Asciminib effective, safe as late-line treatment for chronic-phase CML
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Asciminib appeared to be more effective than bosutinib for certain patients with chronic-phase chronic myeloid leukemia who had been treated with at least two tyrosine kinase inhibitors, according to results of the phase 3 ASCEMBL study.
The findings, presented during the late-breaking abstract session of the virtual ASH Annual Meeting and Exposition, also showed asciminib (ABL001, Novartis) had a favorable safety profile.
“ASCEMBL is the first controlled study comparing different TKIs for resistant or intolerant patients with CML,” Andreas Hochhaus, MD, researcher at University Hospital Jena in Germany, said during a presentation. “Our results support the use of asciminib as a new treatment option in CML, particularly in patients with resistance or intolerance to two or more TKIs.”
Asciminib is a first-in-class inhibitor that specifically targets the ABL myristoyl pocket (STAMP) with a new mechanism of action. The ATP-competitive TKI bosutinib (Bosulif, Pfizer) has shown clinical efficacy among patients with newly diagnosed CML and among those previously treated with two or more TKIs.
Hochhaus and colleagues compared asciminib with bosutinib among 233 adults with Philadelphia chromosome-positive CML in chronic phase who underwent prior treatment with at least two TKIs.
The researchers randomly assigned patients 2:1 to receive 40 mg twice-daily asciminib (n = 157; median age, 52 years; 47.8% women) or 500 mg once-daily bosutinib (n = 76; median age, 52 years; 59.2% women), with randomization stratified by major cytogenetic response at baseline.
Patients with documented treatment failure with bosutinib were permitted to switch to asciminib.
Major molecular response (MMR) rate at 24 weeks served as the primary endpoint. Secondary endpoints included MMR rate at 96 weeks while on study treatment without meeting any treatment failure criteria prior to week 96, safety and tolerability, and major cytogenetic response and MMR at and by scheduled time points.
Data cutoff was May 25, at which time 97 patients (61.8%) assigned asciminib and 23 patients (30.3%) assigned bosutinib remained on treatment. The most common reason for treatment discontinuation was lack of efficacy for 33 patients (21%) assigned asciminib and 24 patients (31.6%) assigned bosutinib.
Median follow-up was 14.9 months.
At the 24-week follow-up, 25.5% of patients assigned asciminib achieved MMR (median time to MMR, 12.7 weeks) compared with 13.2% of patients assigned bosutinib (median time to MMR, 14.3 weeks). Researchers reported a statistically significant 12.2% (95% CI, 2.19-22.3) common treatment difference for MMR across the cytogenetic response strata.
Moreover, a greater proportion of patients assigned asciminib vs. bosutinib achieved deep molecular response at 24 weeks (MR, 10.8% vs. 5.3%; MR4.5, 8.9% vs. 1.3%).
Median duration of exposure was 43.4 weeks (range, 0.1-129.9) for asciminib vs. 29.2 weeks (range, 1-117) for bosutinib.
Researchers observed a consistent treatment effect across subgroups assessed, supporting the benefit of asciminib treatment.
“Considering the randomization strata of cytogenetic response status, MMR favored asciminib in both subsets of patients,” Hochhaus said. “Notably, MMR at 24 weeks was consistently higher for asciminib vs. bosutinib across all lines of prior therapy.”
After adjusting for major cytogenetic response at baseline between the two groups, researchers calculated an OR for treatment effect of 2.35 (95% CI, 1.08-5.12) favoring asciminib.
“After adjusting for other covariates, the OR remained similar to the unadjusted OR, which indicates that treatment effect is still significant while accounting for imbalances,” Hochhaus added.
The probability of achieving MMR at 24 weeks was 25% with asciminib vs. 11.9% with bosutinib, with a difference in cumulative incidence between the two groups becoming evident at week 12. Moreover, the rate of complete cytogenetic response at 24 weeks was 40.8% with asciminib vs. 22.4% with bosutinib. The common risk difference after adjusting for cytogenetic response at baseline was 17.3% (95% CI, 3.62-31).
BCR-ABL1 remained the key driver of CML, even among patients treated in the third or later line, Hochhaus added.
Asciminib resulted in fewer all-grade (89.7% vs. 96.1%) and grade 3 or higher (50.6% vs. 60.5%) adverse events than bosutinib. The most common grade 3 or higher adverse events included thrombocytopenia (17.3% with asciminib vs. 6.6% with bosutinib), neutropenia (14.7% vs. 11.8%), diarrhea (0% vs. 10.5%) and increased alanine aminotransferase (0.6% vs. 14.5%).
Two deaths occurred in the asciminib group, which were not considered related to study treatment. One patient in the bosutinib group died of sepsis after disease progression.
“Asciminib has demonstrated a favorable benefit-risk profile in this patient population by its unique ability to STAMP,” Hochhaus said.
Perspective
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Amir Fathi, MD
The implications of these findings ultimately depend upon the patient population, but the results are very promising for patients with CML who have progressed beyond initial lines of therapy. It is important to note that the study excludes a specific patient population that often is the most challenging for us — those patients with the “notorious” T315I resistance alteration, against which the comparator-arm drug bosutinib is not active. Asciminib is somewhat effective against this mutation, which has been shown in prior trials. However, this study excludes that population and looked at other patients who had progressed beyond two or more prior lines of therapy.
The study compared bosutinib, commonly used in progressed CML, with asciminib. The researchers found that asciminib was superior in terms of MMR rates and other molecular endpoints, and these results are very intriguing. The safety and tolerability also were relatively reasonable on both treatment arms. It seemed there may have been more cytopenias with asciminib and more diarrhea and gastrointestinal side effects with bosutinib. The major takeaway, however, was that the response rates seemed to be more prominent with asciminib for these challenging patients who progressed beyond two or more lines of treatment.
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Hochhaus A, et al. Abstract LBA4. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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