Molecular Responses with Ponatinib in Patients with Philadelphia Chromosome Positive (Ph+) Leukemia: Results From the PACE Trial
Authors: Hochhaus Andreas , Kim Dong-Wook , Pinilla-Ibarz Javier , le Coutre Philipp , Paquette Ronald , Chuah Charles , Nicolini Franck E. , Apperley Jane , Khoury H. Jean , Talpaz Moshe , DiPersio John F. , DeAngelo Daniel , Abruzzese Elisabetta , Rea Delphine , Baccarani Michele , Muller Martin C , Gambacorti-Passerini Carlo , Wong Stephane , Lustgarten Stephanie , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G , Guilhot Francois , Deininger Michael W. , Hughes Timothy P. , Goldman John M , Shah Neil , Kantarjian Hagop M. , Cortes Jorge E. ,   The PACE Study Group
Published: October 2019

Abstract
Abstract 3763

Background:
Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the TKI resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with chronic phase (CP), accelerated phase (AP), or blast phase (BP) chronic myeloid leukemia (CML), or Ph+ acute lymphoblastic leukemia (Ph+ ALL) were evaluated in a pivotal phase 2, international, open-label clinical trial (PACE).

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

Methods:
The PACE trial enrolled 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I BCR-ABL mutation. Patients were assigned to 1 of 6 cohorts according to disease phase (CP-CML, AP-CML, or BP-CML/Ph+ ALL), R/I to dasatinib or nilotinib, and presence of T315I. Mutation and molecular response analyses were performed at a single central laboratory. Molecular responses are reported on the International Scale (BCR-ABLIS; b2a2/b3a2 [p210] transcript only): major molecular response (MMR), ≤0.1%; MR4, ≤0.01%; MR4.5, ≤0.0032%. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 21] months).

Results:
The median age was 59 (18 to 94) years. The median time from initial diagnosis to start of ponatinib was 6 (0.3 to 28) years. 96% had received prior imatinib, 84% dasatinib, 65% nilotinib; 8% received 1, 39% received 2, and 53% received all 3 prior approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. BCR-ABL mutations were detected in 55% of all patients at baseline: 22.9% T315I only, 26.5% mutations other than T315I, 5.8% mutations in addition to T315I. The most common mutations were T315I (29%), F317L (8%), E255K (4%), F359V (4%), and G250E (3%). Baseline BCR-ABL transcript levels were >10% in 74% (74% in CP-CML) and >1% to ≤10% in 14% (20% in CP-CML). No patients entered the study in MMR. The best response to the most recent dasatinib or nilotinib containing regimen was MMR or better in 4% (3% in CP-CML).
Molecular response rates by cohort are shown below for CP-CML and AP-CML. Deep molecular responses, including MR4.5, were observed in both disease phases. Of 16 BP-CML and 3 Ph+ ALL patients with the b2a2/b3a2 transcript and baseline and post-baseline bone marrow assessments, 5 BP-CML and 0 Ph+ ALL patients achieved MMR. In CP-CML, MMR rates for the most frequent mutations other than T315I were 41% F317L, 50% E255K, 31% F359V, 38% G250E. Subgroup analyses in CP-CML indicated significant differences in the MMR rate for patients with T315I only (56%; p<0.001) and mutations in addition to T315I (50%; p=0.0216) vs. no mutation (21%), and for T315I only vs. mutations other than T315I (34%; p=0.0237). These differences are likely due to younger age (median 51 vs. 61 years) and exposure to fewer prior TKIs (median 2 vs. 3) in CP-CML patients with T315I vs. those without T315I. In CP-CML, 53% maintained or achieved BCR-ABLIS ≤10% by 3 months, with a trend towards higher rates in patients receiving fewer prior approved TKIs (1: 81%; 2: 61%; 3: 45%). The MMR rate (cumulative) in CP-CML improved over time: 13% by 3 months, 24% by 6 months, 28% by 9 months. The median time to MMR for CP-CML patients achieving MMR was 6 (2 to 17) months. CP-CML patients with MMR had an estimated probability of remaining in MMR at 6 months and 1 year of 87% and 84%, respectively (Kaplan-Meier). Ponatinib was generally well-tolerated. Data with a minimum follow-up of 12 months will be presented.

Conclusions:
Ponatinib treatment led to significant and deep molecular responses in this heavily pretreated population. In CP-CML, the MMR rate was ∼10-fold higher than that reported with the most recent dasatinib or nilotinib treatment.

Disclosures:
Hochhaus: ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kim:Novartis, Bristol Myers-Squibb, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, NOVARTIS PHARMA, BRISTOL MYERS SQUIBB, PFIZER: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy; Pfizer: Research Funding; ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding.