ASCIMINIB IN HEAVILY PRETREATED PATIENTS (PTS) WITH PHILADELPHIA CHROMOSOME–POSITIVE (PH+) CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP) SENSITIVE TO TYROSINE KINASE INHIBITOR (TKI) THERAPY
Author(s): ,
Timothy Hughes
Affiliations:
South Australian Health and Medical Research Institute,University of Adelaide,Adelaide,Australia
,
Michael J. Mauro
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,United States
,
Dong-Wook Kim
Affiliations:
Seoul St Mary's Hospital, Leukemia Research Institute, The Catholic University of Korea,Seoul,Korea, Republic Of
,
Jorge Cortes
Affiliations:
Georgia Cancer Center,Augusta,United States
,
Delphine Réa
Affiliations:
Hôpital Saint-Louis,Paris,France
,
Hironobu Minami
Affiliations:
Kobe University Hospital,Kobe,Japan
,
Massimo Breccia
Affiliations:
Sapienza University,Rome,Italy
,
Daniel J. DeAngelo
Affiliations:
Dana-Farber Cancer Institute,Boston,United States
,
Andreas Hochhaus
Affiliations:
Universitätsklinikum Jena,Jena,Germany
,
Yeow Tee Goh
Affiliations:
Singapore General Hospital,Bukit Merah,Singapore
,
Philipp D. le Coutre
Affiliations:
Charité - Universitätsmedizin Berlin,Berlin,Germany
,
Fabian Lang
Affiliations:
Goethe-Universität Frankfurt am Main,Frankfurt am Main,Germany
,
Silvia Cacciatore
Affiliations:
Novartis Pharma AG,Basel,Switzerland
,
Paola Aimone
Affiliations:
Novartis Pharma AG,Basel,Switzerland
,
Laura Stenson
Affiliations:
Novartis Ireland Limited,Dublin,Ireland
,
Fotis Polydoros
Affiliations:
Novartis Pharma AG,Basel,Switzerland
Moshe Talpaz
Affiliations:
University of Michigan,Ann Arbor,United States
(Abstract release date: 05/14/20) EHA Library. Hughes T. 06/12/20; 294990; S170
Timothy Hughes
Timothy Hughes
Contributions
Abstract

Abstract: S170

Type: Oral Presentation

Session title: CML clinical

Background
Asciminib is a novel, specific inhibitor of BCR-ABL1 that targets the myristoyl binding pocket. Its unique mechanism of action is expected to result in improved safety/tolerability compared with available ATP-binding TKIs. In an ongoing Phase I study (NCT02081378), asciminib is being investigated in heavily pretreated pts with Ph+ CML who are relapsed/refractory to or intolerant of TKI therapies. There is increasing interest in improving molecular responses in pts with some, but not deep, response to TKIs. 

Aims
Evaluate the safety and efficacy of asciminib monotherapy in pts with baseline BCR-ABL1IS ≤ 1%, a population considered to be mainly intolerant of the most recent TKI.

Methods
The study enrolled adults with Ph+ CML in CP or accelerated phase who were relapsed/refractory to or intolerant of ≥ 2 TKIs; informed consent was obtained. Pts were assigned to dose-escalation or -expansion cohorts investigating asciminib monotherapy or combination therapies. For the current analysis, pts enrolled in the monotherapy cohorts (any dose) who had BCR-ABL1IS ≤ 1%, regardless of the reason for TKI discontinuation, and did not have a centrally confirmed T315I mutation at baseline were included. The cutoff date was 30 Aug 2019.

Results
In total, 48 pts in 9 dose cohorts (20, 40, 80, 150, 160, and 200 mg twice daily; 80, 120, and 200 mg once daily) were included; all 48 pts had CML-CP, with a median age of 51 y (range, 30-81). One (2.1%, unconfirmed T315I mutation at baseline), 19 (39.6%), and 28 (58.3%) pts received 1, 2, and > 2 TKIs, respectively; 24 pts (50.0%) discontinued TKIs due to both resistance and intolerance, 13 (27.1%) due to intolerance only, and 11 (22.9%) did not report any prior intolerance. By the cutoff date, 6 pts (12.5%) discontinued treatment due to adverse events (AEs; n = 3: 1 due to chronic kidney disease, 2 due to pancreatic enzyme elevations), progressive disease (n = 2: 1 blast crisis [with unconfirmed T315I mutation at baseline], 1 per investigator decision–increasing BCR-ABL1 levels), or pt decision (n = 1). Median duration of study treatment exposure was 161 wk (range, 2-271), with 42 pts (87.5%) still on treatment and 36 (75.0%) in major molecular response (MMR) or better at the data cutoff. The most common grade 3/4 AEs (> 10%), regardless of study drug relationship, were lipase increase (27.1%) and hypertension (12.5%). Serious AEs, regardless of study drug relationship, were reported in 16/48 pts (33.3%), with myocardial infarction being the most common (n = 2; 4.2%). Among pts without MMR, MR4, or MR4.5 at baseline, cumulative response rates continued to increase over time, even beyond 48 wk, with 18/24 (75.0%), 16/38 (42.1%), and 18/42 (42.9%) pts achieving MMR, MR4, and MR4.5, respectively (Table 1). Median time to MMR among responders was 30 d. All 18 pts who achieved MMR maintained this level of response or better for ≥ 2 y, apart from 3 whose BCR-ABL1IS fluctuated around 0.1% but who were still in MMR at ≈ 60 mo. Among the 6 pts who did not achieve MMR by the cutoff date, 1 pt had BCR-ABL1IS > 1%, and 5 remained between BCR-ABL1IS 0.1% and 1%. Among pts who achieved MR4 or MR4.5, 9/16 (56.3%) and 10/18 (55.6%), respectively, maintained the response for ≥ 2 y.

Conclusion
Asciminib monotherapy was well tolerated and showed promising clinical activity in pts with baseline BCR-ABL1IS ≤ 1%, with 75.0% remaining on therapy and in MMR at the data cutoff. These results support further investigation of asciminib in pts who did not reach an optimal treatment outcome and discontinued TKIs. 

Session topic: 08. Chronic myeloid leukemia - Clinical

Keyword(s): BCR-ABL, Chronic myeloid leukemia, Philadelphia chromosome, Targeted therapy

Abstract: S170

Type: Oral Presentation

Session title: CML clinical

Background
Asciminib is a novel, specific inhibitor of BCR-ABL1 that targets the myristoyl binding pocket. Its unique mechanism of action is expected to result in improved safety/tolerability compared with available ATP-binding TKIs. In an ongoing Phase I study (NCT02081378), asciminib is being investigated in heavily pretreated pts with Ph+ CML who are relapsed/refractory to or intolerant of TKI therapies. There is increasing interest in improving molecular responses in pts with some, but not deep, response to TKIs. 

Aims
Evaluate the safety and efficacy of asciminib monotherapy in pts with baseline BCR-ABL1IS ≤ 1%, a population considered to be mainly intolerant of the most recent TKI.

Methods
The study enrolled adults with Ph+ CML in CP or accelerated phase who were relapsed/refractory to or intolerant of ≥ 2 TKIs; informed consent was obtained. Pts were assigned to dose-escalation or -expansion cohorts investigating asciminib monotherapy or combination therapies. For the current analysis, pts enrolled in the monotherapy cohorts (any dose) who had BCR-ABL1IS ≤ 1%, regardless of the reason for TKI discontinuation, and did not have a centrally confirmed T315I mutation at baseline were included. The cutoff date was 30 Aug 2019.

Results
In total, 48 pts in 9 dose cohorts (20, 40, 80, 150, 160, and 200 mg twice daily; 80, 120, and 200 mg once daily) were included; all 48 pts had CML-CP, with a median age of 51 y (range, 30-81). One (2.1%, unconfirmed T315I mutation at baseline), 19 (39.6%), and 28 (58.3%) pts received 1, 2, and > 2 TKIs, respectively; 24 pts (50.0%) discontinued TKIs due to both resistance and intolerance, 13 (27.1%) due to intolerance only, and 11 (22.9%) did not report any prior intolerance. By the cutoff date, 6 pts (12.5%) discontinued treatment due to adverse events (AEs; n = 3: 1 due to chronic kidney disease, 2 due to pancreatic enzyme elevations), progressive disease (n = 2: 1 blast crisis [with unconfirmed T315I mutation at baseline], 1 per investigator decision–increasing BCR-ABL1 levels), or pt decision (n = 1). Median duration of study treatment exposure was 161 wk (range, 2-271), with 42 pts (87.5%) still on treatment and 36 (75.0%) in major molecular response (MMR) or better at the data cutoff. The most common grade 3/4 AEs (> 10%), regardless of study drug relationship, were lipase increase (27.1%) and hypertension (12.5%). Serious AEs, regardless of study drug relationship, were reported in 16/48 pts (33.3%), with myocardial infarction being the most common (n = 2; 4.2%). Among pts without MMR, MR4, or MR4.5 at baseline, cumulative response rates continued to increase over time, even beyond 48 wk, with 18/24 (75.0%), 16/38 (42.1%), and 18/42 (42.9%) pts achieving MMR, MR4, and MR4.5, respectively (Table 1). Median time to MMR among responders was 30 d. All 18 pts who achieved MMR maintained this level of response or better for ≥ 2 y, apart from 3 whose BCR-ABL1IS fluctuated around 0.1% but who were still in MMR at ≈ 60 mo. Among the 6 pts who did not achieve MMR by the cutoff date, 1 pt had BCR-ABL1IS > 1%, and 5 remained between BCR-ABL1IS 0.1% and 1%. Among pts who achieved MR4 or MR4.5, 9/16 (56.3%) and 10/18 (55.6%), respectively, maintained the response for ≥ 2 y.

Conclusion
Asciminib monotherapy was well tolerated and showed promising clinical activity in pts with baseline BCR-ABL1IS ≤ 1%, with 75.0% remaining on therapy and in MMR at the data cutoff. These results support further investigation of asciminib in pts who did not reach an optimal treatment outcome and discontinued TKIs. 

Session topic: 08. Chronic myeloid leukemia - Clinical

Keyword(s): BCR-ABL, Chronic myeloid leukemia, Philadelphia chromosome, Targeted therapy

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