Update of the Ascend-CML Study of Frontline Asciminib: High Rate of Optimal Response and Resistance Due to Mutations Is Rare
Authors: Yeung David T , Shanmuganathan Naranie , Yong Agnes S. M. , Shortt Jake , Chee Lynette C.Y. , Vialla Nicholas , Cunningham Ilona , Ross David M , D'Souza Alwyn , Wright Matthew P.F. , Harrup Rosemary , Forsyth Cecily , Filshie Robin , Lane Steven W , Browett Peter J. , Grove Carolyn S. , Walia Mannu , Branford Susan , Reynolds John , Grigg Andrew P , Hughes Timothy P 
Published: December 2024

Asciminib, a Myristoyl Pocket BCR::ABL1 inhibitor, recently demonstrated its safety and efficacy in newly diagnosed CP-CML in the Phase III ASC4FIRST (Hochhaus, 2024), and the phase II ALLG CML13 ASCEND studies. Here, we update the ASCEND trial outcomes out to 24 months (mos) including molecular response and outcomes in patients (pts) failing asciminib or with suboptimal responses, and those with BCR::ABL1 mutations.

In ASCEND, pts started asciminib (ASC) 40mg twice a day (BID) at diagnosis and switched to 80 mg daily after 12 mos. Pts with treatment failure (BCR::ABL1 &gt;10% at 3 or 6 mos; BCR::ABL1 &gt;1% at 12 or 18 mos) continued ASC, and add either imatinib, dasatinib (DAS) or nilotinib, according to physician preference. Pts without treatment failure, but failed to achieve MMR (BCR::ABL1 ≤0.1%) at 12 mos, or MR4 (BCR::ABL1 ≤0.01%) at 18 mos, could double their ASC dose to 80mg BID. The co-primary end points were Early Molecular Response (EMR, BCR::ABL1 ≤10% at 3 mos) and MMR by 12 mos.

ASCEND enrolled 101 pts at 14 Australasian sites. The co-primary endpoints, EMR (BCR::ABL1 ≤10% by 3 mos) and MMR by 12 mos, were achieved in 93% and 79%, respectively. The most common AEs were hypertension (22%) and increased lipase (21%). With a median follow up of 28 mos (range 0-42), 20 pts have discontinued ASC due to: loss to follow up/consent withdrawn N=5; loss of response N=5; lipase elevation N=3; EMR failure N=2. cytopenia N=2; pancreatitis N=1; lymphoid blast crisis N=1 (the only progression event); enrolled but never started N=1. No deaths have been reported. A landmark analysis at 18 mos of 95 pts showed that 25 (26%), 49 (52%) and 77 (81%) achieved MR4.5, MR4 and MMR respectively. At 24 mos (n=76), 24 (32%), 44 (58%) and 62 (82%) were in MR4.5, MR4 and MMR respectively. Only 5 pts had high ELTS risk - 3/5 were in MMR at 12 mos, and 0/5 in MR4 at 18 mos.

Three pts were eligible for combination therapy due to treatment failure. Pt 69 had BCR::ABL1 of 24% at 3 mos, on the background of cytopenia from ASC. MR2 (BCR::ABL1 ≤1%) was achieved after switching to dasatinib, maintained at last follow-up (27 mos). Pt 86 had BCR::ABL1 of 210% at 3 mos despite full dose ASC, had grade III headaches with combination ASC/DAS, subsequently failed 3 therapies, then received an allogeneic stem cell transplant (ASCT). Pt 87 had BCR::ABL1 of 1.1% at 12 mos; combination ASC/DAS was interrupted by lipase elevations. MR2 has been achieved at month 18 with DAS monotherapy.

Six pts had loss of molecular response - all had MR2 or better at 3 mos, and all but one had low ELTS risk. Pt 26 had BCR::ABL1 of 0.37% at 3 mos, then lymphoid blast crisis with A337T/V & P465S mutations at 6 mos, and has subsequently had ASCT post chemotherapy. Pt 34 achieved a BCR::ABL1 nadir of 0.067% at 6 mos, rose to 0.28% with loss of MMR at 9 mos, without BCR::ABL1 mutations, and has since regained MMR on DAS. Pt 42 was high ELTS, lost MR2 at 6 mos with a V506L mutation, with BCR::ABL1 rising from a nadir of 0.2% to 49%. They switched to DAS and achieved MR4 at 14 mos. Pt 59 had loss of MMR at 6 mos with a A337T mutation without further follow up. Pt 88 achieved MR4.5 at 3 mos, then lost MMR at 12 mos with BCR::ABL1 of 0.16% and T315I (35%) / M224V (70%) mutations in the P-loop domain; ponatinib 45mg for 6 mos has re-established MMR. Pt 101 achieved MR4 at 3 mos, then lost MR4 at 18mo with BCR::ABL1 of 0.066% and A337T; further follow up on DAS is pending.

Thirteen pts failed to achieve MMR at 12 mos but with BCR::ABL1 ≤1%: 7 had ASC dose increase to 80mg BID, of whom 5 have subsequently achieved MMR after 3 - 18 mos. Five continued ASC at 40mg QD, of whom 2 subsequently achieved MMR after 6 mos.

Thirty-three pts failed to achieve MR4 at 18 mos, (including 3 pts without MMR, with BCR::ABL1 0.12%, 0.28% & 0.31%); 21 of whom had follow up at 24 mos. In this latter cohort, 3 of 12 pts with a dose increase to 80mg BD achieved MR4; one of 9 who remained on 80mg QD achieved MR4.

In conclusion, ASC is associated with a high rate of molecular response. Previous studies have suggested EMR achievement significantly protect against the development of secondary resistance, though our results suggest continued vigilance is warranted. Pts without MMR at 12 mos may achieve this milestone with continuing treatment, and numbers are too small to assess the benefit of dose escalation. BCR::ABL1 mutation acquisition rates appears similar to second generation TKIs in the frontline setting; these were mostly myristoyl pocket mutations which have so far responded well to salvage with DAS.