Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase

Eun-Ji Choi

doi:10.5045/br.2023.2023017

Quick links

Most Cited Most Read Ahead of Print Archives Go to E-submission

Review Article

Split Viewer

Blood Res 2023; 58(S1):

Published online April 30, 2023

https://doi.org/10.5045/br.2023.2023017

Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase

Eun-Ji Choi

Author Info. +

Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to : Eun-Ji Choi, M.D.
Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
E-mail: eunjichoi@amc.seoul.kr

*This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI20C1586).

Received: January 18, 2023; Revised: February 18, 2023; Accepted: March 2, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Go to

Abstract

The prognosis of patients with chronic phase (CP) chronic myeloid leukemia (CML) has significantly improved due to the development of potent BCR::ABL1 tyrosine kinase inhibitors (TKIs). However, approximately 15‒20% of patients ultimately experience treatment failure due to resistance or intolerance to TKI therapy. As the prognosis of patients in whom multiple TKIs fail remains poor, an optimal therapeutic approach is required to treat the condition. Asciminib, an allosteric inhibitor that targets ABL1 myristoyl pocket, has been approved by the Food and Drug Administration for use in patients with CP-CML resistant or intolerant to ≥2 prior TKIs or those with T315I mutation. In a phase 1 trial, asciminib monotherapy showed a relatively favorable safety profile and potent efficacy in patients with and without the T315I mutation. In a subsequent phase 3 trial, asciminib treatment was associated with a significantly higher major molecular response rate and lower discontinuation rate than bosutinib in patients with CP-CML for whom two previous TKIs failed. Several clinical trials are being performed in various clinical settings to evaluate the role of asciminib as a frontline treatment for newly diagnosed CP-CML, either as a single agent or in combination with other TKIs as a second-line or additive treatment to improve treatment-free or deep remission. This review summarizes the incidence, available therapies, and outcomes of patients with CP-CML who experienced treatment failure, the mechanism of action, preclinical and clinical data, and ongoing trials for asciminib.

Keywords Asciminib, Allosteric inhibitor, Chronic myeloid leukemia

Article

Review Article

Blood Res 2023; 58(S1): S29-S36

Published online April 30, 2023 https://doi.org/10.5045/br.2023.2023017

Asciminib: the first-in-class allosteric inhibitor of BCR::ABL1 kinase

Eun-Ji Choi

Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Correspondence to:Eun-Ji Choi, M.D.
Department of Hematology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea
E-mail: eunjichoi@amc.seoul.kr

*This study was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (grant number: HI20C1586).

Received: January 18, 2023; Revised: February 18, 2023; Accepted: March 2, 2023

Abstract

Keywords: Asciminib, Allosteric inhibitor, Chronic myeloid leukemia

Abstract

Fig 1.

Download

Figure 1.Mechanism of action of asciminib. (A) Under normal conditions, ABL1 activity is autoregulated by binding of myristoylated N-terminus to the myristoyl pocket of the kinase domain. (B) In CML, ABL1 kinase is constitutively activated due to loss of regulatory function with BCR::ABL1 fusion oncoprotein formation (left side). Asciminib binds to the myristoyl pocket of the ABL1 kinase domain, inducing an inactive conformational change and inhibiting kinase activity.

Blood Research 2023; 58: S29-S36https://doi.org/10.5045/br.2023.2023017

Table 1 . Milestones for patients with CP-CML treated with tyrosine kinase inhibitors..

European Leukemia Net (2020)
	Optimal	Warning	Failure
3 months	BCR::ABL1 ≤10%	BCR::ABL1 >10%	BCR::ABL1 >10% if confirmed within 1–3 months
6 months	BCR::ABL1 ≤1%	BCR::ABL1 >1–10%	BCR::ABL1 >10%
12 months	BCR::ABL1 ≤0.1%	BCR::ABL1 >0.1–1%	BCR::ABL1 >1%
Any time	BCR::ABL1 ≤0.1%	BCR::ABL1 >0.1–1%, loss of MMR	BCR::ABL1 >1%, resistance mutations, high-risk ACA

National Comprehensive Cancer Network (2023)
	TKI-sensitive	Possible TKI-resistant	TKI-resistant
3 months	BCR::ABL1 ≤10%	BCR::ABL1 >10%
6 months	BCR::ABL1 ≤10%		BCR::ABL1 >10%
12 months	BCR::ABL1 ≤1%	BCR::ABL1 1–10%	BCR::ABL1 >1%

European Society for Medical Oncology (2017)
	Optimal	Warning	Failure
3 months	Ph ≤35%, BCR::ABL1 <10%	Ph 36–95%, BCR::ABL1 >10%	No CHR, Ph >95%
6 months	Ph 0%, BCR::ABL1 <1%	Ph 1–65%, BCR::ABL1 1–10%	Ph >35%, BCR::ABL1 >10%
12 months	BCR::ABL1 <0.1%	BCR::ABL1 0.1–1%	Ph ≥1%, BCR::ABL1 >1%
>18 months	BCR::ABL1 <0.01%	BCR::ABL1 0.1–1%
Any time			Relapse, loss of MMR

Abbreviations: ACA, additional chromosomal abnormality; CHR, complete hematological response; MMR, major molecular response; Ph, Philadelphia chromosome-positive; TKI, tyrosine kinase inhibitor..

Table 2 . Treatment recommendations based on BCR::ABL1 kinase domain mutation and responses to TKI therapy..

Treatment	Contraindicated mutations
Dasatinib	T315I/A, F317L/V/I/C, or V299L
Nilotinib	T315I, Y253H, E255K/V, or F359V/C/I
Bosutinib	T315I, V299L, G250E, or F317L
Asciminib	A337T or P465S
Ponatinib	None

Contraindicated treatment	BCR::ABL1 mutations	Bosutinib [18]	Dasatinib [33]		Nilotinib [34]		Ponatinib [35]
Contraindicated treatment	BCR::ABL1 mutations	MCyR	CCyR	MCyR	CCyR	MCyR	MCyR
Contraindication for bosutinib	G250E	0/5 (0%)	20/60 (33%)	29/60 (48%)	3/5 (60%)	3/5 (60%)	8/12 (67%)
Contraindication for bosutinib and dasatinib	F317L	1/7 (14%)	1/14 (7%)	2/14 (14%)	-	-	13/29 (45%)
Contraindication for bosutinib and dasatinib	V299L	0/2 (0%)	-	-	-	-	3/8 (38%)
Contraindication for nilotinib	E255K	-	6/16 (38%)	9/16 (56%)	0/7 (0%)	3/7 (43%)	8/13 (62%)
	E255V	-	4/11 (36%)	4/11 (36%)	0/7 (0%)	3/7 (43%)	1/4 (25%)
	F359C	1/2 (50%)	3/5 (60%)	3/5 (60%)	0/11 (0%)	1/11 (9%)	1/7 (14%)
	F359V	2/3 (67%)	14/27 (52%)	17/27 (63%)	0/11 (0%)	1/11 (9%)	11/20 (55%)
	F359I	2/2 (100%)	7/12 (58%)	10/12 (83%)	-	-	3/4 (75%)
	Y253H	5/6 (83%)	14/23 (61%)	15/23 (65%)	0/8 (0%)	1/8 (13%)	1/2 (50%)

Abbreviations: CCyR, complete cytogenetic response; MCyR, major cytogenetic response..

Table 3 . Ongoing clinical trials for asciminib..

Phase	Study title	Treatment	Target population	Primary endpoint
3 First-line (NCT05456191)	A phase IIIb, open-label, randomized study of tolerability and efficacy of asciminib versus nilotinib in patients with newly diagnosed philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase (ASC4START)	Asciminib 80 mg qd vs. nilotinib 300 mg bid	Newly diagnosed CP-CML	Time to discontinuation of study treatment due to an adverse event (TTDAE)
3 First-line (NCT04971226)	A phase III, multicenter, open-label, randomized study of oral asciminib versus investigator selected TKI in patients with newly diagnosed philadelphia chromosome positive chronic myelogenous leukemia in chronic phase	Asciminib 80 mg qd vs. investigator-selected TKIs (imatinib, nilotinib, dasatinib, or bosutinib)	Newly diagnosed CP-CML	MMR at week 48
3b Third-line (NCT04948333)	A phase 3b, multicenter, open-label, treatment optimization study of oral asciminib in patients with chronic myelogenous leukemia in chronic phase (CML-CP) previously treated with 2 or more tyrosine kinase inhibitors	Asciminib 40 mg bid or 80 mg qd, with possible dose escalation upto 200 mg qd	CP-CML with warning or resistance criteria based on ELN 2020 recommendations	MMR rate at week 48
3b Third-line (NCT04666259)	An open label, multicenter phase IIIb study of asciminib (ABL001) monotherapy in previously treated patients with chronic myeloid leukemia in chronic phase (CML-CP) with and without T315I mutation	Asciminib 40 mg bid, 80 mg qd, or 200 mg bid	CP-CML failed ≥2 prior TKIs (no T315I) or 1 prior TKI (T315I)	Number of AE and SAE up to 24 weeks
3 TFR (NCT05413915)	A phase 3, multicenter, randomized, open-label, trial evaluating the efficacy and safety of asciminib used in consolidation with imatinib vs. imatinib to achieve treatment-free remission in chronic phase-chronic myelogenous leukemia patients	Consolidation with asciminib 60 mg qd for 52 weeks added to imatinib vs. imatinib for 52 weeks followed by TFR	CP-CML in DMR (≥MR⁴) for at least 12 months with imatinib	EFS at 12 months
2 First-line (NCT05143840)	Asciminib as initial therapy for patients with chronic myeloid leukemia in chronic phase	Asciminib 40 mg bid (nilotinib added for patients not achieving a response after 24 months of treatment)	Newly diagnosed CP-CML	MMR at week 24
2 Second-line (NCT05384587)	A phase II multicenter, open-label, single-arm dose escalation study of asciminib monotherapy in 2nd line chronic phase - chronic myelogenous leukemia (ASC2ESCALATE)	Asciminib 80 mg qd with possible dose escalation upto 200 mg bid	CP-CML failed 1L-TKI without T315I mutation	MMR at 12 months
2 DMR (NCT03578367)	A phase 2, multicenter, open-label, randomized study of oral asciminib added to imatinib vs. continued imatinib versus switch to nilotinib in patients with CML-CP who have been previously treated with imatinib and have not achieved deep molecular response	Asciminib 60 mg qd+imatinib 400 mg qd vs. asciminib 40 mg qd+imatinib 400 mg qd vs. imatinib 400 mg qd vs. nilotinib 300 mg bid vs. asciminib 80 mg qd	CP-CML with BCR::ABL1 >0.01% and ≤0.1% receiving 1L-imatinib >12 months	MR^4.5 at week 48
2 DMR (NCT04216563)	Phase II study of dual targeting of BCR::ABL1 by adding the allosteric inhibitor ABL001 in patients with chronic myeloid leukemia (CML) and minimal residual disease (MRD) while on therapy with tyrosine kinase inhibitors	Asciminib bid for up to 36 months while receiving standard-of-care dasatinib or nilotinib	CP-CML in CCyR but detectable BCR::ABL1 transcript on TKIs ≥24 months	Molecular response rate at 12 months
2 TFR (NCT03874858)	A phase II, single-arm study of de-escalation and treatment-free remission in patients with chronic myeloid leukemia treated with nilotinib in first-line therapy followed by a second attempt after nilotinib and asciminib combination: DANTE Study	(Second stage) Asciminib 40 mg bid and nilotinib 300 mg bid for patients failed a first TFR attempt with nilotinib consolidation	CP-CML, failed the first TFR attempt, followed by nilotinib retreatment ≥1 yr and MR4 or better	TFR rate 48 weeks after the second TFR attempt