Population Pharmacokinetics of Asciminib in Tyrosine Kinase Inhibitor-Treated Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic and Acute Phases.

Asciminib, a first-in-class, highly potent and specific ABL/BCR-ABL1 inhibitor, has shown superior efficacy compared to bosutinib in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase, treated with two or more tyrosine kinase inhibitors. This study aimed to describe pharmacokinetic (PK) properties of asciminib and to identify clinically relevant covariates impacting its exposure. A population PK (PopPK) model was developed using a two-compartment model with delayed first-order absorption and elimination. The analysis included PK data from two clinical studies (Phases 1 and 3) involving 353 patients, with total daily dose of asciminib in the range of 20-400 mg. The nominal total daily dose was incorporated as a structural covariate on clearance (CL), and body weight (BW) was included as a structural covariate via allometric scaling on CL and central volume. Renal function and formulation were included as statistically significant covariates on CL and absorption (ka), respectively. The simulation results revealed a modest but clinically non-significant effect of baseline BW and renal function on ka. Correlations between covariates, such as baseline demographics and disease characteristics, heavy smoking status, hepatic function, and T315I mutation status, were not statistically significant with respect to CL, and they were not incorporated in the final model. Additionally, the final model-based simulations demonstrated comparable exposure and CL for asciminib 40 mg twice daily and 80 mg once daily (an alternative regimen not studied in the Phase 3 trial), as well as similar PK properties in patients with and without the T315I mutation. The final PopPK model adequately characterized the PK properties of asciminib and assessed the impact of key covariates on its exposure. The model corroborates the use of the approved asciminib dose of 80 mg total daily dose as 40 mg twice daily, and supports the use of 80 mg once daily as an alternative dose regimen to facilitate patient's compliance. TRIAL REGISTRATION NUMBER [DATE OF REGISTRATION]: First-in-human (CABL001X2101, Phase 1), ClinicalTrials.gov identifier: NCT02081378 [28 February 2014]; ASCEMBL (CABL001A2301, Phase 3), ClinicalTrials.gov identifier: NCT03106779 [10 April 2017].

Li YF ，Combes FP ，Hoch M ，Lorenzo S ，Sy SKB ，Ho YY ... -  《-》

Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure.

Asciminib is an allosteric inhibitor that binds a myristoyl site of the BCR-ABL1 protein, locking BCR-ABL1 into an inactive conformation through a mechanism distinct from those for all other ABL kinase inhibitors. Asciminib targets both native and mutated BCR-ABL1, including the gatekeeper T315I mutant. The safety and antileukemic activity of asciminib in patients with Philadelphia chromosome-positive leukemia are unknown. In this phase 1, dose-escalation study, we enrolled 141 patients with chronic-phase and 9 with accelerated-phase chronic myeloid leukemia (CML) who had resistance to or unacceptable side effects from at least two previous ATP-competitive tyrosine kinase inhibitors (TKIs). The primary objective was to determine the maximum tolerated dose or the recommended dose (or both) of asciminib. Asciminib was administered once or twice daily (at doses of 10 to 200 mg). The median follow-up was 14 months. Patients were heavily pretreated; 70% (105 of 150 patients) had received at least three TKIs. The maximum tolerated dose of asciminib was not reached. Among patients with chronic-phase CML, 34 (92%) with a hematologic relapse had a complete hematologic response; 31 (54%) without a complete cytogenetic response at baseline had a complete cytogenetic response. A major molecular response was achieved or maintained by 12 months in 48% of patients who could be evaluated, including 8 of 14 (57%) deemed to have resistance to or unacceptable side effects from ponatinib. A major molecular response was achieved or maintained by 12 months in 5 patients (28%) with a T315I mutation at baseline. Clinical responses were durable; a major molecular response was maintained in 40 of 44 patients. Dose-limiting toxic effects included asymptomatic elevations in the lipase level and clinical pancreatitis. Common adverse events included fatigue, headache, arthralgia, hypertension, and thrombocytopenia. Asciminib was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ponatinib had failed and those with a T315I mutation. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02081378.).

Hughes TP ，Mauro MJ ，Cortes JE ，Minami H ，Rea D ，DeAngelo DJ ，Breccia M ，Goh YT ，Talpaz M ，Hochhaus A ，le Coutre P ，Ottmann O ，Heinrich MC ，Steegmann JL ，Deininger MWN ，Janssen JJWM ，Mahon FX ，Minami Y ，Yeung D ，Ross DM ，Tallman MS ，Park JH ，Druker BJ ，Hynds D ，Duan Y ，Meille C ，Hourcade-Potelleret F ，Vanasse KG ，Lang F ，Kim DW ... -  《-》

Dose Justification for Asciminib in Patients with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia with and Without the T315I Mutation.

Asciminib is approved in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) treated with ≥ 2 prior tyrosine kinase inhibitors. Here, we aimed to demonstrate similarity in efficacy/safety of asciminib 80 mg once daily (q.d.) versus 40 mg twice daily (b.i.d.) in patients with CML-CP without T315I mutation and support the use of the 200-mg b.i.d. dosage in patients harboring T315I, using model-informed drug development. Data were collected from 199 patients in the phase I (NCT02081378; 10-200 mg b.i.d. or 10-400 mg q.d.) and 154 patients in the phase III (NCT03106779; 40 mg b.i.d.) studies. Evaluations were based on population pharmacokinetics (PopPK) and exposure-response (efficacy/safety) analyses. PopPK showed comparable exposure (area under the curve, AUC0-24h) for 40 mg b.i.d. and 80 mg q.d. (12,638 vs 12,646 ng*h/mL); average maximum and minimum plasma concentrations for 80 mg q.d. were 1.61- and 0.72-fold those of 40 mg b.i.d., respectively. Exposure-response analyses predicted similar major molecular response rates for 40 mg b.i.d. and 80 mg q.d. (Week 24: 27.6% vs 24.8%; Week 48: 32.3% vs 30.6%). Results also established adequacy of 200 mg b.i.d. in patients with T315I mutation (Week 24: 20.7%; Week 48: 23.7%), along with a similar safety profile for all dose regimens. Similarity between 40 mg b.i.d. and 80 mg q.d. regimens was investigated, demonstrating similar and substantial efficacy with well-tolerated safety in patients without T315I mutation. The 200-mg b.i.d. dose was deemed safe and effective for patients with T315I mutation.

Combes FP ，Sy SKB ，Li YF ，Lorenzo S ，Dasgupta K ，Kapoor S ，Hoch M ，Ho YY ... -  《-》

Exposure-Efficacy Analysis of Asciminib in Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase.

Asciminib (Scemblix) is a first-in-class BCR::ABL1 inhibitor that works by specifically targeting the ABL myristoyl pocket (STAMP) and has potent activity against the T315I mutation. This study aimed to characterize the effect of asciminib exposure on disease progression and to elucidate factors influencing efficacy. Our analysis included 303 patients with chronic myeloid leukemia in chronic phase recruited in a phase I study with dose ranging from 10 to 200 mg twice a day (b.i.d.) or 40 to 200 mg once a day (q.d.) (NCT02081378) and in the phase III ASCEMBL (Study of Efficacy of CML-CP Patients Treated With ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs) study receiving asciminib 40 mg b.i.d. (NCT03106779). A total of 67 patients harbored the T315I mutation. A longitudinal pharmacokinetic/pharmacodynamic model was developed to characterize the exposure-efficacy relationship, in which the efficacy was assessed through BCR::ABL1 transcript levels over time. Specifically, a three-compartment model representing quiescent leukemic stem cells, proliferating bone marrow cells, and resistant cells was developed. Drug killing of the proliferating cells by asciminib was characterized by a power model. A subgroup analysis was performed on the patients with the T315I mutation using a maximum drug effect model to characterize the drug effect. The model demonstrated the appropriateness of a total daily dose of asciminib 80 mg in patients without the T315I mutation and 200 mg b.i.d. in patients with the T315I mutation with further validation in light of safety data. This model captured key characteristics of patients' response to asciminib and helped inform dosing rationale for resistant and difficult-to-treat populations.

Combes FP ，Li YF ，Hoch M ，Lorenzo S ，Ho YY ，Sy SKB ... -  《-》

Asciminib vs bosutinib in CML patients pretreated with ≥2 tyrosine kinase inhibitors: Results from the Japanese subgroup analysis of ASCEMBL study.

Asciminib, a first-in-class, allosteric inhibitor of BCR-ABL1 that acts by STAMP (Specifically Targeting the ABL Myristoyl Pocket), is a novel therapeutic option for patients with chronic myeloid leukemia (CML). In the global, phase 3, open-label ASCEMBL study in patients with CML in chronic phase (CML-CP) pretreated with ≥2 tyrosine kinase inhibitors (TKIs) (NCT03106779), asciminib (40 mg twice-daily) demonstrated significant superiority over the ATP-competitive TKI bosutinib (500 mg once daily) for the primary endpoint of major molecular response (MMR; BCR::ABL1 transcript levels on the international scale [BCR::ABL1IS ] ≤0.1%) at week 24. Here, we report results from a descriptive subgroup analysis of Japanese patients enrolled in ASCEMBL study (data cut-off: May 25, 2020). Overall, 16 Japanese patients were randomized (asciminib, n = 13; bosutinib, n = 3). At week 24, the MMR rate with asciminib was 30.8% (4/13; 95% confidence interval [CI], 9.09-61.43). BCR::ABL1IS ≤1% and complete cytogenic response (CCyR) at week 24 were 61.5% (8/13 patients) and 50.0% (4/8 patients), respectively. In the bosutinib group, no patient achieved MMR, CCyR, or BCR::ABL1IS ≤1%, but results were limited by the low number of patients. The safety profile of asciminib was comparable to that previously observed in the overall study population. Findings from this Japanese subgroup analysis of the ASCEMBL study support the use of asciminib for the treatment of Japanese patients with CML-CP previously treated with ≥2 TKIs. ClinicalTrials.gov Identifier: NCT03106779.

Yuda J ，Doki N ，Matsuoka H ，Yokota T ，Tomita A ，Takahashi N ，Matsumura I ，Kubo K ，Goto T ，Kirito K ，Maki A ，Aoki M ，Allepuz A ，Minami Y ... -  《Cancer Medicine》