Andreas Hochhaus, MD of the Klinik für Innere Medizin II, Jena, Germany speaks about the ASH 2020 abstract – LBA-4 Efficacy and Safety Results from ASCEMBL, a Multicenter, Open-Label, Phase 3 Study of Asciminib, a First-in-Class STAMP Inhibitor, vs Bosutinib (BOS) in Patients (Pts) with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Previously Treated with ≥2 Tyrosine Kinase Inhibitors (TKIs).
Introducing:
Asciminib is a first-in-class STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor with a new mechanism of action, unlike all licensed TKIs binding to the ATP site of the BCR-ABL1 oncoprotein. In prospective clinical trials, BOS, an ATP-competitive TKI, has demonstrated clinical efficacy in pts that obtained ~2 TKIs and in newly diagnosed CML. Based on the clinical activity of asciminib monotherapy in heavily pretreated pts with CML in a phase 1 trial, we asked if asciminib could provide superior efficacy for BOS beyond the 2nd line.
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Methodology:
Adults with CML-CP previously treated with ⇠2 TKIs were randomized to asciminib 40 mg twice daily (BID) or BOS 500 mg once daily to asciminib 40 mg twice daily (BID) 2:1 (QD). Significant cytogenetic response (MCyR; Ph+ metaphases ~35 percent) status at baseline was stratified by randomization. If they had BCR-ABL1IS >0.1 percent at screening, pts intolerant to their most recent TKI were qualified (19 pts with BCR-ABL1IS <1 percent enrolled). BOS pts with treatment failure (as suggested by the European LeukemiaNet in 2013) are allowed to turn to asciminib by investigator decision. Pts with identified T315I or V299L mutations resistant to bosutinib were omitted. A significant molecular response (MMR) rate at 24 wks was the primary endpoint. Primary efficacy and safety findings are reported from ASCEMBL (cutoff: May 25, 2020).
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Results:Â
Due to lack of effectiveness, fewer pts on asciminib discontinued their last TKI and fewer earned 3 previous TKI therapy lines (Table 1). Treatment was ongoing at the cutoff at 97 (61.8 percent) and 23 (30.3 percent) pts, respectively; lack of effectiveness was the most common explanation for discontinuation of treatment (asciminib, 33 [21.0 percent] pts; BOS, 24 [31.6 percent]) (Table 1). BCR-ABL1 >10% or Ph+ >65% was the most common loss of efficacy after 6 months of therapy (asciminib 10.8 percent, BOS 25.0 percent ). 22 switched to asciminib among the 24 pts that discontinued BOS due to lack of efficacy. At baseline, ⇠1 mutation of BCR-ABL1 was present on asciminib in 12.7 percent pts (most common: F359C/V) and 17.1 percent on BOSS (most common: M244V, F317L). The median follow-up period was 14.9 months, from randomization to cutoff. The median period of exposure for asciminib was 43.4 wks (range, 0.1-129.9) and for BOS was 29.2 wks (range, 1.0-117.0); the median relative dose level was 99.7% (87-100) and 95.4%, respectively (74-100).
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MMR was 25.5 percent with asciminib and 13.2 percent with BOS at 24 wks, meeting the primary target. After adjustment for MCyR status at baseline, the between-arm typical treatment difference for MMR at 24 wks was 12.2 percent (95 percent CI, 2.19-22.3: 2-sided P=.029). The median time for MMR was 12.7 wks and 14.3 wks for asciminib and BOS, respectively, among those pts that achieved MMR. More pts on asciminib (17 [10.8 percent] and 14 [8.9 percent]) than on BOS (4 [5.3 percent] and 1 [1.3 percent]) obtained a deep molecular response at 24 wks (17 [10.8 percent] and 14 [8.9 percent]) (MR4 and MR4.5, respectively). At 24 wks, the CCyR rate with asciminib was 40.8 percent vs 24.2 percent with BOS. Preplanned subgroup analysis found that in most major demographic and prognostic subgroups, including pts who received ⇠3 prior TKIs, the MMR rate at 24 wks was higher with asciminib than BOS in those who discontinued prior TKI due to treatment failure, and regardless of baseline cytogenetic response.
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In 50.6 percent and 60.5 percent of pts receiving asciminib and BOS, respectively, Grade 3 adverse events (AEs) occurred. The number of pts who stopped therapy due to AEs was lower with asciminib (5.8%) than with BOS (21.1 percent ). Grade 3 AEs and AEs requiring dose interruption and/or changes with asciminib have been recorded less frequently than with BOS (Table 2). Thrombocytopenia (17.3 percent; 6.6 percent), neutropenia (14.7 percent; 11.8 percent), diarrhea (0 percent, 10.5 percent), and increased alanine aminotransferase were the most common grade <3 AEs (occurring in >10 percent of pts in either treatment arm) with asciminib vs BOS (0.6 percent, 14.5 percent ). On-treatment deaths occurred in asciminib (ischemic stroke and arterial embolism, 1 pt each) at 2 pts (1.3 percent) and BOS (1.3 percent) at 1 pt (1.3 percent) (septic shock).
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Findings:
In this first controlled trial comparing resistant/intolerant (R/I) pts to CML therapy, asciminib, a first-in-class STAMP inhibitor, showed statistically significant and clinically significant efficacy superiority compared to BOS (primary objective), deeper MR, and a favorable safety profile. These findings support the use of asciminib in CML as a new treatment choice, particularly in R/I pts that have received ~2 previous TKIs.