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In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 7084-7084

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2014.32.15_suppl.7084

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2014

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 15_suppl ( 2014-05-20), p. 7023-7023

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2014.32.15_suppl.7023

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2014

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. e18052-e18052

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2015.33.15_suppl.e18052

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2015

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 7012-7012

Abstract: 7012 Background: The tyrosine kinase inhibitor (TKI) ponatinib has potent activity against native and mutant BCR-ABL1 and is approved for use in pts with relapsed/intolerant CML or Ph+ ALL, or with BCR-ABL1/T315I. Methods: In the pivotal PACE study (NCT01207440), ponatinib (starting dose 45 mg/d) was assessed in pts with CML or Ph+ ALL resistant/intolerant to dasatinib or nilotinib, or with T315I. In Oct ’13, dose reductions were implemented due to observed arterial occlusive events (AOEs). Efficacy and safety at 5 yrs (data as of 3 Oct ’16) for CP-CML pts are reported. Results: Of 270 CP-CML pts in the safety population, 60% received ≥3 prior TKIs. At initiation of study closure, 99 pts were ongoing; among these pts, minimum follow-up was 52 months, and most (78%) had 15 mg/d as their last dose. In all CP-CML pts (n = 267, efficacy evaluable), cumulative response rates were: MCyR, 60%; CCyR, 54%; MMR, 40%; and MR 4.5 , 24%. Among pts who achieved MCyR (n = 148) or MMR (n = 108), the Kaplan-Meier (KM) estimated probability of remaining in response at 5 yrs was 74% (95% CI, 62 – 83) and 61% (95% CI, 51 – 70), respectively. Regardless of dose reduction in Oct ’13, maintenance of response was high (Table). KM estimated 5-yr rate for PFS/OS was 49%/77%. TEAEs in ≥45% of CP-CML pts were rash 47%, abdominal pain 46%, and thrombocytopenia 46%. Most newly occurring AEs were observed within the first year. The incidence of any AOEs/serious AOEs for CP-CML pts was 29%/23%. Among CP-CML pts with no prior AOEs who had a prospective dose reduction, 17% (11/63) had a first AOE occurring after Oct ‘13. Conclusions: Long-term (5-yr) results from PACE demonstrate that ponatinib continues to show clinical benefit, irrespective of dose reductions, with deep and lasting responses in heavily pretreated CP-CML pts. Safety results were consistent with the safety profile across the ponatinib clinical program. Clinical trial information: NCT01207440. [Table: see text]

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2017.35.15_suppl.7012

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2017

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 7013-7013

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2016.34.15_suppl.7013

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2016

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 140, No. Supplement 1 ( 2022-11-15), p. 1495-1497

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2022-157822

Language: English

Publisher: American Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 163-163

Abstract: Abstract 163 Background: Despite progress in Ph+ leukemia therapy, patients who experience failure of tyrosine kinase inhibitors (TKIs) and those with the T315I BCR-ABL mutation have limited treatment options. Ponatinib is an oral TKI developed using computational and structure-based design with optimal binding to the BCR-ABL active site. At clinically achievable concentrations, ponatinib demonstrated potent in vitro activity against native BCR-ABL and all BCR-ABL mutants tested, including T315I. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with Ph+ leukemia were evaluated in a phase 2, international, open-label clinical trial. Methods: 449 patients resistant or intolerant (R/I) to dasatinib or nilotinib or with the T315I mutation confirmed at entry were enrolled and assigned to 1 of 6 cohorts: chronic phase (CP)-CML R/I (N=203), CP-CML T315I (N=64), accelerated phase (AP)-CML R/I (N=65), AP-CML T315I (N=18), blast phase (BP)-CML/Ph+ALL R/I (N=48), BP-CML/Ph+ALL T315I (N=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I and not R/I to dasatinib or nilotinib were treated, but not assigned to a cohort; they were included in safety analyses. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months for CP-CML and major hematologic response (MaHR) at any time within 6 months for advanced Ph+ leukemia. The trial is ongoing. Data as of 23 July 2012 are reported: median follow-up 11 (0.1 to 21) months; minimum follow-up 9 months. Results: Median age was 59 (18–94) yrs; 53% were male. Median time from diagnosis to ponatinib was 6 (0.3–28) yrs. Patients were heavily pretreated: 96% received prior imatinib, 84% dasatinib, 65% nilotinib; median number of prior TKIs was 3, with 53% exposed to all 3 approved TKIs. In patients previously treated with dasatinib or nilotinib (N=427), 88% had a history of resistance and 12% were purely intolerant to dasatinib or nilotinib. Best prior response to most recent dasatinib or nilotinib was 26% MCyR or better in CP-CML, and 23% MaHR or better in advanced Ph+ leukemia. Frequent BCR-ABL mutations confirmed at entry were: 29% T315I, 8% F317L, 4% E255K, 4% F359V, 3% G250E. No mutations were detected in 44%. The primary endpoint response rates (see Table) in each cohort exceeded the prespecified statistical criteria for success. In CP-CML and AP-CML R/I (the 3 largest cohorts), 95% CIs exceeded the prespecified response rate. Median time to response (for responders) was 84 days in CP-CML, 112 days in AP-CML, 55 days in BP-CML/Ph+ALL. Responses were durable; the estimated (Kaplan-Meier) probability of responders maintaining the primary endpoint at 1 yr was 91% in CP-CML, 42% in AP-CML, 35% in BP-CML/Ph+ALL. In CP-CML, 46% had complete cytogenetic response and molecular response rates were 32% MMR, 20% MR4, and 12% MR4.5. Response rates were higher in patients exposed to fewer prior TKIs and those with shorter disease duration. Similar response rates were observed in patients with and without BCR-ABL mutations. In CP-CML, response rates were higher in those with T315I; however, a post hoc analysis found that presence of T315I was not a predictor of response. Instead, the difference in response rate was explained by T315I patients' younger age, shorter duration of leukemia, and exposure to less prior therapy. At the time of analysis, 52% of patients remained on therapy (66% CP-CML). The most frequent reasons for discontinuation were progression (18%) and AEs (12%). The most common drug-related AEs were thrombocytopenia (36%), rash (33%), and dry skin (31%). Pancreatitis was the most common drug-related SAE (5%); however, it occurred early and was managed with dose modification (1 patient discontinued due to pancreatitis). Conclusions: Ponatinib has substantial activity and is generally well tolerated in these heavily pretreated Ph+ leukemia patients who have limited available treatment options. Data with a minimum follow-up of 12 months will be presented. Disclosures: Cortes: Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Kim:Novartis, BMS, Pfizer, ARIAD, Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis, Bristol-Myers Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Deciphera: Research Funding; ARIAD: Research Funding; Celgene: Research Funding; Millenium: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:BMS, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers Squibb, Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, BMS, Pfizer, MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Briston-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.163.163

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3749-3749

Abstract: Abstract 3749 Background: Ponatinib is a potent pan-BCR-ABL inhibitor that is active against native and mutated forms of BCR-ABL, including the uniformly TKI-resistant T315I mutant. The efficacy and safety of ponatinib (45 mg orally once daily) in patients with CP-CML were evaluated in a pivotal phase 2, international, open-label clinical trial. Objectives: This prospectively defined analysis was performed to evaluate the impact that previous exposure to approved TKIs had on the efficacy and safety of ponatinib treatment among patients with CP-CML. Methods: The PACE trial enrolled 449 patients, including 270 patients with CP-CML. Enrolled patients were required to be resistant or intolerant (R/I) to dasatinib or nilotinib, or they had to have the T315I mutation at baseline. Patients with CP-CML were assigned to 1 of 2 cohorts: R/I (N=203) or T315I (N=64). Three patients were post-imatinib and did not have T315I at baseline; they were treated but not assigned to a cohort. The primary endpoint was major cytogenetic response (MCyR) at any time within 12 months after treatment initiation. The trial is ongoing. Data as of 23 July 2012 are reported, with a minimum follow-up of 9 months (median 12 [0.1 to 19] months). The efficacy and safety of ponatinib according to prior approved TKI therapy (imatinib, dasatinib, nilotinib) is presented for the total CP-CML (N=270) population. Results: The median age of CP-CML patients was 60 (18 to 94) years. Median time from initial diagnosis to start of ponatinib was 7 (0.5 to 27) years. Patients were heavily pretreated: 97% had received prior imatinib, 80% dasatinib, 68% nilotinib; 7% of patients had received 1 prior approved TKI, 40% 2 prior approved TKIs, 53% all 3 prior approved TKIs; 60% had received ≥3 prior approved/investigational TKIs. In patients previously treated with dasatinib or nilotinib (N=256), 84% had a history of resistance and 16% were purely intolerant to dasatinib or nilotinib. At the time of analysis, 66% of patients remained on study. The most common reasons for discontinuation were adverse events (AEs; 12%) and progressive disease (7%). Response rates according to the number of prior approved TKIs are shown in the table below. Patients receiving fewer prior approved TKIs had higher response rates. The difference in MCyR rate was statistically significant for patients previously treated with 1 vs. 3 approved TKIs (p=0.003) and for patients previously treated with 2 vs. 3 approved TKIs (p=0.011). Differences in MMR rates were not statistically significant. Of patients achieving MCyR, 98% of patients receiving 2 prior approved TKIs and 83% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MCyR at 1 year. Of patients achieving MMR, 86% of patients receiving 2 prior approved TKIs and 80% of patients receiving 3 prior approved TKIs were predicted (Kaplan-Meier) to remain in MMR at 1 year. Kaplan-Meier estimates were not calculable for patients receiving 1 prior TKI. The most common treatment-related AEs according to number of prior approved TKIs (1, 2, 3, respectively) were thrombocytopenia (32%, 38%, 44%), rash (37%, 37%, 39%), dry skin (37%, 36%, 39%), abdominal pain (21%, 26%, 28%), and headache (26%, 28%, 19%). Rash, dry skin, abdominal pain, and headache were generally grade 1 or 2 in severity. Thrombocytopenia was typically reported early in treatment and was manageable with or without dose reductions and/or dose interruptions. Conclusions: Ponatinib has substantial activity in patients with CP-CML, with higher response rates and improved tolerability observed in patients receiving fewer prior approved TKIs. Data with a minimum follow-up of 12 months will be presented. Disclosures: Kim: Novartis, BMS, Pfizer, ARIAD, and Il-Yang: Consultancy, Employment, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Cortes:Novartis, BMS, ARIAD, Pfizer, and Chemgenex: Consultancy, Research Funding. Pinilla-Ibarz:Novartis, BMS: Research Funding, Speakers Bureau. le Coutre:Novartis and BMS: Honoraria. Paquette:ARIAD: Consultancy. Chuah:Novartis and Bristol Myers-Squibb: Honoraria. Nicolini:Novartis, Bristol Myers Squibb, Pfizer, ARIAD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Apperley:Novartis, Bristol Myers-Squibb, and ARIAD: Honoraria, Research Funding. Talpaz:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Celgene: Research Funding; ARIAD: Research Funding; Deciphera: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Abruzzese:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rea:Bristol Myers-Squibb, Novartis, and Teva: Honoraria. Baccarani:ARIAD, Novartis, Bristol Myers-Squibb, and Pfizer: Consultancy, Honoraria, Speakers Bureau. Muller:ARIAD: Consultancy. Wong:MolecularMD Corp: Employment, Equity Ownership. Lustgarten:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Rivera:ARIAD Pharmaceuticals, Inc.: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Turner:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership. Guilhot:ARIAD: Honoraria. Hochhaus:ARIAD, Novartis, Bristol Myers-Squibb, Pfizer, and MSD: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hughes:Novartis, BMS, ARIAD: Honoraria, Research Funding. Goldman:Novartis, Bristol Myers-Squibb, and Amgen: Honoraria. Shah:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy. Kantarjian:Pfizer: Research Funding; BMS: Research Funding; Novartis: Consultancy, Research Funding; ARIAD: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.3749.3749

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 307-307

Abstract: 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-ABL1 IS in cohorts A and B. Pts could re-escalate to their original starting dose for loss of response. The primary endpoint is ≤1% BCR-ABL1 IS 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 ( & gt;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-ABL1 IS 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-ABL1 IS 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-ABL1 IS. 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-ABL1 IS 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. Figure 1 Figure 1. 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: Steward Cross: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Other: Travel, Research Funding; Novartis, Korea Otsuka Pharmaceutical: Honoraria. Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: 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: Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Sun Pharma / SPARC: Research Funding; Pfizer: Consultancy. 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: 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; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-145995

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 2550-2550

Abstract: Introduction: Ponatinib is a potent, oral, third-generation tyrosine kinase inhibitor (TKI) that is FDA approved for treatment of patients with relapsed/refractory CML. Patients with resistant or intolerant CP-CML demonstrated deep, lasting responses to ponatinib 45 mg once daily in the pivotal phase 2 PACE trial (Ponatinib Ph+ ALL and CML Evaluation, NCT01207440; completed). The phase 2 OPTIC trial (Optimizing Ponatinib Treatment in CP-CML, NCT02467270; ongoing) prospectively evaluated a response-based dose-reduction strategy in an attempt to optimize the dose schedule of ponatinib in patients with CP-CML resistant to second-generation (2G) BCR-ABL1 TKI therapy or with a T315I mutation. Unique dosing strategies in the 2 trials (PACE and OPTIC) provide the opportunity to closely evaluate the dose and schedule of ponatinib. Here, we conduct an in-depth analysis of dosing dynamics between the 2 trials and compare efficacy and safety outcomes. Methods: In this analysis, adults with resistant or intolerant CP-CML from the PACE and OPTIC trials were enrolled and received an initial dose of ponatinib 45 mg once daily (PACE) or were randomly assigned (1:1:1) to an initial oral dose of ponatinib 45 mg, 30 mg, or 15 mg once daily (OPTIC). In PACE, proactive dose reductions were mandated in ≈2 years from initiation of first patient (in 2013) as arterial occlusive events (AOEs) emerged as notable adverse events (AEs); patients who achieved major cytogenetic response (MCyR) had doses reduced to 15 mg once daily and those without MCyR reduced to 30 mg once daily, unless benefit-risk analysis justified treatment with a higher dose. OPTIC was designed to incorporate a mandatory response-based dose-reduction strategy; patients in the 45-mg and 30-mg cohorts in OPTIC achieving ≤1% BCR-ABL1 IS reduced their dose to 15 mg once daily; doses also were reduced to manage AEs. Data from patients with CP-CML in PACE and from the 45-mg starting dose cohort in OPTIC are included in this analysis. Efficacy outcomes included ≤1% BCR-ABL1 IS, progression-free survival (PFS), and overall survival (OS). Safety and dosing data are also presented, including treatment-emergent adverse events (TEAEs) and treatment-emergent AOE (TE-AOE) rates. Results: Overall, 364 patients with CP-CML had at least 1 prior 2G TKI or had a T315I mutation and received a starting dose of ponatinib 45 mg (PACE, n=270; OPTIC, n=94). Median follow-up, 57 months (PACE) and 32 months (OPTIC). Efficacy outcomes were generally comparable or better in OPTIC when compared with PACE, including ≤1% BCR-ABL1 IS response by 24 months (PACE, 52%; OPTIC, 56%), 2-year PFS (68%; 80%), and 2-year OS (86%; 91%). Median time to ≤1% BCR-ABL1 IS response, 5.6 months (PACE) and 6 months (OPTIC). Median duration of response was not reached in either trial. Overall, median relative dose intensity (Table 1) was 27 mg/d in PACE and 15 mg/d in OPTIC, and dose reduction occurred more rapidly compared with PACE median (Figure). Dose reductions due to AEs occurred in 82% of patients in PACE and 46% in OPTIC. Median time to dose reduction for AEs was 2.85 months in PACE and 3.64 months in OPTIC. Median time on therapy was 12.6 months in PACE and 19.5 months in OPTIC. Exposure-adjusted TE-AOEs were 15.8 events per 100-patient years at 0 to & lt;1 year in PACE and 7.6 events per 100-patient years at 0 to & lt;1 year in OPTIC (Table 2). There were differences in baseline characteristics between the 2 trials, including differences in cardiovascular baseline status; however, these were accounted for in the propensity score analyses comparing AOE incidence, which after adjusting for baseline differences, showed a 60% reduction in relative risk for AOEs in OPTIC vs PACE. In-depth individual dosing dynamics by safety and efficacy will be presented. Conclusions: The response-based dose-reduction strategy in the OPTIC trial resulted in more rapid dose reductions, lower overall median relative dose intensity, fewer dose reductions related to AEs, and longer median time on therapy in OPTIC compared with PACE, further demonstrating the benefit of the response-based dosing regimen used in OPTIC. These data from the PACE and OPTIC trials suggest that treatment with a response-based dose-reduction strategy may provide comparable or better efficacy while mitigating risk of AEs/AOEs with ponatinib. Furthermore, this abstract supports the rationale to explore response-based dose-modification strategies for other BCR-ABL1 TKIs. Figure 1 Figure 1. Disclosures Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Deininger: 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; Novartis: Consultancy, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Incyte: Consultancy, Honoraria, Research Funding. Abruzzese: Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes: Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Chuah: Pfizer: Other: Travel, Research Funding; Steward Cross: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis, Korea Otsuka Pharmaceutical: Honoraria. DeAngelo: Abbvie: Research Funding; Takeda: Consultancy; Servier: Consultancy; Pfizer: Consultancy; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Incyte: Consultancy; Forty-Seven: Consultancy; Autolus: Consultancy; Amgen: Consultancy; Agios: Consultancy; Blueprint: Research Funding; Glycomimetrics: Research Funding. Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Nicolini: BMS: Honoraria; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau; MEI, Sunesis: Research Funding; Sellas: Other: ), patents/royalties/other intellectual property; AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rosti: Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb, Incyte, Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Mauro: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding. Shah: Bristol-Myers Squibb: Research Funding. Talpaz: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support ; Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Imago: Consultancy; Celgene: Consultancy. Vorog: Takeda: Current Employment. Lu: Takeda: Current Employment. Kantarjian: Daiichi-Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; BMS: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; KAHR Medical Ltd: Honoraria; Pfizer: Honoraria, Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Astellas Health: Honoraria; NOVA Research: Honoraria; Ascentage: Research Funding; Aptitude Health: Honoraria; Immunogen: Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-146175

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7