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Clinical Trial
. 2018 Jul 26;132(4):393-404.
doi: 10.1182/blood-2016-09-739086. Epub 2018 Mar 22.

Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial

Jorge E Cortes  1 , Dong-Wook Kim  2 , Javier Pinilla-Ibarz  3 , Philipp D le Coutre  4 , Ronald Paquette  5 , Charles Chuah  6 , Franck E Nicolini  7 , Jane F Apperley  8 , H Jean Khoury  9 , Moshe Talpaz  10 , Daniel J DeAngelo  11 , Elisabetta Abruzzese  12 , Delphine Rea  13 , Michele Baccarani  14 , Martin C Müller  15 , Carlo Gambacorti-Passerini  16 , Stephanie Lustgarten  17 , Victor M Rivera  17 , Frank G Haluska  17 , François Guilhot  18   19 , Michael W Deininger  20 , Andreas Hochhaus  21 , Timothy P Hughes  22 , Neil P Shah  23 , Hagop M Kantarjian  1
Affiliations
Clinical Trial

Ponatinib efficacy and safety in Philadelphia chromosome-positive leukemia: final 5-year results of the phase 2 PACE trial

Jorge E Cortes et al. Blood. .

Abstract

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.

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Conflict of interest statement

Conflict-of-interest disclosure: J.E.C. has received research funding from ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, and Teva, and has served as a consultant for ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer. D.-W.K. has received research funding from ARIAD. J.P.-I. has received honoraria from Bristol-Myers Squibb; has received research funding from ARIAD and Novartis; and has served as a consultant or speaker for ARIAD, Bristol-Myers Squibb, Novartis, Pfizer, and Teva. P.D.l.C. has received honoraria from ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and research funding from ARIAD. R.P. has received honoraria from, and has served as a speaker for, ARIAD, Bristol-Myers Squibb, Incyte, and Novartis; has served in a consulting or advisory role for AstraZeneca; and has received research funding from ARIAD. C.C. has received research funding from ARIAD. F.E.N. has received honoraria from ARIAD, Bristol-Myers Squibb, and Novartis; has served in a consulting or advisory role for Bristol-Myers Squibb and Novartis; has served on speakers’ bureaus for ARIAD, Bristol-Myers Squibb, and Novartis; has received research funding from ARIAD and Novartis; and has received travel, accommodations, or other expense reimbursements from Bristol-Myers Squibb and Novartis. J.F.A. has received honoraria from ARIAD, Bristol-Myers Squibb, MSD, Novartis, and Pfizer, and has received research funding from ARIAD and Novartis. H.J.K. received honoraria and research funding from ARIAD. M.T. has served in a consulting or advisory role for ARIAD, Novartis, and Pfizer; has received research funding from ARIAD, Incyte, Novartis, Pfizer, and Sanofi; and has received travel, accommodations, or other expense reimbursements from ARIAD, Incyte, Novartis, and Pfizer. D.J.D. has served in a consulting or advisory role for Amgen, ARIAD, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer, and has received research funding from ARIAD. E.A. has served in a consulting or advisory role for ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. D.R. has received honoraria for nonpromotional oral presentations from, and has served on advisory boards for, ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. M.B. has served as a consultant and speaker for, and received honoraria from, ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer, and has received research funding from ARIAD. M.C.M. has received honoraria for consulting or advisory roles and research funding from ARIAD, Bristol-Myers Squibb, and Novartis. C.G.-P. has served in an advisory role to Bristol-Myers Squibb and Pfizer and has received research funding from ARIAD. S.L. is an employee of, and may own stock/stock options in, ARIAD. V.M.R. is an employee of, and may own stock/stock options in, ARIAD. F.G.H. was an employee of, and may have owned stock/stock options in, ARIAD at the time the work was conducted. F.G. has received honoraria from Novartis and Pfizer; has served in a consulting or advisory role for Celgene; has received travel, accommodations, or other expense reimbursements from Novartis; and has received research funding from ARIAD. M.W.D. has served in a consulting or advisory role for ARIAD, Bristol-Myers Squibb, Incyte, Novartis, and Pfizer; has received travel, accommodations, or other expense reimbursements from ARIAD, Bristol-Myers Squibb, CTI BioPharma, Novartis, and Pfizer; has provided expert testimony for Bristol-Myers Squibb; has received honoraria from ARIAD, Bristol-Myers Squibb, CTI BioPharma, Incyte, Novartis, and Pfizer; and has received research funding from ARIAD, Bristol-Myers Squibb, Celgene, Incyte, and Novartis. A.H. has received research funding from ARIAD, Bristol-Myers Squibb, Novartis, and Pfizer. T.P.H. has received honoraria from, has served in a consulting or advisory role for, and has received research funding from ARIAD, Bristol-Myers Squibb, and Novartis, and has received travel, accommodations, or other expense reimbursements from Bristol-Myers Squibb and Novartis. N.P.S. has received research funding from ARIAD, Bristol-Myers Squibb, Daiichi-Sankyo, Pfizer, and Plexxikon. H.M.K. has received research funding from Amgen, Bristol-Myers Squibb, Novartis, and Pfizer.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Efficacy of ponatinib in patients with CP-CML, overall, and among patients resistant or intolerant to previous treatment with dasatinib or nilotinib or with the BCR-ABL1T315I mutation. (B-C) Results are shown in CP-CML patients remaining on study as of the last response assessment. (B-E) The 95% confidence intervals are shown. (A) Response at any time. MR4 is the 4-log molecular response (≤0.01% BCR-ABL1IS or undetectable disease in cDNA with ≥10 000 ABL1 transcripts); MR4.5 is the 4.5-log molecular response (≤0.0032% BCR-ABL1IS or undetectable disease in cDNA with ≥32 000 ABL1 transcripts). MCyR and MMR rates in patients who were resistant to dasatinib or nilotinib were 54% and 41%, respectively. (B) Duration of MCyR. Patients who achieved MCyR by 12 months (n = 148) are shown. Because of a data correction between the original PACE publication and the current report, 148 (55%) rather than 149 (56%) of 267 CP-CML patients achieved MCyR by 12 months. Of 267 CP-CML patients evaluated for efficacy, 148 achieved MCyR, and 21 of these patients lost MCyR, leaving 127 (48%) of 267 CP-CML patients with continuous MCyR as of the last response assessment. *Failed to meet criteria for MCyR in 2 consecutive assessments ≥28 days apart, or discontinued after a single assessment in which the criteria for MCyR were not met. †Kaplan-Meier estimate. (C) Duration of MMR. Patients who achieved MMR at any time are shown. Of 267 CP-CML patients evaluated for efficacy, 108 achieved MMR, and 28 of these patients lost MMR, leaving 80 (30%) of 267 CP-CML patients with continuous MMR as of last response assessment. *Failed to meet criteria for MMR at any single time point after initial response. †Kaplan-Meier estimate. (D) PFS. Progression from CP was defined as death, development of AP or BP, loss of complete hematologic response (in absence of cytogenetic response), loss of MCyR, or increasing white blood cell count without complete hematologic response. (E) OS.
Figure 2.
Figure 2.
Maintenance of response following prospective dose reduction in October 2013 in CP-CML patients. (A) MCyR maintenance. (B) MMR maintenance. Of the 42 CP-CML patients without MCyR who remained on study as of 10 October 2013, 17 had a dose reduction (45 to 30 mg per day, n = 7; 45 to 15 mg per day, n = 2; 30 to 15 mg per day, n = 6; other reduction, n = 2), whereas 3, 6, and 16 patients continued to receive 45, 30, and 15 mg per day, respectively. *Response maintained as of last response assessment. †Number of patients with response as of 10 October 2013.
Figure 3.
Figure 3.
Efficacy in patients with advanced disease, overall, and among patients resistant or intolerant to previous treatment with dasatinib or nilotinib or with the BCR-ABL1T315Imutation. (A-C) AP-CML, (D-F) BP-CML, and (G-I) Ph+ ALL. (B-C,E-F,H-I) The 95% confidence intervals are shown. BP-CML includes myeloid BP (n = 52) and lymphoid BP (n = 10). (A) AP-CML: Response at any time. (B) AP-CML: PFS. Progression from AP was defined as death, development of confirmed BP, loss of previous major or minor hematologic response over a 2-week period, or no decrease from baseline levels in percentage of blasts in peripheral blood or bone marrow on all assessments over a 4-week period, or increasing blasts over a 4-week period. (C) AP-CML: OS. (D) BP-CML: Response at any time. (E) BP-CML: PFS. Progression from BP was defined as death, or increasing blasts in peripheral blood or bone marrow over a 4-week period. (F) BP-CML: OS. (G) Ph+ ALL: Response at any time. (H) Ph+ ALL: PFS. (I) Ph+ ALL: OS. NE, not evaluable.
Figure 4.
Figure 4.
Exposure-adjusted yearly incidence rates for newly occurring arterial occlusive events and median dose intensity by year. (A) CP-CML patients. For CP-CML patients, in the 5 intervals shown (0 to <1 year, 1 to <2 years, 2 to <3 years, 3 to <4 years, and 4 to <5 years): 32, 21, 14, 8, and 3 patients had events, respectively, of 270, 152, 121, 91, and 73 patients in each interval, respectively. (B) All patients. For all patients, in the 5 intervals shown (0 to <1 year, 1 to <2 years, 2 to <3 years, 3 to <4 years, and 4 to <5 years): 47, 27, 15, 11, and 3 patients had events, respectively, of 449, 212, 158, 115, and 93 patients in each interval, respectively. Median follow-up was 56.8 months for CP-CML patients and 37.3 months for all patients.
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