Asciminib (ASC) Add-on to Imatinib (IMA) Demonstrates Sustained High Rates of Ongoing Therapy and Deep Molecular Responses (DMRs) with Prolonged Follow-up in the ASC4MORE Study

INTRODUCTION: As tyrosine kinase inhibitors (TKIs) have led to a life expectancy close to that of the general population for responding patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP), there is increased emphasis on quality of life and potential for treatment (Tx)-free remission (TFR). However, Tx strategies enabling more pts to safely achieve durable DMRs as entry criteria for TFR are needed in early therapy lines.

ASC is the only approved BCR::ABL1 inhibitor that Specifically Targets the ABL Myristoyl Pocket (STAMP). Preclinical studies of ASC combined with ATP-competitive TKIs showed suppression of BCR::ABL1 mutants, suggesting the potential for enhanced BCR::ABL1 inhibition via combination therapy.

In the primary (wk 48) analysis of the ASC4MORE (NCT03578367) study, ASC add-on to IMA led to rapid and deep responses, with no new or worsening safety findings vs those observed with ASC alone. Here, we report results of ASC add-on to IMA vs continued IMA vs switch to nilotinib (NIL) and of pts who crossed over from continued IMA to ASC add-on after 96 wks of Tx in pts not achieving DMR with ≥1 y of IMA as their first TKI (cutoff: 6 Mar 2023).

METHODS: Eligible adults with CML-CP were randomized 1:1:1:1 to receive ASC (40 or 60 mg once daily [QD]) add-on to IMA 400 mg QD, continue IMA 400 mg QD, or switch to NIL 300 mg twice daily in this qualitative trial. Pts must have received only IMA 400 mg QD for ≥1 y as their first TKI with BCR::ABL1^IS >.01% to ≤1% at randomization with no DMR at any point and no Tx failure per European LeukemiaNet 2013 criteria. Molecular response (MR) 4.5 (MR^4.5, BCR::ABL1^IS ≤.0032%) rate at wks 48 and 96 were the primary and secondary endpoints, respectively. Pts not achieving MR^4.5 at wk 48 with IMA could add on ASC 60 mg QD. The safety and efficacy of ASC monotherapy vs ASC add-on to IMA will be evaluated in future analyses.

RESULTS: Pts (N=84) were randomized (n=21 in each Tx arm). With median (range) durations of exposure of 141.7 (27-203), 124.3 (1-192), 53.4 (50-186), and 110.1 (1-189) wks for pts receiving ASC 40 mg add-on, ASC 60 mg add-on, IMA, and NIL, respectively, 85.7%, 76.2%, 19.0%, and 52.4% of pts completed randomized Tx. The top reasons for discontinuation were pt decision (9.5% with ASC 40 mg add-on), adverse events (AEs; 14.3% and 33.3%, with ASC 60 mg add-on and NIL, respectively), and physician decision (66.7% with IMA, all of whom crossed over to ASC 60 mg add-on).

At wk 96, 19.0%, 19.0%, 4.8%, and 9.5% of pts in the 40-mg ASC add-on, 60-mg ASC add-on, IMA, and NIL arms, respectively, were in MR^4.5, with 38.1%, 23.8%, 9.5%, and 28.6%, respectively, in MR⁴ (BCR::ABL1^IS ≤.01%) (Figure). Cumulative MR^4.5 rates at wk 96 were 28.6%, 28.6%, 9.5%, and 19.0%, respectively. MR^4.5 was achieved by 14.3%, 21.4%, and 14.3% of pts at wks 24, 48, and 96 post crossover, respectively, for pts crossing over from IMA to ASC 60 mg add-on.

With longer follow-up, there were no new or worsening safety findings with ASC add-on to IMA (Table). Despite longer median durations of exposure with ASC add-on, fewer pts experienced AEs leading to discontinuation with ASC 40 mg (4.8%) and 60 mg (14.3%) add-on vs switching to NIL (33.3%). Rates of discontinuation with ASC add-on did not increase with longer follow up compared with the primary analysis. An arterial-occlusive event (AOE) occurred in 1 pt in the NIL arm; no AOEs occurred with ASC add-on. Serious AEs occurred more frequently with NIL (23.8%) than with ASC 40 mg (14.3%) and 60 mg (19.0%) add-on. No new deaths occurred since the primary analysis.

CONCLUSIONS: Among pts not achieving DMR after ≥1 y on IMA, more pts achieved MR^4.5 with ASC add-on to IMA than with continuing IMA or switching to NIL at wk 96. Pts crossing over from IMA to ASC 60 mg add-on were still able to achieve DMRs. ASC add-on to IMA was well-tolerated, with no new or worsening safety findings compared with those known for ASC alone. The high rate of pts completing randomized Tx with ASC add-on (>75%) after >2 y on study is particularly notable and contrasts with the completion rate observed when switching to NIL (52.4%). The high rates of DMRs in these pts are promising and warrant further study. Future analyses from this study involving the ASC monotherapy arm will assess whether ASC alone can provide similar responses as ASC add-on to IMA.