STAMP inhibitor Asciminib is expected to bring good news to CML patients!

Since the advent of targeted drug tyrosine kinase inhibitors (TKI), the efficacy of patients with chronic myeloid leukemia (CML) has been significantly improved, but patients with resistant/intolerant CML who have received two or more TKIs The need for treatment remains unmet
.

Asciminib, as an allosteric modulator of ABL1, has the potential to overcome the resistance or intolerance of TKIs due to different drug action mechanisms and binding targets.
It is expected to solve the resistance and intolerance of TKIs in future CML treatments.
Problem
.

Based on the data from the ASCEMBL Phase III trial (NCT03106779), the US Food and Drug Administration (FDA) granted priority review qualification for the New Drug Application (NDA) of Asciminib for the treatment of CML
.

Yimaitong invited Professor Wang Jianxiang from the Hematology Hospital of the Chinese Academy of Medical Sciences to combine the results of the ASCEMBL Phase III clinical study on Asciminib in chronic myeloid leukemia (CML-CP) adult patients who have previously received two or more TKI treatments Application for wonderful interpretation and review! Professor Wang Jianxiang, Chief Physician, Professor, Doctoral Supervisor, Director, Leukemia Diagnosis and Treatment Center, Hematology Hospital, Chinese Academy of Medical Sciences, Vice President, Chinese Medical Doctor Association, Hematologist Branch, Vice President, Chinese Medical Doctor Association, Chinese Medical Doctor, Hematology Branch, Former Chairman, J Hematol & Oncol Deputy Chief Editor, Blood Editorial Board Member, Chief Editor of Chinese Journal of Hematology (2012-2016) Chairman of the Hematology and Tumor Committee of the Chinese Anti-Cancer Association (2012-015) "Outstanding Youth", "New Century Talent Project" National Candidate , Tugong experts from the Ministry of Health, and special stickers from the State Council CD19 and CD33 CAR-T are the leading developers of leukemia treatment, prognostic stratification, intensified induction, and full-process management, and significantly improved the curative effect of acute leukemia.
", "Acute Lymphoblastic Leukemia", "Chronic Myelogenous Leukemia" Multi-section Diagnosis and Treatment Guide NIH Postdoctoral Outstanding Research Award, the 10th "Wu Jieping Medical Research Award-Paul Janssen Pharmaceutical Research Award" first prize, Tianjin Science and Technology Progress First prize (first completion person) Research background When CML-CP patients are resistant or intolerant to two or more TKIs, the patient is very likely due to disease biology and insufficient efficacy/safety of current therapies There was a bad ending
.

Although Ponatinib is effective in patients who have previously received treatment, it is associated with high iatrogenic cardiovascular risk
.

Asciminib, as a new type of inhibitor specifically targeting ABL myristoyl pocket (STAMP), has the potential to overcome the resistance or intolerance of TKIs
.

The ASCEMBL study aims to compare the efficacy and safety of Asciminib and Bosutinib in the treatment of CML patients who have previously received TKI treatment
.

Study Design ASCEMBL is a multi-center, open-label, randomized phase III study, carried out in 233 CML-CP patients who have previously received two or more ATP-binding site TKIs, and compared the efficacy of Asciminib and Bosutinib And safety
.

The trial recruited 233 CML-CP patients who had previously received treatment.
The patients were randomly divided into two groups at a 2:1 ratio.
One group (157 cases) received 40 mg Asciminib twice a day, and the other group (76 Example) Received 500 mg of Bosutinib once a day for 96 weeks (Figure 1)
.

Participants were stratified according to the status of the primary cytogenetic response (MCyR)
.

The primary endpoint of the study was the rate of major molecular response (MMR) after 24 weeks
.

Figure 1.
The results of the ASCEMBL study design.
At the last follow-up, 97 patients (61.
8%) and 23 (30.
3%) patients were still receiving treatment (Table 1)
.

Of the 24 patients who discontinued Bosutinib treatment due to ineffectiveness, 22 cases were switched to Asciminib treatment
.

From randomization to the last follow-up time, the median follow-up time was 14.
9 months
.

The median duration of treatment with Asciminib was 43.
4 weeks (range 0.
1-129.
9) and Bosutinib was 29.
2 weeks (range 1.
0-117.
0)
.

The median relative dose intensity was 99.
7% (87-100) and 95.
4% (74-100)
.

Table 1.
Patients' baseline characteristics.
In terms of efficacy, the MMR rates of Asciminib group and Bosutinib group at 24 weeks were 25.
5% and 13.
2%, respectively, reaching the primary study endpoint
.

After adjusting the MCyR status at baseline, at 24 weeks, the difference in efficacy of MMR between groups was 12.
2% (95% CI, 2.
19-22.
3; P = 0.
029)
.

Other indicators in week 24 were (ASC vs BOS): MR4: 10.
8% vs 5.
3%, MR4.
5: 8.
9% vs 1.
3%, CCyR: 40.
8% vs 24.
2%
.

Subgroup analysis showed that in most major demographic and prognostic subgroups, including patients who had previously received ≥3 TKI treatments and patients who had discontinued their previous TKI due to treatment failure, Asciminib’s The MMR rate is better than Bosutinib
.

Figure 2.
The incidence of MMR.
In terms of safety, adverse events (AE) ≥ grade 3 in the Asciminib group and Bosutinib group were 50.
6% and 60.
5%, respectively (Table 2)
.

The rate of discontinuation of treatment due to adverse events in the Asciminib group (5.
8%) was lower than that in the Bosutinib group (21.
1%)
.

The incidence of grade 3 AEs and AEs requiring dose interruption and/or dose adjustment in the Asciminib group was lower than that in the Bosutinib group
.

Table 2.
Overview of the occurrence of adverse events.
The conclusions of the study are first confirmed by a randomized controlled study of drug-resistant/intolerant CML patients.
Compared with Bosutinib, the “first-in-class” new drug STAMP inhibitor Asciminib has efficacy and safety It has the advantages of statistical significance and clinical significance
.

These results provide evidence support for Asciminib as a new treatment option for CML, especially for resistant/intolerant CML patients who have received two or more TKIs
.

Big coffee commented that Professor Wang Jianxiang CML is a malignant myeloproliferative tumor that occurs in pluripotent hematopoietic stem cells
.

Although there are currently a variety of TKIs that can be used to treat CML, there are very few new drugs available for drug-resistant/intolerant CML patients who have previously received two or more TKIs
.

Asciminib is an allosteric inhibitor of ABL1, which binds to the myristoyl pocket of ABL1 and inhibits the activity of BCR-ABL1
.

Because its binding site with BCR-ABL1 is different from common tyrosine kinase inhibitors, Asciminib is expected to solve the problem of TKI resistance and intolerance in the follow-up treatment of CML patients
.

Asciminib, as the first BCR-ABL1 allosteric inhibitor to enter the clinic, has a significant effect in the phase I clinical trial, and obtained Fast Track (FTD) qualification from the US FDA.
Subsequently, it quickly launched the phase III clinical study ASCEMBL
.

ASCEMBL is the first head-to-head randomized controlled study of CML patients who have previously received TKI treatment.
It was selected as a blockbuster study (LBA) at the 2020 American Society of Hematology (ASH) meeting
.

Its phase III clinical study showed that compared with Bosutinib, the STAMP inhibitor Asciminib had a significant effect on CML-CP after treatment with two or more TKIs at week 24: Asciminib’s MMR rate was 25.
5%, while Bosutinib’s 13.
2%, the common risk difference of MMR was 12.
2% (95% CI, 2.
19-22.
3; P = 0.
029)
.

Based on the data of the ASCEMBL Phase III trial (NCT03106779), the US FDA has granted Asciminib the NDA priority review qualification for the treatment of CML, and the China National Medical Products Administration Center for Evaluation (CDE) publicity also shows that Asciminib is intended to be developed for the treatment of chronic CML.
Adult patients
.

Looking forward to Asciminib's clinical trials in China, bringing new treatment options to Chinese patients
.

References: Rea D, Mauro MJ, Boquimpani C, et al.
A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After ≥2 Prior TKIs.
Blood.
2021 Aug 18: blood.
2020009984.
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