Treatment with Asciminib As a Second Line after One Prior Tyrosine Kinase Inhibitor (TKI) in Patients with Chronic-Phase Chronic Myeloid Leukemia (CML-CP) – a Chart Review Study in the United States

Ehab L. Atallah, M et al, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI

In CML-CP, first-line treatment switching due to intolerance or resistance is frequent with ATP-competitive TKIs and patients typically experience poor response rates in second-line and beyond. Treatments that optimize tolerability and efficacy are needed to allow patients to stay on therapy and achieve treatment goals. Asciminib, an ABL/BCR::ABL1 TKI targeting the ABL myristoyl pocket is approved for patients with CML-CP previously treated with ≥2 TKIs or with the T315I mutation, recently demonstrated positive phase 3 study results in newly diagnosed CML (ASC4FIRST), and is being assessed in clinical trial of patients previously treated with one TKI (ASC2ESCALATE). Dr. Ehab L. Atallah  et al here describe real-world clinical outcomes of patients treated with asciminib after one prior TKI in the US.

In this retrospective panel-based chart review study, eligible oncologists/hematologists from the US with experience treating patients with CML reported de-identified data via an online case report form from February to April 2024. Eligible adult patients with CML-CP did not have the T315I mutation and initiated asciminib (index) between January 2022 and June 2023 after one prior TKI. Time to treatment discontinuation, and time to BCR::ABL1 ≤0.1% (MR3 or better; major molecular response) and BCR::ABL1 ≤1% (MR2 or better) were measured using Kaplan-Meier analyses. BCR::ABL ≤0.01% (MR4 or better, including undetectable; deep molecular response) as best response, progression to accelerated phase/blast crisis (AP/BC), and adverse events (AEs; any grades) were also assessed. Subgroup analyses were conducted in patients who discontinued the first TKI due to resistance/suboptimal response, and by first- or second-generation (1G/2G) TKI as first TKI.

A total of 149 eligible patient charts reported by 51 physicians (49.0% community, 51.0% academic; 82.4% ≥10 years of practice) were reviewed. The 149 patients had median age 63.0 years and were 45.0% female, 56.4% White, 24.2% Black/African American, and 15.4% Hispanic/Latino. At CML diagnosis, 65.8% had an intermediate-risk and 12.8% a high-risk Sokal score, and 11.4% had ECOG performance score ≥2. Patients received imatinib (48.3%), dasatinib (38.9%), nilotinib (9.4%), or bosutinib (3.4%) as first TKI, with a median treatment duration of 52.1 weeks. The primary reason for first TKI discontinuation included resistance (43.6%), suboptimal response (34.9%), and intolerance/management of adverse events (4.7%). Asciminib was initiated at 40 mg twice daily by 42.3% and 80 mg once daily by 43.6% of patients.

By 48 weeks post index, 93.3% of patients remained on asciminib (resistance/suboptimal response to first TKI: 93.7%; 1G TKI as first TKI: 92.9%; 2G TKI as first TKI: 93.7%). Median time to MR3 or better was 35.0 weeks and the median time to MR2 or better was 21.4 weeks. By 48 weeks post index, 68.2% of patients achieved or maintained MR3 or better (resistance/suboptimal response to first TKI: 70.2%; 1G TKI as first TKI: 61.6%; 2G TKI as first TKI: 73.1%) and 87.8% of patients achieved or maintained MR2 or better (resistance/suboptimal response to first TKI: 92.6%; 1G TKI as first TKI: 86.0%; 2G TKI as first TKI: 88.9%).

Over a median follow-up of 50.8 weeks, MR4 or better was achieved by 45.0% of patients as best response on asciminib (resistance/suboptimal response to first TKI: 49.5%; 1G TKI as first TKI: 40.3%; 2G TKI as first TKI: 49.4%), and no patients were observed to progress to AP/BC post index. Constitutional AEs including fatigue (8.7%), headache (4.7%), rash (3.4%) and abdominal pain (2.0%); gastrointestinal AEs including nausea (8.7%), diarrhea (5.4%) and vomiting (5.4%); and cytopenia (4.0%) were observed post index.

This real-world study of asciminib demonstrated that over two-thirds of patients achieved or maintained MR3, and nine out of ten patients reached the key response milestone goal of MR2 by 48 weeks, despite inclusion of a majority with resistance/suboptimal response to a prior TKI. Deep molecular response was reported as the best response for nearly half of patients during the first year of treatment with asciminib. Low discontinuation rates, regardless of type of prior TKI used, and low frequency of AEs were observed post asciminib initiation. These results suggest that asciminib is well-tolerated and rapidly effective among patients with CML who received one prior TKI in the US clinical practice.

Asciminib (ASC) Demonstrates Favorable Safety and Tolerability Compared with Each Investigator-Selected Tyrosine Kinase Inhibitor (IS TKI) in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) in the Pivotal Phase 3 ASC4FIRST Study

About 1/3rd of patients (pts) with newly diagnosed CML discontinue/switch treatments (Tx) regardless of TKI (imatinib [IMA], nilotinib [NIL], dasatinib [DAS], or bosutinib [BOS]). Many pts have poor quality of life on existing therapies. Tx-free remission is a key Tx goal, but only 30%-40% pts on IMA and 40%-50% on 2nd-generation (2G) TKIs meet discontinuation criteria. A frontline agent with a superior benefit-risk profile is needed. ASC is the first BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket. ASC4FIRST is a randomized phase 3 study of ASC vs all standard-of-care TKIs in newly diagnosed CML-CP.

The authors, Dr, Jorge E. Cortes et al, present primary efficacy results and additional safety/tolerability data for ASC vs each IS TKI from the primary analysis (wk 48) data cutoff. Key secondary results from the wk 96 cutoff (Oct 21, 2024) will be presented at the 2024 ASH Meeting.

Adults with newly diagnosed CML-CP were stratified by ELTS risk category and TKI (IMA/2G TKIs [NIL, DAS, or BOS]) selected by investigators before randomization, accounting for pt preference. Pts were randomized 1:1 to receive either ASC 80 mg once daily or an IS TKI at label doses. The 2 primary and 2 key secondary efficacy endpoints are major molecular response (MMR) rate at wk 48 and 96, respectively, with ASC vs IS TKI and with ASC vs IS TKI in the IMA stratum; time to Tx discontinuation due to adverse events (AEs) is a secondary safety endpoint.

In ASC4FIRST, 201 pts randomized to ASC and 204 to IS TKIs (IMA/2G TKIs) were included in efficacy analyses. Safety analyses were done in pts who received ASC (n=200), IMA (n=99), and 2G TKIs (NIL, n=49; DAS, n=42; BOS, n=11). At the wk 48 cutoff, after a median duration of follow-up of ≈16 months across study arms, Tx was ongoing in 86%, 62%, and 75% of pts on ASC, IMA, and 2G TKIs, respectively. Both primary objectives were met: MMR rate at wk 48 was superior with ASC (67.7%) vs IS TKIs (49.0%) (difference, 18.9%; 95% CI, 9.6%-28.2%; adjusted 2-sided P<.001) and with ASC (69.3%) vs IMA (40.2%) in the IMA stratum (difference, 29.6%; 95% CI, 16.9%-42.2%; adjusted 2-sided P<.001).

The rates of optimal responses at wk 12 (BCR::ABL1IS ≤10%) and wk 24 (BCR::ABL1IS ≤1%), respectively, were higher with ASC vs IS TKIs (89.6% vs 70.1%; 88.6% vs 63.7%), ASC vs IS TKI in the IMA stratum (88.1% vs 59.8%; 88.1% vs 52.9%), and ASC vs IS TKI in the 2G TKI stratum (91.0% vs 80.4%; 89.0% vs 74.5%).

Safety/tolerability of ASC was more favorable vs IMA and individual 2G TKIs. Grade ≥3 AEs were lower with ASC (38.0%) vs IMA (44.4%), NIL (51.0%), DAS (54.8%), and BOS (72.7%). Any-grade AEs leading to Tx discontinuation were lower with ASC (4.5%) vs IMA (11.1%), NIL (8.2%), DAS (11.9%), and BOS (9.1%), the most frequent (≥2% in any arm) being generalized edema (BOS, 9.1%), pleural effusion (DAS, 4.8%), cardiac failure, colitis, hypersensitivity, and muscular weakness (DAS, 2.4% each), lymphopenia and diarrhea (IMA, 2.0% each), QT prolongation, rash, and maculopapular rash (NIL, 2.0% each), and thrombocytopenia (ASC, 1.0%; NIL, 2.0%). Any-grade AEs leading to dose adjustment and/or interruption were lower with ASC (30.0%) vs IMA (39.4%), NIL (49.0%), DAS (54.8%), and BOS (63.6%). Arterial occlusive events occurred in 2 (1.0%) pts with ASC (arteriosclerosis coronary artery, n=1; cerebrovascular accident, n=1), 1 (1.0%) with NIL (vertebral artery arteriosclerosis), and 1 (1.0%) with DAS (myocardial infarction and ischemia). Two pts had cardiac failure with DAS.

Any-grade AEs of special interest (≥5% in any arm), defined as serious or nonserious safety events of medical concern, were lower with ASC vs IMA and/or 2G TKIs and included gastrointestinal toxicity (34.5%, 42.4%, 48.0%), myelosuppression (43.0%, 51.5%, 62.7%), hypersensitivity (24.0%, 41.4%, 41.2%), hepatotoxicity (16.5%, 19.2%, 34.3%), acute pancreatitis (isolated enzyme elevations) (13.0%, 16.2%, 14.7%), hemorrhage (6.0%, 7.1%, 9.8%), edema and fluid retention (3.5%, 13.1%, 11.8%), and ischemic heart and CNS conditions (6.0%, 5.1%, 7.8%).

In ASC4FIRST, ASC had a better benefit-risk profile compared with IS TKIs. ASC’s superior efficacy vs all IS TKIs and more favorable safety/tolerability compared with each IS TKI (IMA, NIL, DAS, and BOS) suggests that ASC may transform the CML Tx paradigm. Key secondary endpoints, including MMR rate at week 96, and other long-term secondary efficacy and safety/tolerability results, will be presented at ASH 2024.

Update of the Ascend-CML Study of Frontline Asciminib: High Rate of Optimal Response and Resistance Due to Mutations Is Rare

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. Dr. David T Yeung et al here 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 >10% at 3 or 6 mos; BCR::ABL1 >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 patients 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 patients 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. Patients without MMR at 12 months 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.

ASC4REAL: Efficacy and Tolerability Comparison between Ascembl Study, a Phase 3 Randomized Clinical Trial (RCT), and Consolidated Real-World (RW) Evidence with Asciminib in CML Patients Beyond 2 TKIs

Despite advancements in managing chronic myeloid leukemia (CML), there are limited effective treatment options available in later lines of therapy. With each successive line of treatment, the rates of treatment failure increase, and sequential tyrosine kinase inhibitor (TKI) therapy is linked to higher resistance. It is worth noting that most TKIs currently used in clinical practice target the ATP binding site, which may lead to off-target effects and long-term tolerability issues. ASCEMBL is a phase 3 randomized controlled trial (RCT) evaluating the efficacy of asciminib (ASC), a novel allosteric TKI that targets the myristoyl pocket, in CML patients who have received two prior TKIs. While there is emerging efficacy and safety data for ASC, the limited number of patients in individual ASC real-world (RW) studies hampers a robust comparison with larger phase 3 RCTs. The data presented in this study, carried out by Dr Anchit Khanna et al, builds upon previous efforts to aggregate RW evidence from studies conducted in multiple countries (Italy, Spain, the Netherlands, Australia, Russia, the United Kingdom, and Canada). This analysis expands the dataset to include US RW evidence as well as additional patient accrual and longer follow-up times in several of the original studies to contextualize and generalize the results of the ASCEMBL study.

A total of 10 RW studies were included in this analysis, with a total of 421 CML patients that received ASC after 2 or more prior TKIs. 9 of the RW studies were previously identified with a systematic literature search conducted in May 2023. In this previous search, data was extracted from published or publicly presented RW studies of patients that received ASC after 2 or more prior TKIs, and RW studies that had fewer than 10 patients were excluded. The 10th RW study (n=97), using US RW data, was presented following the previous search. Where updated data for the original 9 studies was published or publicly presented prior to July 2024, that updated data was used in this analysis. Data in the RW studies meeting the analysis criteria was generated during managed access programs or included from Flatiron Health’s nationwide US electronic health record-derived de-identified database. The RW studies had a mean sample size of 42 patients, with a range of 20 to 97 patients. Key endpoints from the RW studies were compared to the ASCEMBL study (n=157), including major molecular response (MMR) rates, deep molecular response (DMR) rates, reason for ASC discontinuation, and adverse event occurrence. Data on patient MMR (n=393) and DMR (n=343) was available for a subset of the total RW patient population. DMR was operationalized as either MR4 (≤0.01% BCR::ABL1) or as MR4.5 (≤0.0032% BCR::ABL1) in the RW studies and as MR4 in the RCT.

The average age of CML patients was slightly higher in the RW studies (59 years) than in the RCT (52 years). Importantly, compared to the RCT, RW studies showed similar or higher efficacy based on MMR and DMR rates, achieved in shorter time. RW studies reported a mean of 52% of patients achieving MMR (range: 37-70%) at a median 13 months (range: ≤12-24 months), and RCT reported 38% of patients achieving MMR at 22 months. RW studies reported a mean of 32% of patients achieving DMR (range: 16-70%) at a median 13 months (range: ≤12-24 months), and RCT reported 17% of patients achieving DMR at 22 months. Rate of discontinuation of ASC was comparable or lower in the RW setting. For discontinuation due to intolerance, RW studies reported a mean of 9% (range: 0-16%), and RCT reported 8%. For discontinuation due to resistance, RW studies reported a mean of 12% (range: 6-23%), and RCT reported 24%. Similarly, some adverse events, specifically thrombocytopenia and arterial occlusive events, were less frequent in the RW settings, while some such as myalgia and muscle spasms were slightly higher in the RW setting when compared with the RCT.

The aggregated RW evidence data across varied global contexts demonstrates asciminib is an effective and tolerable TKI for CML patients who have received two or more prior TKIs in the RW setting, supporting the results of the ASCEMBL RCT. Furthermore, the similarity of the RW results to the RCT results demonstrates the generalizability of the ASCEMBL RCT outcomes, indicating external validity despite the varying country and age contexts in the RW studies.

Asciminib Shows High Efficacy and Favorable Tolerability at 80 Mg Once Daily and 40 Mg Twice Daily in Patients with Chronic Phase Chronic Myelogenous Leukemia Previously Treated with 2 or More Tyrosine Kinase Inhibitors: Primary Analysis from the ASC4OPT Study

Asciminib, a BCR::ABL1 inhibitor intentionally designed to Specifically Target the ABL Myristoyl Pocket (STAMP), has been approved for the treatment of adult patients (pts) with Philadelphia chromosome–positive chronic myelogenous leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). A once daily (QD) regimen is likely to improve quality of life and increase treatment adherence. Pharmacokinetic modelling showed 40 mg twice daily (BID) and 80 mg QD regimens had similar and substantial efficacy in patients with CML-CP without the T315I mutation; both schedules have been recommended as standard doses. In this study, carried out by Dr Andreas Hochhaus et al, the authors present the primary results from the ASC4OPT (NCT04948333) trial, assessing safety and efficacy of once and twice daily schedules for asciminib (80 mg total daily dose) in pretreated adult pts with CML-CP.

ASC4OPT is an international, multi-center, non-comparative phase 3b study in adults with CML-CP without the T315I mutation and previously treated with ≥2 TKIs. Eligible patients were in treatment failure or warning categories according to ELN 2020, or intolerant to their most recent TKI and not in major molecular response (MMR, BCR::ABL1IS ≤0.1%). Pts intolerant to their most recent TKI and in MMR at baseline were also enrolled and analyzed separately. Pts were randomized 1:1 to receive asciminib 40 mg BID or 80 mg QD, fasting. In pts not achieving MMR at 48 weeks or losing response after week 48 and up to week 108, asciminib dose could be escalated to 200 mg QD at investigator’s discretion. The primary endpoint was MMR rate at week 48; pts who discontinued earlier were considered as non-responders at week 48. Secondary endpoints included time to MMR, deep molecular response (MR4 [BCR::ABL1IS ≤0.01%] and MR4.5 [BCR::ABL1IS ≤0.0032%]), BCR::ABL1IS ≤1%, and complete cytogenetic response (CCyR) rates, and safety for pts not in MMR at baseline. For pts in MMR at baseline, MMR rate at week 48 was assessed separately.

Overall, 169 patients were randomized to asciminib 40 mg BID (n=85) or 80 mg QD (n=84); 1 pt in the 40 mg BID arm was not treated. Median age was 55 years (range, 18‒86) and 62.1% pts were male. Overall, 49.7%, 29.6%, and 20.1% of pts had received 2, 3, or ≥4 prior lines of therapy, respectively; 28.4% of pts had discontinued their most recent TKI due to intolerance. After a median follow-up of 17.5 months, treatment was ongoing for 136 pts (80.5%); 5.9% had discontinued treatment due to adverse events (AEs, 6 pts on 40 mg BID and 4 pts on 80 mg QD) and 4.1% due to unsatisfactory therapeutic effect (4 pts on 40 mg BID and 3 pts on 80 mg QD).

The overall MMR rate at week 48 was 38.5% (65/169; 95% CI: 31.1%‒46.2%); 42.4% (36/85; 95% CI: 31.7%‒53.6%) in the 40 mg BID arm and 34.5% (29/84; 95% CI: 24.5%‒45.7%) in the 80 mg QD arm. Median time to MMR was 59.3 weeks and 72.1 weeks for pts on asciminib 40 mg BID and 80 mg QD, respectively. CCyR rates (including pts in MMR without bone marrow assessment) at week 48 were 58.8% and 54.8% for pts on asciminib 40 mg BID and 80 mg QD, respectively. BCR::ABL1IS ≤1% was achieved at week 48 in 64.7% and 59.5% pts on 40 mg BID and 80 mg QD, respectively. MR4 and MR4.5 rates at week 48 were 20.0% and 11.8% for pts on 40 mg BID, and 13.1% and 8.3% for pts on 80 mg QD, respectively.

Overall, 89.3% of patients experienced any-grade AEs and 29.8% of pts experienced Grade ≥3 AEs (90.5% and 25.0% on 40 mg BID, and 88.1% and 34.5% on 80 mg QD, respectively). The most common AEs for all pts were thrombocytopenia (15.5%), arthralgia (13.7%), COVID-19 (11.9%), leukopenia (11.3%), and pruritus (10.1%). AEs led to treatment discontinuation in 6.0% of pts and to dose reduction or interruption in 30.4% of pts. One on-treatment death was reported on the 80 mg QD arm (cerebrovascular accident).

Among patients already in MMR at baseline, 28/30 pts (93.3%; 14/14 [100%] on 40 mg BID and 14/16 [87.5%] on 80 mg QD) remained in MMR at week 48. Two pts on 80 mg QD discontinued treatment due to AEs.

Asciminib at both 40 mg BID and 80 mg QD doses is efficacious and shows favorable tolerability in pts with CML-CP previously treated with ≥2 TKIs. MMR rates in ASC4OPT were numerically higher than in ASCEMBL (NCT03106779, 29.0% for asciminib 40 mg BID at week 48). An analysis will be conducted to investigate numerical differences between the schedules and in comparison to the ASCEMBL study. Results complement those of the ASCEMBL study to support asciminib as a standard of care in non-optimally treated pts with CML.