OPTIC PRIMARY ANALYSIS: A DOSE-OPTIMIZATION STUDY OF 3 STARTING DOSES OF PONATINIB (PON)
Author(s): ,
Jorge E. Cortes
Affiliations:
Georgia Cancer Center,Augusta,United States
,
Jane Apperley
Affiliations:
Centre for Haematology, Imperial College London, South Kensington Campus,London,United Kingdom
,
Elza Lomaia
Affiliations:
Almazov National Medical Research Centre of Ministry of Health of Russian Federation,Saint Petersburg,Russian Federation
,
Beatriz Moiraghi
Affiliations:
Hospital Jose Maria Ramos Mejia,Buenos Aires,Argentina
,
Maria Undurraga Sutton
Affiliations:
Hospital del Salvador,Santiago,Chile
,
Carolina Pavlovsky
Affiliations:
Fundaleu,Buenos Aires,Argentina
,
Charles Chuah
Affiliations:
Singapore General Hospital, Duke-NUS Graduate Medical School,Singapore,Singapore
,
Tomasz Sacha
Affiliations:
Department of Hematology,Jagiellonian University Hospital,Kraków,Poland
,
Jeffrey Howard Lipton
Affiliations:
University of Toronto,Toronto,Canada
,
James K. McCloskey
Affiliations:
The John Theurer Cancer Center at Hackensack Meridian Health,Hackensack,United States
,
Andreas Hochhaus
Affiliations:
Universitätsklinikum Jena,Jena,Germany
,
Philippe H. Rousselot
Affiliations:
Service d’Hématologie et Oncologie, Hôpital de Versailles, Université Versailles Saint Quentin en Yvelines,Le Chesnay,France
,
Gianantonio Rosti
Affiliations:
IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) 'Dino Amadori',Meldola,Italy
,
Hugues De Lavallade
Affiliations:
King's College Hospital NHS Foundation,London,United Kingdom
,
Michael J. Mauro
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Tracey Hall
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Vickie Lu
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
,
Shouryadeep Srivastava
Affiliations:
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited,Cambridge,United States
Michael W. Deininger
Affiliations:
University of Utah Health Care,Salt Lake City,United States
EHA Library. E Cortes J. 06/09/21; 324561; S153
Jorge E Cortes
Jorge E Cortes
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S153

Type: Oral Presentation

Session title: Response, resistance and treatment-free remission in CML

Background
PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. 

Aims
Evaluate the safety and efficacy of ponatinib response–based dosing regimens in patients with resistant/intolerant CP-CML.

Methods
Informed consent was obtained and pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee.

Results
283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/30%.

Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively.

Conclusion
The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤1% BCR-ABL1IS; 30 mg →15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations.

Keyword(s): BCR-ABL, Chronic myeloid leukemia, Clinical trial, Tyrosine kinase inhibitor

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S153

Type: Oral Presentation

Session title: Response, resistance and treatment-free remission in CML

Background
PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep and long-lasting responses and survival in patients (pts) with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and both adverse events and response. Here we present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial with a novel response-based dosing regimen of PON in pts with resistant/intolerant CP-CML. 

Aims
Evaluate the safety and efficacy of ponatinib response–based dosing regimens in patients with resistant/intolerant CP-CML.

Methods
Informed consent was obtained and pts with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. The primary endpoint is ≤1% BCR-ABL1IS at 12 mo; secondary endpoints include cytogenetic and molecular responses and safety outcomes. AOEs were adjudicated prospectively by an independent review committee.

Results
283 pts were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18‒81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At the primary analysis with 32 mo median follow-up, 134 pts (47%; n=50/41/43) remained on treatment and 204 pts (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS (Table); primary endpoint was met by cohort A. Dose reductions to 15 mg after achieving response (A/B) were 48/30%.

Most common grades ≥3 TEAEs were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. AOEs/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively.

Conclusion
The OPTIC primary analysis demonstrates the optimal benefit:risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤1% BCR-ABL1IS; 30 mg →15 mg and 15 mg cohorts may provide benefit, especially in pts without T315I mutation (Table). The observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in pts with CP-CML resistant to second-generation BCR-ABL1 TKI therapy, both with and without BCR-ABL1 mutations.

Keyword(s): BCR-ABL, Chronic myeloid leukemia, Clinical trial, Tyrosine kinase inhibitor

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