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307 Post Hoc Analysis of Responses to Ponatinib in Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML) By Baseline BCR-ABL1 Level and Baseline Mutation Status in the Optic TrialClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Mechanisms of resistance and expanded therapies
Hematology Disease Topics & Pathways:
Clinical Trials, Workforce
Saturday, December 11, 2021: 4:00 PM

Michael W. Deininger, MD, PhD1, Jane F Apperley, FRCP, FRCPath, MB 2, Christopher Kevin Arthur, MBBS, FRACP, FRCPA3, Charles Chuah4, Andreas Hochhaus, MD5, Hugues De Lavallade6*, Jeffrey H. Lipton, MD, PhD7, Elza Lomaia, MD, PhD8*, James K McCloskey, MD9, Lori J. Maness, MD10, Michael J. Mauro, MD11, Beatriz Moiraghi, MD12*, Carolina Pavlovsky13*, Gianantonio Rosti14*, Philippe Rousselot15*, Soledad S. Undurraga, MD16, Vickie Lu, PhD17*, Alexander Vorog, MD17* and Jorge E. Cortes, MD18

1Division of Hematology and Hematologic Malignancies, University of Wisconsin Milwaukee, Milwaukee, WI
2Imperial College London, London, United Kingdom
3Department of Haematology, Royal North Shore Hospital, Sydney, NSW, Australia
4Singapore General Hospital, Duke-NUS Medical School, Singapore, Singapore
5Univerisitätsklinikum Jena, Jena, Germany
6King's College Hospital NHS Foundation, London, United Kingdom
7Hans Messner Allogeneic Blood and Marrow Transplant Unit, Princess Margaret Cancer Centre, Toronto, Canada
8Almazov National Medical Research Centre, St. Petersburg, Russian Federation
9Division of Leukemia, John Thuerer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
10Division of Hematology & Oncology, Department of Internal Medicine, University of Nebraska Medical Center- Fred and Pamela Buffett Cancer Center, Omaha, NE
11Memorial Sloan-Kettering Cancer Center, New York, NY
12Hospital Jose Maria Ramos Mejia, Buenos Aires, Argentina
13Fundaleu, Buenos Aires, Argentina
14IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy
15Centre Hospitalier de Versailles University de Versailles Saint-Quentin-en-Yvelines, Paris, France
16Hospital Del Salvador, Santiago, CHL
17Takeda Development Center Americas, Inc., Lexington, MA
18Georgia Cancer Center Augusta University, Augusta, GA

Introduction: Ponatinib is a third-generation, pan-inhibitory tyrosine kinase inhibitor (TKI) designed to potently inhibit BCR-ABL1 with or without any single resistance mutation, including T315I. Patients (pts) with resistant disease or with T315I BCR-ABL1 mutations respond inadequately to earlier-generation BCR-ABL1 TKIs, leading to poor survival outcomes. OPTIC (Optimizing Ponatinib Treatment in CP-CML, NCT02467270; ongoing) is a phase 2 trial evaluating the safety and efficacy of ponatinib in pts with CP-CML whose disease is resistant to 2 or more TKIs or who have a T315I mutation. Here, we present an in-depth post hoc analysis of OPTIC trial pt responses by baseline disease burden and mutation status.

Methods: Pts with CP-CML resistant to ≥2 TKIs or with the BCR-ABL1 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. Doses were reduced to 15 mg after achievement of ≤1% BCR-ABL1IS in cohorts A and B. Pts could re-escalate to their original starting dose for loss of response. The primary endpoint is ≤1% BCR-ABL1IS at 12 months; secondary endpoints include cytogenetic and molecular responses and safety outcomes. In this analysis, outcomes are analyzed by baseline T315I mutation status and baseline disease burden in the intent-to-treat (ITT) population. BCR-ABL1 mutations were assessed by Sanger sequencing at a central laboratory (MolecularMD, Portland, OR, USA).

Results: 283 pts were randomized (A/B/C: n=94/95/94). At baseline, 84.1% of pts had a high (>10% BCR-ABL1 IS) disease burden; 23.8% had T315I mutation, 17.0% had a mutation other than T315I, and 57.8% had no mutation. The 45 mg →15 mg cohort showed the highest ≤1% BCR-ABL1IS response rates by 36 months (Figure 1).

Subanalysis of pts across the 3 dosing arms showed that pts with T315I mutations had the highest ≤1% BCR-ABL1IS response rates (60%) by 3 years with the 45 mg → 15 mg dose compared with the other cohorts, with a trend toward higher progression-free survival (PFS) in the 45 mg →15 mg arm (Table 1). Across all 3 cohorts, 97 pts without T315I mutations (ie, no mutation or with mutations other than T315I) achieved ≤1% BCR-ABL1IS. Median duration of response (mDoR) for pts with a T315I mutation at baseline was 27 months for pts (n=15) in the 45 mg → 15 mg cohort and 12 mo for pts (n=5) in the 30 mg → 15 mg cohort. For pts without T315I mutations, the mDoR was not reached. Across all 3 cohorts, 79% of pts who achieved ≤1% BCR-ABL1IS maintained this response during the study. A total of 25 patients lost responses (Table 2). Of those who lost response, 11 had T315I, 10/11 dose re-escalated; of those who re-escalated, 6/10 regained ≤1% BCR-ABL1IS after dose re-escalation (Table 2). The most common nonhematologic treatment-emergent adverse events (TEAEs) in the ITT population for all cohorts combined were arterial hypertension (28%), headache (18%), and lipase increased (17%). The most common hematologic TEAEs were thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Overall, 6.0% of pts experienced a treatment-emergent arterial occlusive event (TE-AOE); 4.6% experienced a Grade ≥3 TE-AOE.

Conclusions: Previous analyses established these largely resistant pts achieved high response rates when treated with ponatinib. Consistent with this, the OPTIC post hoc analysis showed clinical benefit across all 3 dosing regimens regardless of T315I mutation status at baseline; the 45 mg →15 mg cohort showed the highest response rates regardless of baseline disease burden (as assessed by BCR-ABL1IS levels). Regardless of T315I mutation status, most patients were able to maintain their response after dose reduction to 15 mg/day upon achieving BCR-ABL1IS ≤1%. Compared with patients without a T315I mutation, patients with a T315I mutation at baseline were more likely to lose their response upon dose reduction; however, 60% of responses were regained with dose re-escalation. For pts with T315I mutations, PFS was greater with 45 mg → 15 mg dosing compared with the other arms; for pts without T315I mutations, all 3 doses showed robust PFS and OS outcomes. The data presented further support the benefit of using ponatinib post–2nd generation TKI for pts with resistant disease regardless of baseline T315I mutation status.

Disclosures: Deininger: Incyte: Consultancy, Honoraria, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Apperley: Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau. Chuah: Pfizer: Other: Travel, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Steward Cross: Honoraria; Novartis, Korea Otsuka Pharmaceutical: Honoraria. Hochhaus: Incyte: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. De Lavallade: Pfizer, Novartis.: Honoraria; Bristol Myers Squibb, Incyte: Honoraria, Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. McCloskey: Takeda: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; BMS: Honoraria, Speakers Bureau; COTA: Other: Equity Ownership; Incyte: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Mauro: Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Moiraghi: Novartis, Pfizer, Takeda: Speakers Bureau. Pavlovsky: Novartis, BMS, Pfizer, Takeda: Speakers Bureau. Rosti: Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb, Incyte, Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Undurraga: AbbVie, Janssen, Novartis, Pfizer, Roche: Other: Advisory Board; Janssen, Novartis, Pfizer: Speakers Bureau. Lu: Takeda: Current Employment. Vorog: Takeda: Current Employment. Cortes: Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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