ALBERT

Description: All tyrosine kinase inhibitors (TKIs) approved to treat chronic myeloid leukemia (CML) inhibit BCR-ABL1 by targeting the ATP-binding site. Some patients (pts) develop mutations (muts) conferring resistance to these TKIs. The T315I mut confers resistance to all TKIs except ponatinib (PON), which is known to be efficacious. However, pts with cardiovascular (CV) risk factors might not be eligible for PON, and pts failing PON have no other targeted therapies available; thus, new treatments are needed for pts with the T315I mut. Asciminib is a new, potent, and specific TKI targeting the BCR-ABL1 myristoyl-binding site, an allosteric regulatory domain, and has potential to treat pts carrying muts conferring resistance to ATP-binding-site TKIs, including T315I. Preclinical in vitro data showed asciminib activity in BaF3 cells expressing the BCR-ABL1 construct and various muts, including T315I; an approximately 4- to 5-fold increase in exposure was required to inhibit the T315I mut relative to other muts (Wylie et al. Nature. 2017;543:733-737; Wylie et al. Blood. 2014;124 [abstract 398]). This phase 1 study (NCT02081378) enrolled pts ≥ 18 y old with CML in chronic phase (CP) or accelerated phase resistant to or intolerant of (R/I) ≥ 2 prior TKIs; pts carrying the T315I mut were eligible after ≥ 1 prior TKI. Pts with uncontrolled CV conditions were excluded. Previous results showed single-agent asciminib was well tolerated and demonstrated activity in pts with CML (Hughes et al. Blood. 2016;128 [abstract 625]). A dose of 40 mg twice daily (BID) was recommended for pts with CML-CP without the T315I mut. Enrolled pts carrying the T315I mut were assigned to asciminib 20 mg BID (1 pt), 40 mg BID (1 pt), 80 mg BID (4 pts), 150 mg BID (7 pts), 160 mg BID (7 pts), 200 mg BID (24 pts), 80 mg once daily (QD; 1 pt), 120 mg QD (4 pts), or 200 mg QD (1 pt) cohorts. We report results from the largest cohort: pts with confirmed T315I mut at screening (tested locally by Sanger sequencing) and treated with asciminib 200 mg BID, which showed the most robust efficacy (data cutoff: April 30, 2018). At the data cutoff, treatment was ongoing in 23/24 pts (95.8%) (Table); 1 pt (4.2%) had ended treatment. Median duration of follow-up and asciminib exposure were both 28.5 wk (range, 0.1-74.7 wk). Most pts had received multiple prior TKIs, and PON was the most recent TKI for 12/24 (50.0%). Pts who were PON naive had underlying conditions, such as CV risk factors. Eight of 24 pts achieved MMR by 24 wk; 1 achieved MMR after 24 wk. Ten of 24 pts had BCR-ABL1 〈 10% on the International Scale (IS) at screening and ≥ 1 postbaseline evaluation; 6/10 (60%) achieved a ≥ 1-log reduction in BCR-ABL1IS by 24 wk. Among PON-naive and PON-R/I pts, 5/11 and 3/13, respectively, achieved MMR by 24 wk (Figure). One PON-R/I pt with isolated T315I at screening lost MMR 3 mo after achieving it (prior TKIs: imatinib, dasatinib, and PON). Analysis of 200 mg BID pharmacokinetic data is planned. A total of 20/24 pts (83.3%) experienced any-grade AEs (grade 3/4, 8/24 [33.3%]); the most frequent any-grade AEs were arthralgia, fatigue, lipase increased, and nausea (4/24 [16.7%] each). Any-grade AEs suspected to be study drug related were reported in 15/24 pts (62.5%; grade 3/4, 3/24 [12.5%]) and most frequently included arthralgia and nausea (3/24 [12.5%] each). One pt experienced a serious AE of grade 3 peripheral arterial occlusive disease requiring angioplasty, not considered study drug related, after 17 mo of treatment. This pt was previously treated with imatinib (33 mo), dasatinib (10 mo), bosutinib (5 mo), and PON (17 mo), started asciminib 3 d after stopping PON, had history of hypertension and stroke (on PON), and was on clopidogrel; the pt had asciminib dose reductions to 160 mg BID at 1.5 mo and 120 mg BID at 4 mo due to AEs but remained on asciminib. No deaths were reported. Overall, asciminib 200 mg BID monotherapy showed a favorable safety profile and clinical efficacy in PON-naive and PON-R/I pts carrying the T315I mut. This cohort will be expanded to enroll additional pts carrying the T315I mut. Asciminib may represent a new option for pts with CML and the T315I mut who are not eligible for PON or have failed PON treatment. Disclosures Rea: Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria. Lang:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Kim:Pfizer: Research Funding; Ilyang: Research Funding; BMS: Research Funding; Novartis: Research Funding. Cortes:Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding; Novartis: Consultancy, Research Funding. Hughes:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: 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. Minami:Taisho-Toyama: Research Funding; Ohtsuka: Honoraria; DaiichiSankyo: Honoraria, Other: Clinical Trial, Research Funding; Sanofi: Honoraria, Research Funding; Ono Yakuhin: Honoraria, Other: Clinical Trial, Research Funding; Eizai: Honoraria, Research Funding; Nippon Chemiphar: Honoraria, Research Funding; Nihon Shinyaku: Research Funding; Mochida: Honoraria; Merck Serono: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Kowa: Honoraria; Yakult: Research Funding; Shire Japan: Honoraria; Teijin Pharma: Research Funding; Takeda: Honoraria, Research Funding; Asahi-Kasei Pharma: Research Funding; DaiNihonSumitomo: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Lilly: Honoraria, Research Funding; MSD: Honoraria, Other: Clinical Trial, Research Funding; Bristol-Myers Squibb: Honoraria, Other: Clinical Trial, Research Funding; Celgene: Clinical Trial, Honoraria; Taiho: Honoraria, Other: Clinical Trial, Research Funding; Pfizer: Honoraria, Research Funding; Janssen: Honoraria; Astellas: Research Funding; AstraZeneca: Other: Clinical Trial; Bayer: Honoraria, Other: Clinical Trial, Research Funding; Behringer: Honoraria, Research Funding; Chugai: Honoraria, Other: Clinical Trial, Research Funding. Breccia:BMS: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Deangelo:Novartis: Consultancy. Hochhaus:Takeda: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Goh:Takeda: Other: Non-financial support, Research Funding; Novartis AG: Honoraria, Other: Non-financial support, Research Funding. le Coutre:Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Deininger:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Blueprint: Consultancy. Etienne:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Sondhi:Novartis: Employment. Mishra:Novartis: Employment. Aimone:Novartis: Employment. Ng-Sikorski:Novartis: Employment. Mauro:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Takeda: Consultancy.

Description: Introduction: In Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd), patients with CML-CP achieved deeper molecular responses and lower rates of progression to accelerated phase/blast crisis (AP/BC) with nilotinib (NIL) vs imatinib (IMA) during the first 5 y of follow-up. Here, we report long-term outcomes with ≥ 10 y of follow-up. Methods: Patients with newly diagnosed CML-CP were randomized to receive NIL 300 mg twice daily (NIL300; n = 282), NIL 400 mg twice daily (NIL400; n = 281), or IMA 400 mg once daily (n = 283) in the ENESTnd core study. Some patients who discontinued their assigned core treatment due to suboptimal response/treatment failure entered an extension study to receive NIL 400 mg twice daily (for those assigned to NIL300 [n = 26] or IMA [n = 48] in the core study) or IMA 400 mg twice daily (for those assigned to NIL400 [n = 3]). In the current analysis, cumulative efficacy and safety results were analyzed by combining all data from the core and extension studies; extension study results were ascribed to each patient's assigned core study treatment arm. Progressions, deaths, and cardiovascular events (CVEs) were also analyzed according to time intervals (time since randomization for progressions; time since treatment initiation for deaths and CVEs), defined as events occurring up to 5 y and those occurring beyond 5 y. Analyses were based on a data cutoff date of April 1, 2019, when all patients had completed ≥ 10 y of treatment or discontinued. Results: As previously reported, patient demographics were well balanced between arms. By the data cutoff, 105 (37.2%), 96 (34.2%), and 98 (34.6%) patients assigned to NIL300, NIL400, and IMA, respectively, completed the full study treatment duration; 175 (62.1%), 182 (64.8%), and 184 (65.0%) patients, respectively, discontinued core treatment early. Cumulative 10-y major molecular response (MMR) rates among patients assigned to NIL300, NIL400, and IMA were 82.6%, 80.4%, and 69.6%, respectively. The cumulative MMR rate reached a plateau at ≈ 3.5 y with NIL300 or NIL400 and 4.5 y with IMA. With NIL300, NIL400, and IMA, cumulative 10-y MR4 rates were 72.7%, 68.7%, and 55.5%, respectively, and cumulative MR4.5 rates were 63.8%, 61.6%, and 45.2%, respectively. The difference between MR4.5 rates achieved with NIL vs IMA by 5 y was similar to that observed by 10 y of study treatment (Figure). Among patients assigned to NIL300, NIL400, and IMA, a total of 11, 7, and 24 patients, respectively, progressed to AP/BC by the data cutoff (including 1, 1, and 5, respectively, after 5 y) (Table). A total of 32, 23, and 29 deaths on study from any cause were reported in the NIL300, NIL400, and IMA arms, respectively; the most common causes were CML (6, 5, and 15 patients, respectively) and infections/infestations (5, 3, and 8, respectively). Of all deaths on study, 16, 14, and 11 in the NIL300, NIL400, and IMA arms, respectively, occurred after 5 y; almost all (37/41) were not CML related (including 10 due to general disorders, 9 due to infections/infestations, 8 due to neoplasms, and 7 due to cardiac or vascular disorders). Kaplan-Meier-estimated 10-y rates of event-free survival and overall survival (OS) are shown in the Table. Adverse events (AEs) leading to discontinuation of study treatment occurred in 67 (24.0%), 98 (35.4%), and 56 (20.0%) patients assigned to NIL300, NIL400, and IMA, respectively; serious AEs occurred in 112 (40.1%), 127 (45.8%), and 97 (34.6%) patients, respectively. Safety profiles of NIL and IMA remained consistent with previous analyses (nonhematologic AEs in ≥ 30% of patients: NIL [either dose], rash, headache, nausea; IMA, diarrhea, nausea, muscle spasms). In each arm, CVE rates in the first 5 y of study treatment were similar to the rates beyond 5 y (Table). Conclusions: NIL showed better long-term efficacy than IMA, with fewer progressions to AP/BC during both the early and later years of the study, and fewer CML-related deaths. MMR and deep molecular response rates were higher with NIL than with IMA throughout the follow-up period. However, CVEs were more frequent with NIL than with IMA in the first 5 y and continued to occur at similar rates beyond 5 y. While the study was not powered for OS, observed 10-year OS rates were similar between NIL and IMA. Overall, these results suggest that the superior efficacy but higher vascular toxicity observed early on with frontline NIL treatment is maintained with long-term treatment. Disclosures Hughes: Novartis: Other: Advisory Board and Symposia, Research Funding; BMS: Research Funding. Saglio:Ariad: Consultancy; Incyte: Consultancy; Jansen: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Larson:Agios: Consultancy; Celgene: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Kantarjian:Daiichi-Sankyo: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Jazz Pharma: Research Funding; Immunogen: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Research Funding. Kim:Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; Il-Yang co.: Research Funding; Takeda: Research Funding. Le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Boquimpani:Novartis: Speakers Bureau; BMS: Speakers Bureau. Clark:Ariad/Incyte: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Flinn:F. Hoffmann-La Roche Ltd: Research Funding; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding; Acerta Pharma, Agios, Calithera Biosciences, Celgene, Constellation Pharmaceuticals, Genentech, Gilead Sciences, Incyte, Infinity Pharmaceuticals, Janssen, Karyopharm Therapeutics, Kite Pharma, Novartis, Pharmacyclics, Portola Pharmaceuticals: Research Funding; AbbVie, Seattle Genetics, TG Therapeutics, Verastem: Consultancy; TG Therapeutics, Trillum Therapeutics, Abbvie, ArQule, BeiGene, Curis, FORMA Therapeutics, Forty Seven, Merck, Pfizer, Takeda, Teva, Verastem, Gilead Sciences, Astra Zeneca (AZ), Juno Therapeutics, UnumTherapeutics, MorphoSys, AG: Research Funding. Sondhi:Novartis: Employment, Other: Stock; Sanofi: Other: Stock. Titorenko:Novartis: Employment. Nourry-Boulot:Novartis: Employment. Aimone:Novartis: Employment. Hochhaus:Incyte: Research Funding; BMS: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. OffLabel Disclosure: This pivotal study of nilotinib for frontline therapy of CML-CP was designed to investigate 2 nilotinib doses. One of the 2 doses is now the approved frontline dose. To accurately report the study results, data for both doses will be presented.

Description: Key Points Nilotinib demonstrated efficacy and a manageable safety profile in pediatric patients with newly diagnosed and pretreated Ph+ CML-CP.

Description: Introduction: Asciminib, unlike all approved TKIs that bind to the ATP site of the BCR-ABL1 oncoprotein, is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action. BOS, an ATP-competitive TKI, has shown clinical efficacy in pts who received ≥2 TKIs and in newly diagnosed CML, in prospective clinical trials. We asked if asciminib could provide superior efficacy to BOS beyond 2nd line, based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 study. Methods: Adults with CML-CP previously treated with ≥2 TKIs were randomized 2:1 to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily (QD). Randomization was stratified by major cytogenetic response (MCyR; Ph+ metaphases ≤35%) status at baseline. Pts intolerant of their most recent TKI were eligible if they had BCR-ABL1IS 〉0.1% at screening (19 pts with BCR-ABL1IS 10% or Ph+ 〉65% after 6 months of therapy (asciminib 10.8%, BOS 25.0%). Among the 24 pts who discontinued BOS due to lack of efficacy, 22 switched to asciminib. At baseline, ≥1 BCR-ABL1 mutation was present in 12.7% pts on asciminib (most common: F359C/V) and 17.1% on BOS (most common: M244V, F317L). Median duration of follow-up was 14.9 months from randomization to cutoff. Median duration of exposure was 43.4 wks (range, 0.1-129.9) for asciminib and 29.2 wks (range, 1.0-117.0) for BOS; median relative dose intensity was 99.7% (87-100) and 95.4% (74-100). MMR rate at 24 wks was 25.5% with asciminib and 13.2% with BOS, meeting the primary objective. The between-arm common treatment difference for MMR at 24 wks, after adjustment for MCyR status at baseline, was 12.2% (95% CI, 2.19-22.3: 2-sided P=.029). Among those pts who achieved MMR, median time to MMR was 12.7 wks and 14.3 wks with asciminib and BOS, respectively. At 24 wks, more pts on asciminib (17 [10.8%] and 14 [8.9%]) than on BOS (4 [5.3%] and 1 [1.3%]) achieved deep molecular response (MR4 and MR4.5, respectively). CCyR rate at 24 wks was 40.8% with asciminib vs 24.2% with BOS. Preplanned subgroup analysis showed that the MMR rate at 24 wks was superior with asciminib than BOS across most major demographic and prognostic subgroups, including in pts who received ≥3 prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline cytogenetic response (Figure). Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of pts receiving asciminib and BOS, respectively. The proportion of pts who discontinued treatment due to AEs was lower with asciminib (5.8%) than BOS (21.1%). Grade ≥3 AEs and AEs requiring dose interruption and/or adjustments were reported less frequently with asciminib than BOS (Table 2). Most frequent grade ≥3 AEs (occurring in 〉10% of pts in any treatment arm) with asciminib vs BOS were thrombocytopenia (17.3%; 6.6%), neutropenia (14.7%; 11.8%), diarrhea (0%, 10.5%), and increased alanine aminotransferase (0.6%, 14.5%). On-treatment deaths occurred in 2 pts (1.3%) on asciminib (ischemic stroke and arterial embolism, 1 pt each) and 1 pt (1.3%) on BOS (septic shock). Conclusions: In this first controlled study comparing treatments for resistant/intolerant (R/I) pts with CML, asciminib, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy compared with BOS (primary objective), deeper MR rates, and a favorable safety profile. These results support the use of asciminib as a new treatment option in CML, particularly in R/I pts who received ≥2 prior TKIs. Disclosures Hochhaus: Novartis: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Boquimpani:Novartis: Speakers Bureau. Rea:BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: 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. Minami:Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria. Lomaia:Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Voloshin:Novartis: Honoraria, Speakers Bureau. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding. Abdo:Novartis: Honoraria; Takeda: Honoraria. Kim:Paladin: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding. le Coutre:Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria. Hughes:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chee:Novartis: Other: Travel support for attendance at investigator meeting. 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. Sasaki:Pfizer Japan: Consultancy; Otsuka: Honoraria; Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy. Aimone:Novartis: Current Employment. Allepuz:Novartis: Current Employment. Quenet:Novartis: Current Employment. Bédoucha:Novartis: Current Employment. Mauro:Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Sun Pharma/SPARC: Research Funding.

Description: Background: Data from the phase 2, single-arm ENESTfreedom study (NCT01784068) have demonstrated the feasibility of treatment-free remission (TFR) following front-line nilotinib (NIL) treatment, with substantial TFR rates being sustained over time among patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). Results for long-term outcomes after a 5-year follow-up are presented here. The current subanalysis evaluated the efficacy and safety of TFR after upfront treatment with NIL in older (≥65 years [yrs] at study entry) vs younger (

Description: Introduction: Tyrosine kinase inhibitors (TKIs) are an effective therapy for pts with CML. However, resistance to treatment driven by point mutations in the ABL kinase domain, particularly the T315I mutation, represents a clinical challenge. The T315I mutation confers resistance to all approved ATP-competitive TKIs except ponatinib (PON) and is associated with significantly worse clinical outcomes. PON use, however, is limited in many patients by its safety profile. Asciminib has a distinct mechanism of action and is the first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor. Asciminib demonstrated clinical activity in heavily pretreated CML pts with or without mutations, with promising efficacy in pts with T315I, including those resistant to/intolerant of (R/I) PON. Methods: This phase 1 study enrolled adults with CML in chronic phase (CP) or accelerated phase (AP) R/I ≥ 2 TKIs; pts with T315I were eligible after receiving ≥ 1 TKI if no other effective therapy was available. Pts with uncontrolled cardiovascular conditions were excluded. Pts with T315I were assigned to varying dose levels in phase 1, and 200 mg twice daily (BID) was selected for cohort expansion. Here, we report updated efficacy and safety results in pts with T315I who received 200 mg BID (data cutoff: April 2, 2020). Results: A total of 52 pts with T315I received asciminib 200 mg BID. At the data cutoff, treatment was ongoing in 35/52 pts (67.3%); 17 (32.7%) discontinued treatment, a majority of whom (10 [19.2%]) discontinued due to physician's decision, mainly for unsatisfactory response (Table 1). Of pts still on treatment, 31/35 (88.6%) received treatment for 〉 48 wk. The median duration of exposure was 68.4 wk (range, 2-175 wk) and median dose intensity was 399.0 mg/day (range, 188-400 mg/day). Among evaluable pts not in major molecular response (MMR) at baseline, 23/49 (46.9%) achieved MMR and 21 of these responders were still in MMR at the time of data cutoff; 40.8%, 42.9%, 44.9%, and 46.9% had MMR by 24, 48, 72, and 96 wk, respectively. The Kaplan-Meier-estimated rate of durable first MMR among pts who achieved MMR was 87% (95% CI, 68.4-100.0) at 96 wk and remained unchanged until 144 wk. The median time to MMR was 12.1 wk (range, 4-84 wk). By 24 wk, 57.1% of PON-naive pts and 28.6% of PON-pretreated pts achieved MMR (Table 2). Three additional pts achieved MMR after 24 wk: 2 PON naive and 1 PON pretreated. The estimated cumulative MMR rate at 60 wk increased to 66% and 32% in PON-naive and PON-pretreated pts, respectively (Figure). Among 26 pts who did not achieve MMR, 3 had additional mutations (E255K, E355G, F359I) at baseline and 6 acquired new mutations after baseline (F359I [n = 2], A337T/F359V, M351T, M244V, E453Q). Among 2 pts who lost MMR, 1 acquired a new F359V mutation. Among evaluable pts without MMRat baseline, 13/49 (26.5%) and 10/49 (20.4%) achieved MR4 and MR4.5, respectively. Treatment-related adverse events (AEs) were reported in 45/52 pts (86.5%) and were mainly mild in severity; grade ≥ 3 AEs were reported in 17/52 pts (32.7%). All-grade serious AEs were reported in 12 pts (23.1%), with 2 (3.8%) deemed treatment related. No on-treatment deaths were reported. On-treatment AEs leading to discontinuation were reported in 4 pts (7.7%; disease progression, grade 2 thrombocytosis, grade 3 lipase elevation, and grade 4 pancytopenia, 1 pt each). Dose reductions and interruptions (excluding dosing errors) were reported in 21 (40.4%) and 22 (42.3%) pts, respectively (reduction and/or interruption in 29 pts total); they were mainly due to AEs (13 [25.0%] and 18 [34.6%] pts, respectively). The most frequent any-grade AEs of special interest (occurring in ≥ 10% of pts) were gastrointestinal toxicity (48.1%), hypersensitivity (26.9%), myelosuppression (25.0%), pancreatic toxicity (25.0%), hepatotoxicity (23.1%), thrombocytopenia (21.2%), hemorrhage (17.3%), leukopenia (15.4%), and edema and fluid retention (13.5%). Ischemic stroke and peripheral arterial occlusive disease were each reported in 1 pt; both pts had underlying cardiovascular disease. Conclusions: Asciminib 200 mg BID monotherapy continued to demonstrate a favorable safety profile and clinical efficacy in pts with CML-CP/AP harboring the T315I mutation, with durable MMR seen in almost half of the patients. Asciminib is a promising therapeutic option for pts with CML-CP/AP with T315I, including those for whom PON treatment has failed. Disclosures Cortes: Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Amphivena Therapeutics: Research Funding; Telios: Research Funding; Immunogen: Research Funding; Merus: Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding. Hughes:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mauro: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; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Hochhaus:Takeda: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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. Janssen:MSD: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Roche: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Daiichi-Sankyo: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Takeda: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Janssen: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Abbvie: Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda; BMS: Other: Founder of the HematologyApp which is supported by Janssen, BMS, Incyte, MSD, Pfizer, Daiichi-Sankyo, Roche and Takeda, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Steegmann:Novartis: Honoraria, Other: Speaker; Bristol-Myers Squibb: Honoraria, Other: Speaker; Incyte: Honoraria, Other: Speaker; Pfizer: Honoraria, Other: Speaker. Heinrich:Novartis: Consultancy, Patents & Royalties: Patent on treatment of GIST licensed to Novartis; Blueprint Medicines: Consultancy; Deciphera: Consultancy, Speakers Bureau. Talpaz:IMAGO: Consultancy; Novartis: Research Funding; 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. Etienne:Pfizer: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Deininger: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; Medscape: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fusion Pharma: Consultancy; Novartis: Consultancy, Other, Research Funding; Incyte: Consultancy, Honoraria, Other, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; SPARC: Research Funding; Pfizer: Honoraria, Other, Research Funding; DisperSol: Consultancy; Galena: Consultancy, Honoraria, Other; Celgene: Research Funding; Gilead Sciences: Research Funding; Leukemia & Lymphoma Society: Research Funding; Ariad: Consultancy, Honoraria, Other; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding. le Coutre:Incyte: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Lang:Bristol-Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding. Aimone:Novartis: Current Employment. Polydoros:Novartis: Current Employment, Current equity holder in publicly-traded company. Cacciatore:Novartis: Current Employment. Stenson:Novartis: Current Employment. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Sun Pharma.: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau.