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2871 Ponatinib Versus Imatinib in Patients with Newly Diagnosed Ph+ ALL: Subgroup Analysis of the Phase 3 Phallcon Study

Program: Oral and Poster Abstracts
Session: 614. Acute Lymphoblastic Leukemias: Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, Research, clinical trials, ALL, adult, Clinical Research, Diseases, Lymphoid Malignancies, Study Population, Human
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Ibrahim Aldoss, MD1, Josep-Maria Ribera, MD, PhD2, Hagop Kantarjian, MD3, Pau Montesinos, PhD, MD4*, Jessica T. Leonard, MD5, David Gomez-Almaguer, MD6, Maria R. Baer, MD7, Carlo Gambacorti-Passerini, MD8, James McCloskey, MD9, Yosuke Minami, MD, PhD10, Cristina Papayannidis, MD, PhD11*, Vanderson Rocha, MD, PhD, MS12*, Philippe Rousselot, MD, PhD13*, Pankit Vachhani, MD14, Eunice S. Wang, MD15, Meliessa Hennessy, MPH16*, Niti Patel, PhD16*, Alexander Vorog, MD16*, Bingxia Wang, PhD16* and Elias Jabbour17

1City of Hope National Medical Center, Duarte, CA
2ICO Badalona-Hospital Universitari Germans Trias i Pujol, Josep Carreras Leukaemia Research Institute, Badalona, Spain
3Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
4Hospital Universitari i Politecnic La Fe de Valencia, Valencia, Spain
5Oregon Health and Science University, Portland, OR
6Hospital Universitario, UANL; Dr. José Eleuterio Gonzalez, Monterrey, Mexico
7Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
8University Milano-Bicocca, Monza, Italy
9Hackensack University Medical Center, Hackensack, NJ
10National Cancer Center Hospital East, Kashiwa, Japan
11IRCCS Azienda Ospedaliero-Universitaria di Bologna Istituto di Ematologia “Seràgnoli”, Bologna, Italy
12Instituto do Câncer do Estado de São Paulo, University of São Paulo, São Paulo, Brazil
13Centre Hospitalier de Verailles, UMR1184, University Versailles Paris-Saclay, Versailles, France
14University of Alabama at Birmingham, Birmingham, AL
15Roswell Park Comprehensive Cancer Center, Buffalo, NY
16Takeda Development Center Americas, Inc., Lexington, MA
17University of Texas M.D. Anderson Cancer Ctr., Houston, TX

Background: BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy or steroids remain the standard of care in patients with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). Most patients treated with first- or second-generation TKIs eventually experience disease progression due to treatment resistance. Ponatinib is the only currently approved pan-BCR::ABL1 inhibitory TKI that potently inhibits wild-type and single resistance mutation variants of BCR::ABL1, including T315I. Multiple studies have shown promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with ponatinib in combination with chemotherapy or chemotherapy-free regimens. PhALLCON (NCT03589326) is the first randomized study comparing frontline TKIs in adults with Ph+ ALL. The primary endpoint for PhALLCON was met, with a clinically significantly higher MRD-neg complete remission (CR) rate at end of induction (EOI) with ponatinib vs imatinib (34.4% vs 16.7%; risk difference: 0.18 [95% confidence interval (CI): 0.06‒0.29]; P=0.0021) and a manageable safety profile comparable with imatinib. Here we report subgroup efficacy analyses from PhALLCON.

Methods: This global, registrational, phase 3, open-label study randomized newly diagnosed adult patients with Ph+ ALL 2:1 to receive ponatinib (30 mg once daily [QD]) or imatinib (600 mg QD) plus reduced-intensity chemotherapy through EOI (Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). Following post-consolidation, patients continued to receive single-agent ponatinib or imatinib until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg (BCR::ABL1 ≤0.01% [MR4]) CR for 4 weeks at EOI. Event-free survival (EFS; any-cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. A post-hoc analysis of progression-free survival (PFS; EFS-defined events, failure to achieve MRD-neg by the end of treatment, and loss of MRD-neg) was conducted. Subgroup analyses were performed relative to baseline demographic and disease characteristics.

Results: Of 245 randomized patients, 232 (ponatinib, n=154; imatinib, n=78) had baseline BCR::ABL1 p190/p210 variants verified by central lab (efficacy-evaluable population); median age was 54 years (37.1% ≥60 years). As of Aug 2022, 78 patients (ponatinib/imatinib: 68 [41.5%]/10 [12.3%]) remained on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (HSCT; 30.5%/37.0%), adverse events (12.2%/12.3%), and lack of efficacy (7.3%/25.9%). Median follow-up in the ponatinib and imatinib arms was 20 months and 18 months, respectively. Benefit for ponatinib was observed across all subgroups analyzed (Table). All age subgroups had higher rates of MRD-neg CR with ponatinib vs imatinib, with the greatest benefit observed in patients ≥60 years (40.0% ponatinib vs 10.3% imatinib; P=0.0005). MRD-neg CR rate was higher for ponatinib vs imatinib among those with the BCR::ABL1 p190 variant (38.6%/17.0%; P=0.0017); it was higher for the p210 variant as well, but not significantly (22.5% vs 16.0%; P=0.51). Median PFS was longer with ponatinib vs imatinib regardless of age, with the greatest difference observed in the subgroup of patients ≥60 years (22.5 months for ponatinib vs 8.3 months for imatinib; hazard ratio: 0.594 [95% CI: 0.332–1.063]).

Conclusions: Ponatinib was superior to imatinib in combination with reduced-intensity chemotherapy in the front-line setting for patients with Ph+ ALL, with a clinically significantly higher MRD-neg CR rate at EOI. Benefit was observed across all subgroups, particularly for patients ≥60 years and for those with the BCR::ABL1 p190 variant.

Disclosures: Aldoss: Jazz: Consultancy; Takeda: Consultancy; Pfizer: Consultancy; Sobi: Consultancy; Amgen: Consultancy, Honoraria; KiTE: Consultancy. Ribera: AMGEN: Research Funding; Takeda: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding. Kantarjian: Bristol-Myers Squibb (Inst): Research Funding; Novartis (Inst): Research Funding; Daiichih-Sankyo (Inst): Honoraria, Research Funding; AstraZeneca/MedImmune: Honoraria; Ipsen: Honoraria; Precision Biosciences: Honoraria; Novartis: Honoraria; Immunogen (Inst): Honoraria, Research Funding; Astellas Pharma: Honoraria; Ascentage Pharma Group: Honoraria; Jazz Pharmaceuticals (Inst): Honoraria, Research Funding; Taiho Pharmaceutical: Honoraria; Shenzhen Target Rx: Honoraria; KAHR Medical: Honoraria; Abbvie (Inst): Research Funding; Amgen (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Pfizer: Honoraria; Abbvie: Consultancy, Honoraria; Amgen: Honoraria. Montesinos: Astellas: Consultancy, Speakers Bureau; GILEAD: Consultancy; BMS: Consultancy, Other, Research Funding; Celgene: Consultancy; Janssen: Speakers Bureau; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding, Speakers Bureau; Ryvu: Consultancy; Jazz pharma: Consultancy, Research Funding, Speakers Bureau; Menarini-Stemline: Consultancy, Research Funding; BEIGENE: Consultancy; INCYTE: Consultancy; Abbvie: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding; Kura oncology: Consultancy; OTSUKA: Consultancy; NERVIANO: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Leonard: Pfizer: Consultancy; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, expenses; Kite/Gilead: Consultancy; Takeda: Consultancy. Gomez-Almaguer: AMGEN: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Honoraria; AbbVie: Consultancy, Honoraria. Baer: Kite, a Gilead company (Inst): Research Funding; FORMA Therapeutics (Inst): Research Funding; Ascentage Pharma (Inst): Research Funding; Abbvie (Inst): Research Funding; Kura Oncology (Inst): Research Funding; Takeda (Inst): Research Funding. McCloskey: Bristol-Myers Squibb/Pfizer: Consultancy, Honoraria, Speakers Bureau; Amgen: Speakers Bureau; BluPrint Oncology: Honoraria; Blueprint Medicines: Consultancy; Incyte: Speakers Bureau; Jazz Pharmaceuticals: Speakers Bureau; Novartis: Consultancy; BluePrint Health: Speakers Bureau; Stemline Therapeutics: Speakers Bureau; Takeda: Speakers Bureau. Minami: Taiho Pharmaceutical: Research Funding; Takeda: Research Funding; Tejin Pharma: Research Funding; Sumitomo Pharma Oncology: Research Funding; Shionogi: Research Funding; Sanofi: Research Funding; Otsuka: Research Funding; Nippon Shinyaku: Research Funding; Nihonkayaku: Research Funding; Kyowa Hakko Kirin: Research Funding; Dainippon Sumitomo Pharma: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Honoraria; Shinogi: Honoraria; Sanofi: Honoraria; Otsuka: Honoraria; Ono Pharmaceutical: Honoraria; Merck: Honoraria; Meiji Seika Kaisha: Honoraria; Lilly: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Abbvie: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Takeda: Honoraria; Novartis Pharma KK: Honoraria. Rousselot: Takeda: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Incyte: Consultancy. Vachhani: Cogent Biosciences: Consultancy; Incyte: Consultancy, Speakers Bureau; CTI BioPharma Corp: Consultancy, Speakers Bureau; Daiichi Sankyo: Consultancy; GlaxoSmith Kline: Consultancy; Karyopharm: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Genentech: Consultancy; Servier: Consultancy; Stemline: Consultancy; MorphoSys: Consultancy; LAVA therapeutics: Consultancy; Blueprint Medicines: Consultancy, Speakers Bureau; Amgen: Consultancy; AbbVie: Consultancy. Wang: Takeda: Consultancy; Dava oncology: Speakers Bureau; PharmaEssentia: Consultancy; Kura Oncology: Speakers Bureau; Abbvie: Consultancy; Astellas: Consultancy, Speakers Bureau; Kite: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy; Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Consultancy; Gilead: Consultancy; Jazz: Consultancy. Hennessy: Takeda: Current Employment. Patel: Takeda: Current Employment. Vorog: Takeda: Current Employment. Wang: Takeda: Current Employment. Jabbour: Hikma Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Adaptive Biotech: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Ascentage Pharma Group: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astex: Honoraria, Research Funding.

*signifies non-member of ASH