ALBERT

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.