Efficacy and Safety Of Ponatinib Following Failure Of Nilotinib In Patients With Chronic Phase Chronic Myeloid Leukemia (CP-CML) In The PACE Trial
Authors: Kantarjian Hagop M. , Cortes Jorge E. , Kim Dong-Wook , Pinilla-Ibarz Javier , le Coutre Philipp D. , Paquette Ronald , Chuah Charles , Nicolini Franck E. , Apperley Jane F. , Khoury H Jean , Talpaz Moshe , DiPersio John F. , DeAngelo Daniel J. , Abruzzese Elisabetta , Rea Delphine , Baccarani Michele , Müller Martin C. , Gambacorti-Passerini Carlo , Lustgarten Stephanie , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G. , Guilhot Francois , Deininger Michael W. , Hochhaus Andreas , Hughes Timothy P. , Goldman John M. , Shah Neil P. 
Published: October 2019

Abstract

Background
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.

Methods
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.

Results
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.

Conclusions
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.

Disclosures:
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.