LONG-TERM FOLLOW-UP OF PONATINIB EFFICACY AND SAFETY IN PATIENTS (PTS) WITH THE T315I MUTATION IN THE PHASE 1 AND PHASE 2 (PACE) TRIALS
Author(s): ,
Michele Baccarani
Affiliations:
University of Bologna,Bologna,Italy
,
Michael J Mauro
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Jorge E Cortes
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Andreas Hochhaus
Affiliations:
Jena University Hospital,Jena,Germany
,
Timothy P Hughes
Affiliations:
Institute of Medicine and Veterinary Science,Adelaide,Australia
,
François Guilhot
Affiliations:
Inserm CIC 1402, CHU de Poitiers,Poitiers,France
,
Michael W Deininger
Affiliations:
Huntsman Cancer Institute, University of Utah,Salt Lake City,United States
,
Hagop M Kantarjian
Affiliations:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Neil P Shah
Affiliations:
University of California San Francisco,San Francisco,United States
,
Dale Bixby
Affiliations:
Comprehensive Cancer Center, University of Michigan,Ann Arbor,United States
,
Ian W Flinn
Affiliations:
Sarah Cannon Research Institute,Nashville,United States
,
Stephanie Lustgarten
Affiliations:
ARIAD Pharmaceuticals, Inc.,Cambridge,United States
,
Victor M Rivera
Affiliations:
ARIAD Pharmaceuticals, Inc.,Cambridge,United States
,
Frank G Haluska
Affiliations:
ARIAD Pharmaceuticals, Inc.,Cambridge,United States
,
Tim Clackson
Affiliations:
ARIAD Pharmaceuticals, Inc.,Cambridge,United States
Moshe Talpaz
Affiliations:
Comprehensive Cancer Center, University of Michigan,Ann Arbor,United States
EHA Library. Baccarani M. Jun 12, 2015; 100488; P236 Disclosure(s): POLICLINICO SANT'ORSOLA MALPIGHI
Prof. Michele Baccarani
Prof. Michele Baccarani
Contributions
Abstract
Abstract: P236

Type: Poster Presentation

Presentation during EHA20: From 12.06.2015 17:15 to 12.06.2015 18:45

Location: Poster area (Hall C)

Background
Ponatinib is the only oral tyrosine kinase inhibitor (TKI) approved for use in refractory CML or Ph+ ALL pts that inhibits the BCR-ABL T315I mutant, which is uniformly resistant to other approved TKIs.

Aims
The long-term efficacy and safety of ponatinib in pts with the T315I mutation is reported based on pooled data from the ongoing phase 1 and PACE trials.

Methods
The phase 1 trial (NCT00660920) evaluated safety and antileukemic activity of ponatinib (2–60 mg qd) in pts with resistant/refractory hematologic malignancies (N=81), and the PACE trial (NCT01207440) evaluated efficacy and safety of ponatinib (45 mg qd) in pts with CML or Ph+ ALL who were resistant/intolerant to dasatinib/nilotinib or who had the T315I mutation (N=449). All pts gave informed consent. The T315I mutation was detected at baseline by Sanger sequencing at a central laboratory. PFS and OS data were collected in PACE only.

Results
Pooled data from 147 pts with T315I in the phase 1 (n=19) and PACE (n=128) trials are reported. Among 76 CP-CML, 19 AP-CML, 26 BP-CML, and 26 Ph+ ALL pts, median age was 50, 52, 47, and 62 y, respectively; median time since diagnosis was 4.6, 6.3, 2.3, and 1.3 y; and 86%, 84%, 96%, and 73% received ≥2 prior TKIs. At the time of analysis (26 September 2014 for phase 1; 6 October 2014 for PACE), median follow-up for pts with T315I was 36 (1.5–70) mo, 21 (3.1–45) mo, 2.9 (0.4–9) mo, and 2.7 (0.1–40) mo for CP-CML, AP-CML, BP-CML, and Ph+ ALL pts, respectively; 50%, 26%, 0%, and 4% remained on study. Pts discontinued primarily for disease progression (13%, 26%, 62%, and 46% in CP-CML, AP-CML, BP-CML, and Ph+ ALL, respectively) and AEs (12%, 16%, 15%, and 4%). Median dose intensity was 34, 38, 44, and 45 mg/d in these groups. Among CP-CML pts, 75% achieved MCyR; 72%, CCyR; 61%, MMR; 45%, MR4; and 37%, MR4.5. Responses were durable; 83% and 81% of CP-CML pts were estimated to maintain MCyR and CCyR, respectively, for 3 y. Among AP-CML, BP-CML, and Ph+ ALL pts, MaHR rates were 58%, 27%, and 38%, respectively. In phase 1, 11/12 CP?CML pts with T315I remained alive and on study; 1 pt discontinued due to disease progression. In PACE, estimated 3-y PFS/OS rates for 64 CP-CML pts with T315I were 59%/78%. For 18 AP-CML pts in PACE, median PFS was 31.5 mo and median OS was not reached (3-y OS rate was 63%); for 24 BP-CML and 22 Ph+ ALL pts in PACE, median PFS/OS was 4.1/6.9 mo and 2.6/6.5 mo, respectively. Treatment-emergent AEs in ≥30% of all T315I pts were generally grade 1/2 and included: rash, 42%/55% (of total/CP-CML pts); abdominal pain, 39%/42%; headache, 39%/46%; nausea, 36%/41%; dry skin, 34%/49%; fatigue, 34%/39%; constipation, 33%/36%; and pyrexia, 32%/26%. Arterial occlusive events (AOEs) occurred in 21%/32% of total/CP-CML pts and included cardiovascular (13%/18%), cerebrovascular (8%/12%), and peripheral vascular (8%/13%) events. Venous thromboembolic events (VTEs) occurred in 8%/7% of total/CP-CML pts. Exposure-adjusted incidence rates of new AOEs and VTEs (events per 100 pt-years) were 13.0 and 5.0, respectively, among total pts, and 12.8 and 2.7, respectively, among CP-CML pts.

Summary
Ponatinib continues to provide deep and durable responses with up to 6 y of follow-up in CP-CML pts with the T315I mutation, in whom effective treatment options are limited. The response rates and safety profile observed among T315I pts were comparable to, if not better than, those observed among all pts with refractory CML or Ph+ ALL in the phase 1 and PACE trials.

Keyword(s): Chronic myeloid leukemia, Tyrosine kinase inhibitor

Session topic: Chronic myeloid leukemia - Clinical 1

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