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.