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3009 Molecular Response of ≤10% BCR::ABL1IS Is Predictive of Positive Outcomes in Treatment-Resistant Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Ponatinib from the Phase 2 Optic Trial

Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
clinical trials, Research, Clinical Research, CML, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Jane F. Apperley, FRCP, FRCPath, MB1, Jorge E. Cortes, MD2, Elias Jabbour, MD3, Andreas Hochhaus4, Timothy Hughes, MD, MBBS, FRACP, FRCPA5, Charles Chuah, MD6*, Hugues de Lavallade, MD7*, Michael W. Deininger, MD, PhD8, Jeffrey H. Lipton, MD, PhD9, Elza Lomaia, MD, PhD10*, Lori Maness, MD11, Michael Mauro, MD12, James McCloskey, MD13*, Beatriz Moiraghi, MD14*, Carolina Pavlovsky15*, Christine Rojas, MD16*, Philippe Rousselot, MD, PhD17*, Tomasz Sacha, MD, PhD18*, Moshe Talpaz, MD19, Anna Turkina, MD20*, Maria Undurraga Sutton21*, Xiaowei Ren22*, Alexander Vorog, MD22* and Gianantonio Rosti23*

1Imperial College London, London, United Kingdom
2Georgia Cancer Center, Augusta, GA
3The University of Texas, MD Anderson Cancer Center, Houston, TX
4Universitätsklinikum Jena, Jena, Germany
5University of Adelaide, Adelaide, Australia
6Singapore General Hospital, Duke-NUS Medical School, Singapore, Singapore
7King's College Hospital NHS Foundation, London, United Kingdom
8Versiti Blood Research Institute, Milwaukee, WI
9Princess Margaret Cancer Centre, Toronto, ON, Canada
10Almazov National Medical Research Centre, St. Petersburg, Russian Federation
11University of Nebraska Medical Center, Omaha, NE
12Memorial Sloan Kettering, New York, NY
13John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ
14Hospital Jose Maria Ramos Mejia, Buenos Aires, Argentina
15Fundaleu, Buenos Aires, Argentina
16Centro de Investigaciones Clinicas Vina del Mar, Valparaíso, Chile
17Centre Hospitalier de Versailles University de Versailles Saint-Quentin-en-Yvelines, Paris, France
18Jagiellonian University Hospital, Kraków, Poland
19Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI
20National Medical Research Center for Hematology, Moscow, Russian Federation (Russia), Moscow, Russian Federation
21Hospital del Salvador, Santiago, Chile
22Takeda Development Center Americas, Inc., Lexington, MA
23IRST/IRCCS “Dino Amadori,”, Meldola (FC), Ravenna, Italy

Background: BCR::ABL1 mutations are key contributing factors to tyrosine kinase inhibitor (TKI) resistance in patients with chronic myeloid leukemia (CP-CML). Ponatinib is a third-generation BCR::ABL1 tyrosine kinase inhibitor (TKI) designed to potently inhibit BCR::ABL1 with or without any single resistance mutation, including T315I. The Phase 2 OPTIC trial evaluated benefit/risk outcomes of ponatinib using a novel response-based dosing strategy in patients with heavily pretreated resistant CP-CML. In the OPTIC trial, all 3 dosing regimens demonstrated benefit in resistant patients, with optimal benefit/risk outcomes observed in patients who received the response-based dosing of 45 → 15 mg/day. Here we present a post hoc analysis of long-term outcomes (progression-free survival [PFS] and overall survival [OS]) of patients in the OPTIC trial who reached landmark clinical responses (≤1%, >1%–≤10%, and >10% BCR::ABL1IS by Months 3, 6, and 12).

Methods: The OPTIC trial design has been previously described (Cortes J, et al. Blood. 2021;138:2042-50). Overall, 99% of patients had treatment-resistant disease; 61% of patients had a best response to their last prior therapy of complete hematologic response or worse; and 84% had a best response of >10% BCR::ABL1IS to prior therapy. This landmark analysis describes PFS and OS in patients with ≤1%, >1%–≤10%, and >10% BCR::ABLIS by Months 3, 6, and 12. Disease progression was defined as the loss of complete hematologic response or major cytogenetic response, development of acute- or blast-phase CML, death, or 2 instances of white blood cell count increases (>20,000 cells/μL, ≥4 weeks apart) after the first 4 weeks of treatment. Patients with ≤1% BCR::ABL1IS at baseline were excluded from this analysis. The probabilities of PFS and OS at 24 months were calculated using the Kaplan-Meier method. The proportion of patients attaining ≤1% BCR::ABLIS by 36 months was also assessed.

Results: A total of 276 patients with resistant CP-CML were included in the intention-to-treat (ITT) population: 45-mg (n=93), 30-mg (n=93), and 15-mg (n=90) starting dose cohorts. At the cutoff date of May 9, 2022, 56 (20%), 78 (28%), and 95 patients (34%) had reached ≤1% BCR::ABL1IS by Months 3, 6, and 12, respectively. Among patients remaining within each dosing cohort at 36 months, most had attained ≤1% BCR::ABLIS (57%–65%). Among all ITT patients within each dosing cohort (45 mg, n=93; 30 mg, n=93; 15 mg, n=90), the highest response rate by 36 months was observed in the 45-mg cohort (35%). Four patients with ≤1% BCR::ABL1IS at baseline were excluded from the landmark analysis. Based on this landmark analysis, regardless of starting dose, patients who attained landmark response levels of ≤1% and >1–≤10% BCR::ABL1IS in 3–12 months had substantially improved PFS outcomes at 24 months compared with patients with >10% BCR::ABL1IS (Table). In the landmark analysis population, patients who did not reach ≤10% BCR::ABL1IS within 12 months had unfavorable PFS outcomes (Table). Long-term OS outcomes in the landmark analysis population were similar across all BCR::ABL1IS levels, regardless of whether response was reached by 3, 6, or 12 months (Table).

Conclusion: Ponatinib provided robust responses in the OPTIC trial population comprising patients with heavily pretreated, TKI-resistant CP-CML. In this landmark analysis, attainment of ≤10% BCR::ABL1IS with ponatinib within 12 months was associated with improved long-term PFS outcomes compared with PFS outcomes associated with remaining at >10% BCR::ABL1IS. These findings underpin the clinical benefit of achieving molecular responses with ponatinib, especially achieving ≤10% BCR::ABL IS within 12 months.

Disclosures: Apperley: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Sun Pharma: Consultancy, Research Funding; Takeda: Consultancy, Honoraria; Gilead: Consultancy; Forma Therapeutic: Consultancy; Biopath Holdings Inc: Consultancy, Current equity holder in private company; Abbvie: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Jabbour: Pfizer: Other: Advisory Role, Research Funding; Bristol Myers Squibb: Other: Advisory Role, Research Funding; Amgen: Other: Advisory Role, Research Funding; Spectrum: Research Funding; Takeda: Other: Advisory Role, Research Funding; Genentech: Other: Advisory Role, Research Funding; Adaptive Biotechnologies: Other: Advisory Role, Research Funding; AbbVie: Other: Advisory Role, Research Funding. Hochhaus: Pfizer: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Incyte: Research Funding. Hughes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Enliven: Consultancy, Research Funding. Chuah: Novartis: Honoraria; Pfizer: Other: Travel, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Steward Cross: Korea Otsuka International Asia Arab: Honoraria; Otsuka [Philippines] Pharmaceutical: Honoraria; Korea Otsuka Pharmaceutical: Honoraria. de Lavallade: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding. Deininger: Galena Biopharma: Consultancy, Honoraria; Pfizer Inc: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Honoraria, Research Funding. Lipton: Bristol Myers Squibb: Consultancy, Research Funding; ARIAD Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Lomaia: Fusion Pharma: Speakers Bureau; Bristol Myers Squibb: Other: Travel, Accommodation, Expenses ; Pfizer: Other: Travel, Accommodation, Expenses , Speakers Bureau; Novartis: Other: Travel, Accommodation, Expenses , Speakers Bureau. Mauro: Sun Pharma/SPARC: Research Funding; AbbVie, Bristol Myers Squibb, Novartis, Pfizer, Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses , Research Funding. McCloskey: AbbVie, CTI BioPharma, and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Amgen, Bristol Myers Squibb, Incyte, Jazz Pharmaceuticals, Stemline, and Takeda: Speakers Bureau. Moiraghi: Takeda: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau. Pavlovsky: Novartis, Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis, Pfizer, BMS, Pint Pharma: Speakers Bureau. Rojas: Janssen: Other: Personal fees; Novartis: Other: Personal fees; Roche: Other: Personal fees; AstraZeneca: Other: Personal fees. Rousselot: Takeda: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding. Sacha: Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; AOP Orphan: Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Angelini: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMs-Celgene: Honoraria, Speakers Bureau. Talpaz: Novartis: Consultancy, Other: Grant/research support ; BMS: Consultancy; IMAGO: Consultancy; Kirin: Membership on an entity's Board of Directors or advisory committees; SDp: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support . Turkina: Novartis: Other: Travel, Accommodation, Expenses , Speakers Bureau; Pfizer: Other: Travel, Accommodation, Expenses , Speakers Bureau; Fusion Pharma: Speakers Bureau. Sutton: Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ren: Takeda: Current Employment. Vorog: Takeda: Current Employment. Rosti: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee , Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee , Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Steering Committee , Speakers Bureau; BMD: Speakers Bureau.

*signifies non-member of ASH