COMBINATION OF ASCIMINIB PLUS NILOTINIB (NIL) OR DASATINIB (DAS) IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA (CML): RESULTS FROM A PHASE 1 STUDY
Author(s): ,
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:
The University of Texas MD Anderson Cancer Center,Houston,United States
,
Delphine Réa
Affiliations:
Hôpital Saint-Louis,Paris,France
,
Timothy P. Hughes
Affiliations:
South Australian Health and Medical Research Institute,University of Adelaide,Adelaide,Australia
,
Hironobu Minami
Affiliations:
Kobe University Hospital,Kobe,Japan
,
Massimo Breccia
Affiliations:
University of Rome La Sapienza,Rome,Italy
,
Daniel J. DeAngelo
Affiliations:
Dana-Farber Cancer Institute,Boston, United States,United States
,
Moshe Talpaz
Affiliations:
University of Michigan,Ann Arbor,United States
,
Andreas Hochhaus
Affiliations:
Abteilung Hämatologie/Onkologie,Universitätsklinikum Jena,Jena,Germany
,
Yeow Tee Goh
Affiliations:
Singapore General Hospital,Singapore,Singapore
,
Philipp D. Le Coutre
Affiliations:
Charité - Universitätsmedizin Berlin,Berlin,Germany
,
Manu Sondhi
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Kaushal Mishra
Affiliations:
Novartis Pharmaceuticals Corporation,East Hanover,United States
,
Florence Hourcade-Potelleret
Affiliations:
Novartis Pharma AG,Basel,Switzerland
,
Gary Vanasse
Affiliations:
Novartis Pharma AG,Basel,Switzerland
,
Paola Aimone
Affiliations:
Novartis Pharma AG,Basel,Switzerland
Fabian Lang
Affiliations:
Goethe-Universität Frankfurt am Main,Frankfurt am Main,Germany
EHA Library. Mauro M. Jun 15, 2019; 267467; S884
Dr. Michael J. Mauro
Dr. Michael J. Mauro
Contributions
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Abstract

Abstract: S884

Type: Oral Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 16:45 - 17:00

Location: Forum Hall

Background
Asciminib is a potent and specific BCR-ABL1 inhibitor that binds to the myristoyl pocket of ABL1. Preclinical data suggest cooperativity when asciminib is combined with ATP-competitive TKIs. In a mouse xenograft model, asciminib plus NIL prevented emergence of resistance mutations and provided durable complete tumor regression that persisted for >3 mo after stopping treatment. We report results from pts treated with asciminib plus NIL or DAS in a phase 1 study (NCT02081378).

Aims
To assess treatment with asciminib+NIL or asciminib+DAS in CML pts.

Methods
Pts with CML in chronic phase (CP) or accelerated phase (AP) and resistance or intolerance to ≥2 prior TKIs were eligible; pts with uncontrolled CV conditions were excluded. Pts were assigned (based prior intolerance of NIL or DAS) to treatment in continuous 28-d cycles. For asciminib+NIL, pts received asciminib 20 or 40 mg BID combined with NIL 300 mg BID. For asciminib+DAS, pts received asciminib 40 mg BID or 80 mg QD combined with DAS 100 mg QD. Data cut-off date: 15 Jul 2018.

Results
17 pts each enrolled in the asciminib+NIL and asciminib+DAS cohorts; 1 pt in each cohort had CML-AP. Pt characteristics are shown in the Table. At the data cut-off, 9 (53%) and 14 (82%) pts with asciminib+NIL and asciminib+DAS, respectively, were ongoing. Reasons for discontinuation were pt/physician decision (n=4), progressive disease (n=3), and AEs (n=1; myelodysplastic syndrome and decreased neutrophil count) with asciminib+NIL, and physician decision (n=2) and AEs (n=1; peripheral sensory neuropathy and fluid retention) with asciminib+DAS.

With asciminib+NIL, rates of any-grade and grade 3/4 drug-related AEs were 82% (14/17) and 53% (9/17), respectively; most common any-grade AEs were myalgia (35%), increased lipase (29%), and increased amylase, fatigue and pruritus (24% each). 1 pt had a dose-limiting toxicity (DLT) of maculopapular rash during cycle 1. With asciminib+DAS, rates of any-grade and grade 3/4 drug-related AEs were 88% (15/17) and 29% (5/17), respectively; most common any-grade AEs were increased lipase (35%) and diarrhea, headache and nausea (18% each). 1 pt had a DLT of increased lipase during cycle 1.

Peripheral arterial occlusive disease was reported in 1 pt with asciminib 40 mg BID + NIL; pt had a history of CV disease. 2 pts each with asciminib+NIL and asciminib+DAS had pleural effusion. 1 pt in asciminib+NIL cohort progressed to AP; none progressed to blast phase. There were no cases of clinical pancreatitis or on-treatment deaths in either cohort.

Drug-drug interaction (DDI) was observed between asciminib and NIL: asciminib AUC and Cmax increased by ≈2-fold when combined with NIL 300 mg BID, whereas the PK of NIL appeared unaffected by asciminib. No DDI was observed between asciminib and DAS.

Among pts without BCR-ABL1IS <1% at baseline (BL), 6/14 (43%) and 5/9 (56%) pts in the asciminib+NIL and asciminib+DAS cohorts, respectively, achieved this response by 48 wks. Among evaluable pts without major molecular response (MMR; BCR-ABL1IS ≤0.1%) at BL, 4/13 (31%) and 5/14 (36%) pts, respectively, achieved MMR by 48 wks. In pts with MMR at BL, no MMR loss was observed. 2/14 (14%) and 1/14 (7%) pts also achieved MR4.5 (BCR-ABL1IS ≤0.0032%) by 48 wks with asciminib+NIL and asciminib+DAS, respectively.

Conclusion
Asciminib combined with NIL or DAS showed promising preliminary efficacy and a good safety profile in these heavily pretreated CML pts. Based on PK, safety and preliminary efficacy data, these reported combinations may be further explored in clinical trials.

Session topic: 8. Chronic myeloid leukemia - Clinical

Keyword(s): Chronic myeloid leukemia

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