p>0.2). This was likely because patients with T315I received a greater dose intensity, were younger, and were previously treated with fewer TKIs.The probability of achieving MaHR in patients with AP-CML, BP-CML, and Ph+ ALL increased with increasing dose intensity (p<0.001) and with higher numbers of baseline platelets (p=0.0046). As in CP-CML, similar trends in baseline characteristics were observed, and the presence of the T315I mutation was not a significant prognostic factor for MaHR.In all patients, the probability of AEs (pancreatitis, lipase increase, ALT and AST increase, thrombocytopenia, neutropenia, arthralgia, and rash) increased with increasing dose intensity. Hypertriglyceridemia was trend level associated with dose intensity (p=0.054). Presence of T315I was associated with a lower risk of thrombocytopenia (p<0.0001) and neutropenia (p=0.005) after adjustment for dose intensity and the other factors. In general, younger age, less time since diagnosis, and fewer prior TKIs were associated with a lower probability of AEs.These findings suggest that dose intensity and factors related to extent of disease and prior treatment were most predictive of effectiveness and tolerance of ponatinib. T315I was not a significant prognostic factor for efficacy or safety after adjustment for other factors, with the exception of thrombocytopenia and neutropenia; patients with T315I had lower predicted rates of these AEs after adjustment for dose intensity and other factors in the reduced models.Off Label Use: Ponatinib - non FDA approved (experimental) compound. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, 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 : Research Funding, Speakers Bureau; Bristol-Myers Squibb: 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, and Teva: 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; Bristol Myers-Squibb: 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:Bristol Myers-Squibb and Novartis: 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. Dorer:ARIAD: Employment, Equity Ownership. Knickerbocker:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: 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, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:Novartis: Consultancy; Bristol Myers-Squibb: Consultancy, Research Funding; ARIAD: Consultancy, Research Funding. Kantarjian:Pfizer: Research Funding; ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding.

Tyrosine kinase inhibitors (TKIs) are the mainstay of therapy for patients (pts) diagnosed with Philadelphia chromosome-positive (Ph+) leukemia. Failure of therapy may occur as a result of intolerance or resistance. Ponatinib is a potent oral pan-BCR-ABL inhibitor that is active against native BCR-ABL, as well as mutated forms of the protein, including the uniformly refractory T315I mutant.In this ongoing, open-label, dose escalation, phase 1 clinical trial, the safety and anti-leukemic activity of ponatinib were evaluated in pts with Ph+ leukemia and other hematologic malignancies who were refractory or resistant to available therapy or for whom no therapies were available. Pts (N=81) at least 18 yrs of age were enrolled from June 2008 through October 2010. Ponatinib was administered once daily at doses from 2–60 mg. Long-term follow-up of pts with chronic myeloid leukemia (CML) and Ph+ acute lymphoblastic leukemia (ALL) is reported. At the time of analysis (March 23, 2012), the median follow-up among these pts was 19.4 (0.5 to 38) mos.A total of 65 pts with Ph+ leukemia received ponatinib. Of those, 43 had chronic phase CML (CP-CML), 9 had accelerated phase CML (AP-CML), 8 had blast phase CML (BP-CML), and 5 had Ph+ ALL. Fifty-seven percent of pts were male, the median age was 55 yrs, and the median time from diagnosis to first dose was 6.5 (0.8 to 24) yrs. Previous therapies included imatinib (97%), dasatinib (89%), and nilotinib (55%); 94% had experienced failure of ≥2 prior TKIs and 63% had experienced failure of ≥3 prior TKIs. At study entry, baseline BCR-ABL mutations were detected in 42 of 65 (65%) pts; the most common were T315I (19/65; 29%) and F317L (7/65; 11%). Thirty-three (51%) pts remained on therapy (CP-CML [n=31]; AP-CML [n=2]). The most common reasons for discontinuation were disease progression (17%, n=11) and adverse events (AEs; 13.8%, n=9). The AEs observed in this long-term follow-up, as well as their respective incidences, are consistent with those observed in earlier analyses. The most common treatment-related AEs were rash (42%, n=27), thrombocytopenia (32%, n=21), arthralgia (20%, n=13), as well as increased serum lipase and fatigue (18%, n=12 for both). Among the 43 CP-CML pts, 42 (98%) achieved or maintained complete hematologic response (CHR), including all 26 pts who entered the study with CHR. Thirty-one (72%) pts had major cytogenetic response (MCyR), 28 (65%) with complete cytogenetic response (CCyR). Nineteen (44%) pts achieved major molecular response (MMR), including 10 pts who achieved MR4 (4-log reduction of BCR-ABL transcripts). Significant activity was also seen among CP-CML pts with T315I: CHR (12/12, 100%), MCyR (11/12, 92%), CCyR (10/12, 83%), and MMR (8/12, 67%). The duration of response among CP-CML pts ranged from 1.8 to 35.7+ mos for MCyR and from 3.7 to 29.7+ mos for MMR (median not reached for MCyR or MMR). The median follow-up among the 43 CP-CML pts was 23.3 mos; 27 of 31 CP-CML pts who had MCyR remained on study, with 25 in continuous MCyR; 18 of 19 pts who achieved MMR remained on study, with 12 in continuous MMR. Estimates (Kaplan-Meier) suggest that 83% of MCyR responders and 55% of MMR responders will maintain their response at 2 yrs. For pts with T315I, the 2-yr estimates are 82% for MCyR and 50% for MMR. Among the 22 advanced disease pts (AP-CML, BP-CML, or Ph+ ALL), 8 of 20 (40%) achieved MHR (2 pts with MHR at baseline excluded), and 7 (32%) pts had MCyR, including 4 who achieved CCyR. The median duration of MHR in advanced pts was 3.6 (0.02 to 14.7) mos. The impact of ponatinib exposure and other factors (eg, age) on the development of AEs and anti-leukemic activity was examined in exploratory multivariate analyses. The models varied by disease type, but data generally suggest that higher ponatinib plasma concentration, younger age, less pretreatment, and higher dose intensity are positively correlated (P < 0.2) with response; higher exposure was also correlated with pancreatitis, increased serum lipase, rash, and neutropenia. Pts who were younger and less heavily pretreated showed a general trend toward lower AE rates.Ponatinib induced high response rates in heavily pretreated pts with resistant or refractory CP-CML (including those with the T315I mutation); responses to ponatinib were durable. Ponatinib was generally well tolerated, and no new safety findings have emerged during long-term follow-up. Updated data will be presented.Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding. Shah:ARIAD, Bristol Myers-Squibb, and Novartis: Consultancy, Research Funding. Flinn:ARIAD Pharmaceuticals, Inc.: Research Funding. Hu:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Dorer:ARIAD: 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. Druker:ARIAD: OHSU receives clinical trial funding. Dr. Druker is currently principal investigator or co-investigator on Novartis, Bristol-Myers Squibb, and ARIAD clinical trials. His institution has contracts with these companies to pay for patient costs, nurse and da Other; Bristol-Myers Squibb: OHSU receives clinical trial funding, OHSU receives clinical trial funding Other; Novartis: OHSU receives clinical trial funding, OHSU receives clinical trial funding Other; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Scientific Founder; OHSU and Dr. Druker have a financial interest in MolecularMD. OHSU has licensed technology used in some of these clinical trials to MolecularMD. This potential individual and institutional conflict of interest has been reviewed and man, Scientific Founder; OHSU and Dr. Druker have a financial interest in MolecularMD. OHSU has licensed technology used in some of these clinical trials to MolecularMD. This potential individual and institutional conflict of interest has been reviewed and man Other. Talpaz:ARIAD: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Millenium: Research Funding; Celgene: Research Funding; Deciphera: Research Funding.

Abstract 915

Abstract 3749

Abstract 3747

Abstract 3743This icon denotes a clinically relevant abstract

Abstract 3763

Abstract 163

Ponatinib is a potent, oral, pan-BCR-ABL inhibitor active against the native enzyme and all tested resistant mutants, including the uniformly resistant T315I mutation. Initial findings of a phase 1 trial in patients (pts) with refractory hematologic malignancies have been reported. The effect of duration of treatment, prior treatment, and mutation status on response to treatment was examined in CML chronic phase (CP) pts who responded to ponatinib. Methods: An open-label, dose escalation, phase 1 trial of ponatinib in pts with hematologic malignancies is ongoing. The primary aim is to assess the safety; anti-leukemic activity is also being investigated. Pts resistant to prior treatments or who had no standard treatment available were enrolled to receive a single daily oral dose of ponatinib (2 mg to 60 mg). Subset analyses of factors impacting cytogenetic and molecular response endpoints (MCyR and MMR) were performed for pts with CP-CML. Data are presented through April 15, 2011. Results: In total, 81 pts (54% male) received ponatinib. Overall, 43 pts had CP with 34 ongoing at analysis. MCyR was observed as best response in 31/43 (72%), 27 (63%) CCyR. The median time to MCyR was 12 (3 to 104) wks. Response rates were assessed by duration of treatment (1 pt in CCyR at entry was excluded; 6 pts in PCyR had to achieve CCyR). At the 3 month assessment, 22/42 (52%) CP pts achieved MCyR; at 6 months, 24/42 (57%); at 12 months, 29/42 (69%) had MCyR. The impact of prior treatment on response and time to response was assessed. 42 pts (98%) had >2 prior TKIs and 28 (65%) ≥3 prior TKIs, including investigational agents. Of approved TKIs, all pts were previously treated with imatinib, 19 dasatinib or nilotinib after imatinib, and 21 both dasatinib and nilotinib after imatinib. MCyR rate decreased with number of prior TKIs (2 prior TKIs 13/14 [93%], ≥3 prior TKIs 17/28 [61%]) and number of approved TKIs (imatinib followed by dasatinib or nilotinib 17/19 [90%], or by both dasatinib and nilotinib 12/21 [57%]). Time to response was prolonged in pts more heavily treated with prior TKIs. Median time to MCyR increased with the number of prior TKIs and approved TKIs (2 TKIs 12 wks, ≥3 TKIs 32 wks). The effect of mutation status on response and time to response was also evaluated. At entry, 12 pts had the T315I mutation, 15 had other BCR-ABL kinase domain mutations, 12 had no mutations detected, 4 did not allow sequencing. MCyR response rate for CP pts with T315I was 11/12 (92%); for other mutations, 10/15 (67%); and no mutation, 7/12 (58%). Similarly, mutation status had an impact on time to response: median time to MCyR was 12 wks for those with T315I or other mutations and 32 wks in resistant pts with no mutation. All CP patients were evaluable for MMR. At analysis, MMR was 17/43 (40%). MMR rate was inversely related to number of prior TKIs (2 TKIs 10/14 [71%], ≥3 TKIs 6/28 [21%]), approved TKIs (imatinib followed by dasatinib or nilotinib 12/19 [63%], or by both dasatinib and nilotinib 4/21 [19%]), and was higher for T315I pts (7/12, 58%) and those with other mutations (7/15, 47%) compared with no mutation (2/12, 17%). Median time to MMR for CP pts was 97 wks; median time to MMR was shorter for pts who were less heavily treated (2 prior TKIs 24 wks) and those with T315I or other mutations (63 wks). Conclusion: In this subset analysis of the phase 1 data, ponatinib had substantial activity in all subgroups analyzed. Time on treatment, less prior therapy and kinase domain mutations were associated with higher response rates and early responses in CP pts. Cytogenetic responses improved over the first 12 months of treatment and were higher in less heavily treated pts.Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Shah:Ariad: Consultancy, Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Hu:ARIAD: Employment. Clackson:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Druker:MolecularMD: OHSU and Dr. Druker have a financial interest in MolecularMD. Technology used in this research has been licensed to MolecularMD. This potential conflict of interest has been reviewed and managed by the OHSU Conflict of Interest in Research Committee and t. Deininger:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: 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; Celgene: Research Funding; Genzyme: Research Funding. Talpaz:ARIAD: Research Funding.

Ponatinib, an oral multiple tyrosine kinase inhibitor (TKI), is a potent pan-BCR-ABL inhibitor. Preliminary anti-leukemia activity of ponatinib was observed in patients with refractory chronic myeloid leukemia (CML) and advanced hematologic malignancies in a phase 1 study. Due to the QT prolongation noted with other TKIs, the effect of ponatinib on ECGs was examined in this population.This ongoing phase 1, open-label, dose-escalation, multicenter trial was designed to evaluate the safety of oral ponatinib administered to patients with advanced hematologic malignancies who failed available therapies. Patients received ponatinib orally once daily (2 mg to 60 mg) over at least 1 cycle (28 days) of study treatment unless an unacceptable toxicity or disease progression occurred. Inclusion criteria required screening QTc < 450 ms and prohibited concomitant use of medications known to prolong QTc. For the last 3 cohorts (30 mg, 45 mg and 60 mg), 12-lead ECGs (supine) were recorded using GE MAC1200 ECG recorders at the following time-points: C1D1 pre-dose (triplicate); C1D15 pre-dose (single); C2D1 pre-dose (triplicate); C2D1 2-hour post-dose (triplicate); C2D1 4-hour post-dose (triplicate); C2D1 6-hour post-dose (triplicate). Matching plasma ponatinib concentration data were also obtained at these time-points. This analysis of the cardiac safety of ponatinib only included patients who had replicate ECGs at baseline and a minimum of 1 additional on-treatment time-point with matching plasma ponatinib concentration data. The primary assessment was Fridericia corrected QT (QTcF).A total of 81 patients were enrolled in the phase 1 study; 39 patients who received 30 mg or more of ponatinib daily were included in this analysis. There was no significant effect on cardiac repolarization as measured by the lack of a significant change in QTcF at all doses. Mean QTcF change from baseline was −10.9, −3.6, and −5.9 ms for the 30 mg, 45 mg and 60 mg cohorts, respectively. In addition, the pharmacokinetic-pharmacodynamic models show the slope of the relationship for QTcF versus plasma ponatinib concentration was negative, indicating no exposure-effect relationship, with an estimated QTcF mean change of −6.4 (upper confidence interval −0.9) ms at Cmax for the 60 mg group. ECG data revealed no significant change in heart rate (+3.5, −3.3, and +1.0 bpm for 30 mg, 45 mg and 60 mg cohorts, respectively). There was no signal of any effect on atrioventricular conduction as measured by the PR interval duration (mean change: −0.4, −3.6, and −0.7 ms, respectively). There was a slight, dose responsive, non-clinically significant increase in QRS duration (mean change: −0.8, +1.3, and +3.6 ms, respectively) that may be due to variability secondary to the limited sample size. There were 2 subjects with new atrial fibrillation and new T wave inversion. These morphological changes likely reflect the patient population being studied rather than any potential drug effect. Adverse event (AE) reports from the trial had 3 patients with ECG QT prolonged (2 mg, 4 mg and 45 mg) documented as a treatment-related AE; 2 were grade 3 (4 mg and 45 mg). On review, all 3 patients were found to have baseline (C1D1) prolongation of QTc or were on concomitant medications associated with QTc prolongation. There were no clinical consequences of the ECG findings in these patients.This analysis of the QTc intervals of patients who received ponatinib 30 mg or higher in the phase 1 clinical trial revealed there was no significant effect of ponatinib on cardiac repolarization.Sonnichsen: ARIAD: Consultancy. Dorer:ARIAD: Employment. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Talpaz:ARIAD: Research Funding. Deininger:BMS: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; ARIAD: 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; Celgene: Research Funding; Genzyme: Research Funding. Shah:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy; Ariad: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; ARIAD: Research Funding. Bixby:Novartis: Speakers Bureau; BMS: Speakers Bureau; GSK: Speakers Bureau. Mauro:ARIAD: Research Funding. Flinn:ARIAD: Research Funding. Litwin:ARIAD: Consultancy. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership.

Abstract 4441