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48 Outcome By Mutation Status and Line of Treatment in Optic, a Dose-Ranging Study of 3 Starting Doses of Ponatinib in Patients with CP-CML

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Therapy— Building The Future CML
Hematology Disease Topics & Pathways:
Biological, Adult, Diseases, CML, Therapies, Study Population, Myeloid Malignancies, TKI
Saturday, December 5, 2020: 8:15 AM

Jorge E. Cortes, MD1, Jane Apperley, FRCP, FRCPath, MB 2, Andreas Hochhaus, MD3, Michael J. Mauro, MD4, Philippe Rousselot, MD PhD5*, Tomasz Sacha, MD PhD6*, Moshe Talpaz, MD7, Charles Chuah, MD8, Jeffrey H. Lipton, MD, PhD9, Michael W. Deininger, MD, PhD10, Charles A. Schiffer, MD11, Lori J. Maness, MD12, James K. McCloskey, MD13, Valentín García Gutiérrez, MD, PhD14, Hugues de Lavallade, MD, PhD15*, Gabriel Etienne, MD, PhD16*, Vickie Lu, PhD17*, Shouryadeep Srivastava, MBBS, PhD18* and Gianantonio Rosti, MD19*

1Georgia Cancer Center Augusta University, Augusta, GA
2Centre for Haematology, Imperial College, London, United Kingdom
3Jena University Hospital, Jena, Germany
4Myeloproliferative Neoplasms Program, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY
5Hospital Mignot University de Versailles Saint-Quentin-en-Yvelines, Paris, France
6Department of Hematology, Jagiellonian University Medical College, Krakow, Poland
7Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
8Singapore General Hospital and Duke-NUS Medical School, Singapore, Singapore
9Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada
10Huntsman Cancer Institute, University of Utah, Salt Lake City, UT
11Department of Oncology, Karmanos Cancer Institute at Wayne State University, Detroit, MI
12University of Nebraska Medical Center, Omaha, NE
13John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ
14Hematology Department, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, Spain
15Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom
16Institute Bergonie; Institut National de la Sante et de la Recherche Medicale; Groupe France Intergroupe des Leucemies Myeloides Chroniques, Hopital Haut-Leveque, Pessac, France
17Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA
18Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA
19University of Bologna, Bologna, Italy

Introduction: In PACE (NCT01207440), patients with refractory chronic-phase chronic myeloid leukemia (CP-CML) with substantial prior second-generation tyrosine kinase inhibitor (TKI) treatment demonstrated deep, lasting responses to ponatinib. However, long-term follow-up identified rates of arterial occlusive events (AOEs) as a risk. OPTIC (NCT02467270) is a randomized Phase 2 trial evaluating ponatinib at 3 starting doses: 45 mg, 30 mg, and 15 mg daily in patients with CP-CML resistant/intolerant to ≥2 TKIs or with a T315I mutation. The interim analysis showed that the 45-mg (vs 30 mg or 15 mg) starting dose (with reduction to 15 mg upon response) provided the best clinical outcomes and responses were maintained in >75% of patients who dose reduced. Here, we present efficacy and safety outcomes by baseline mutation status and line of treatment for the 3 dose cohorts.

Methods: Patients with CP-CML resistant/intolerant to ≥2 TKIs or with T315I mutation were randomized to ponatinib starting doses of 45 mg (Cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily (qd). Doses were reduced to 15 mg on achievement of ≤1% BCR-ABL1IS in Cohorts A and B. Doses also could be reduced for safety. The primary endpoint is ≤1% BCR-ABL1IS at 12 months. In this analysis, the outcome was analyzed by baseline mutation status (none, any, T315I, and non-T315I) and number of prior TKIs (≤2 or ≥3) in the intent-to-treat (ITT) population. Treatment-emergent adverse events (TEAEs), serious TEAEs, and AOEs by adjudication were summarized by number of prior TKIs (≤2 or ≥3). Interim analysis results are descriptive.

Results: Patients (N=283) were randomized: A/B/C n=94/95/94; median age was 48 y (18‒81 y). Seven patients were excluded from the intent-to-treat population (N=276) because they had atypical transcripts. Mutation status was well balanced between cohorts; 59% had no mutation, 41% had ≥1 baseline mutation, 24% had T315I, and 17% had a non-T315I mutation. In all categories of mutation status, the rate of ≤1% BCR-ABL1IS by 12 months was highest in Cohort A, with the most notable differences seen in patients with T315I (A: 60%, B: 25%, C: 6%) (Table 1). Patients with no mutations or other mutations had smaller differences but the outcomes all still favored 45 mg. Patients in all cohorts were treated with multiple TKIs, with 54% (A), 60% (B), and 53% (C) having 3 or more prior TKIs. The rate of ≤1% BCR-ABL1IS by 12 months was highest in Cohort A, both in patients treated with ≤2 or ≥3 prior TKIs (43% and 49%, respectively) (Table 1). Table 2 shows rates of TEAEs and TE-AOEs by cohort and number or prior TKIs. There was a trend toward higher event rates in Cohort A and for patients treated with ≥3 TKIs. Rates of adjudicated AOEs were low (≤6%) in all 3 cohorts irrespective of the number of prior TKIs.

Conclusions: At this interim analysis with a median follow-up of ~21 months, the maximum benefit:risk, regardless of mutation status or number of prior TKIs, was observed in patients treated with a 45-mg starting dose, with a reduction to 15 mg upon achievement of response. Patients with the T315I mutation who initiated ponatinib at 45 mg experienced better response rates than those who initiated ponatinib at 30-mg or 15-mg starting doses. Primary analysis will provide a refined understanding of the benefit:risk profile of 3 different starting doses of ponatinib.

Disclosures: Cortes: Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; Takeda: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Sun Pharma: Research Funding. Apperley: Pfizer: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau. Hochhaus: Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; MSD: Research Funding. Mauro: Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding. Rousselot: Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Incyte: Consultancy, Research Funding. Sacha: Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Talpaz: Novartis: Research Funding; IMAGO: Consultancy; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Chuah: Korea Otsuka Pharmaceutical: Honoraria; Pfizer: Other: Travel, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Lipton: Bristol-Myers Squibb: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Deininger: SPARC: Research Funding; Novartis: Consultancy, Other, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Sangamo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Fusion Pharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding; Medscape: Consultancy, Honoraria; Gilead Sciences: Research Funding; Celgene: Research Funding; Galena: Consultancy, Honoraria, Other; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Ariad: Consultancy, Honoraria, Other; DisperSol: Consultancy; Leukemia & Lymphoma Society: Research Funding; Pfizer: Honoraria, Other, Research Funding. Schiffer: BMS: Consultancy; Novartis: Consultancy; Takeda: Research Funding. García Gutiérrez: Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. de Lavallade: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Etienne: Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Lu: Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Srivastava: Takeda: Current Employment. Rosti: Novartis: Speakers Bureau; Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.

*signifies non-member of ASH