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Clinical Trial
. 2024 Dec 18;17(1):125.
doi: 10.1186/s13045-024-01642-6.

Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study

Timothy P Hughes  1 , Giuseppe Saglio  2 , Jan Geissler  3 , Dong-Wook Kim  4 , Elza Lomaia  5 , Jiri Mayer  6 , Anna Turkina  7 , Shruti Kapoor  8 , Ana Paula Cardoso  8 , Becki Nieman  8 , Sara Quenet  9 , Jorge E Cortes  10
Affiliations
Clinical Trial

Asciminib add-on to imatinib demonstrates sustained high rates of ongoing therapy and deep molecular responses with prolonged follow-up in the ASC4MORE study

Timothy P Hughes et al. J Hematol Oncol. .

Abstract

Background: Up to 65% of patients with chronic myeloid leukemia (CML) who are treated with imatinib do not achieve sustained deep molecular response, which is required to attempt treatment-free remission. Asciminib is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket. This unique mechanism of action allows asciminib to be combined with adenosine triphosphate-competitive tyrosine kinase inhibitors to prevent resistance and enhance efficacy. The phase II ASC4MORE trial investigated the strategy of adding asciminib to imatinib in patients who have not achieved deep molecular response with imatinib.

Methods: In ASC4MORE, 84 patients with CML in chronic phase not achieving deep molecular response after ≥ 1 year of imatinib therapy were randomized to asciminib 40 or 60 mg once daily (QD) add-on to imatinib 400 mg QD, continued imatinib 400 mg QD, or switch to nilotinib 300 mg twice daily.

Results: More patients in the asciminib 40- and 60-mg QD add-on arms (19.0% and 28.6%, respectively) achieved MR4.5 (BCR::ABL1 ≤ 0.0032% on the International Scale) at week 48 (primary endpoint) than patients in the continued imatinib (0.0%) and switch to nilotinib (4.8%) arms. Fewer patients discontinued asciminib 40- and 60-mg QD add-on treatment (14.3% and 23.8%, respectively) than imatinib (76.2%, including crossover patients) and nilotinib (47.6%). Asciminib add-on was tolerable, with rates of AEs and AEs leading to discontinuation less than those with nilotinib, although higher than those with continued imatinib (as expected in these patients who had already been tolerating imatinib for ≥ 1 year). No new or worsening safety signals were observed with asciminib add-on vs the known asciminib monotherapy safety profile.

Conclusions: Overall, these results support asciminib add-on as a treatment strategy to help patients with CML in chronic phase stay on therapy to safely achieve rapid and deep response, although further investigation is needed before this strategy is incorporated into clinical practice.

Trial registration: NCT03578367.

Keywords: ASC4MORE; Add-on; Asciminib; CML; Combination; Deep molecular response; Imatinib; Tyrosine kinase inhibitors.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The protocol was approved by the sites' institutional review boards and conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. Consent for publication: Not applicable; no individual patient data are included. Competing interests: TPH received research funding from Novartis, and Bristol Myers Squibb, and consultancy fees from Novartis, Takeda, Terns Pharmaceuticals, Enliven Therapeutics, and Ascentage Pharma. JG has received payment for consultancy from Novartis and Incyte. He is a committee member of the European Hematologic Association. He reports grants to his patient advocacy organization from Novartis, Pfizer, Bristol Myers Squibb, Incyte, Takeda, and Terns Pharmaceuticals. D-WK received research funding from Novartis, Bristol Myers Squibb, Enliven, Korea Otsuka, Il-Yang, and PharmaEssentia; honoraria from Novartis, Bristol Myers Squibb, Enliven, Krea Otsuka, and Il-Yang; and speaker bureau fees from Novartis, Bristol Myers Squibb, Korea Otsuka, and Il-Yang. EL received personal fees from Novartis, and Pfizer and is a member of speakers bureaus for Novartis, Pfizer, and Fusion Pharma. JM received research funding from BeiGene. AT received personal fees from Novartis, Pfizer, and R-Pharma and is a member of the speakers bureaus for Novartis, Pfizer, and R-Pharma. JEC received research funding from AbbVie, Ascentage Pharma, Novartis, and Sun Pharma and consultancy fees from Lilly, Nerviano, Novartis, Pfizer, Rigel, Sun Pharma, Syndax, and Biopath Holdings. He holds stock options in and is a board member of Biopath Holdings. BN, and SQ are employees of Novartis. APC and SK are employees and shareholders of Novartis stock. GS declares no competing interests.

Figures

Fig. 1
Fig. 1
The ASC4MORE study design. 1L, first line; ABL1, ABL proto-oncogene 1; BCR, breakpoint cluster region; BID, twice daily; CML, chronic myeloid leukemia; CP, chronic phase; DMR, deep molecular response; IS, International Scale; MR4.5, BCR::ABL1IS ≤ 0.0032%; QD, once daily. a Based on investigators’ feedback, the inclusion criteria have been updated in a protocol amendment on August 24, 2023, to allow enrollment of patients who were treated with imatinib at a dose of ≥ 300 mg QD for ≥ 1 year and have not achieved DMR. b The monotherapy arm was added in a protocol amendment on July 12, 2022, to estimate the safety and efficacy of single-agent asciminib and is now enrolling. c Patients in the imatinib arm were allowed to switch to the asciminib 60 mg + imatinib arm if they had not achieved MR4.5 at week 48
Fig. 2
Fig. 2
MR4.5 at weeks 24, 48, and 96. ABL1, ABL proto-oncogene 1; ASC, asciminib; BCR, breakpoint cluster region; IMA, imatinib; IS, International Scale; MR4.5, BCR::ABL1IS ≤ 0.0032%; NIL, nilotinib; QD, once daily
Fig. 3
Fig. 3
Cumulative rate of MR4.5. ABL1, ABL proto-oncogene 1; ASC, asciminib; BCR, breakpoint cluster region; IMA, imatinib; IS, International Scale; MR4.5, BCR::ABL1IS ≤ 0.0032%; NIL, nilotinib; QD, once daily
Fig. 4
Fig. 4
DMRa (MR4 or deeper response) at week 96. ABL1, ABL proto-oncogene 1; ASC, asciminib; BCR, breakpoint cluster region; DMR, deep molecular response; IMA, imatinib; IS, International Scale; NIL, nilotinib; QD, once daily. a DMR is defined as a response level of at least MR4 (BCR::ABL1IS ≤ 0.01%)
Fig. 5
Fig. 5
BCR:ABL1IS over time post crossover in patients who crossed over to asciminib 60-mg add-on arm.a ABL1, ABL proto-oncogene 1; BCR, breakpoint cluster region; IS, International Scale; MMR, major molecular response; MR4, BCR::ABL1IS ≤ 0.01%; MR4.5, BCR::ABL1IS ≤ 0.0032%; MR5, BCR::ABL1IS ≤ 0.001%. a Patients in the imatinib arm were allowed to switch to the asciminib 60 mg + imatinib arm if they had not achieved MR4.5 at week 48. At crossover, 2 patients had BCR::ABL1IS ≥ 0.1% and 12 were in MMR. Each line on the graph represents BCR::ABL1IS levels over time for an individual patient
Fig. 6
Fig. 6
AEs reported by patients in each treatment arm. AE, adverse event; ASC, asciminib; IMA, imatinib; NIL, nilotinib; QD, once daily. a One patient in the IMA arm was not treated due to patient decision
Fig. 7
Fig. 7
Any-grade AEs (≥ 15% of patients in any arm) in each treatment arm. AE, adverse event; ALT, alanine aminotransferase; ASC, asciminib; IMA, imatinib; NIL, nilotinib; QD, once daily. a One patient in the IMA arm was not treated due to patient decision
Fig. 8
Fig. 8
AEs of special interest in each treatment arm. AE, adverse event; ASC, asciminib; CNS, central nervous system; GI, gastrointestinal; IMA, imatinib; NIL, nilotinib; QD, once daily. a One patient in the IMA arm was not treated due to patient decision. b In the ASC arms, these events were increased blood creatine phosphokinase level. c In the ASC 40-mg QD add-on, ASC 60-mg QD add-on, continued imatinib, and switch to nilotinib arms, 19.0%, 19.0%, 15.0%, and 9.5% of patients, respectively, had increased lipase level, while 4.8%, 4.8%, 10.0%, and 4.8%, respectively, had increased amylase level. d All events in the reproductive toxicity category were cases of Gilbert syndrome
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