Long-Term Anti-Leukemic Activity of Ponatinib in Patients with Philadelphia Chromosome-Positive Leukemia: Updated Results from an Ongoing Phase 1 Study
Authors: Deininger Michael W , Cortes Jorge E. , Kantarjian Hagop M. , Shah Neil , Bixby Dale , Mauro Michael J. , Flinn Ian W. , O'Hare Thomas , Hu Simin , Dorer David J. , Rivera Victor M. , Clackson Tim , Turner Christopher D. , Haluska Frank G , Druker Brian J. , Talpaz Moshe 
Published: October 2019

Abstract
Abstract 3743

Background:
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.

Methods:
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.

Results:
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.

Conclusion:
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.

Disclosures:
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.