Asciminib Significantly Improves Major Molecular Response in Pretreated Chronic Phase-CML

Andreas Hochhaus, MD

Asciminib demonstrated a statistically significant and clinically meaningful improvement in the major molecular response (MMR) rate at 24 weeks compared with bosutinib (Bosulif) in patients with chronic myeloid leukemia (CML) in chronic phase (CP) who have received at least 2 prior TKIs, according to results from the phase 3 ASCEMBL study (NCT03106779) that were presented during the 2020 ASH Annual Meeting and Exposition.¹

Results showed that the MMR rate was 25.5% with asciminib compared with 13.2% with bosutinib; the common risk difference for MMR was 12.2%, which was found to be statistically significant (95% CI, 2.19-22.3; 2-sided P = .029).

“Asciminib demonstrated statistically significant superior efficacy compared with bosutinib and a favorable safety profile,” lead study author Andreas Hochhaus, MD, professor of internal medicine, hematology and oncology, and interim Head of the Department of Hematology and Medical Oncology at the University Medical Center Jena in Germany, said in a virtual press briefing during the meeting. “The ASCEMBL data support the use of asciminib as a new treatment option in CML, particularly in patients with resistance or intolerance to at least 2 TKIs.”

Current therapies for patients who have resistance or intolerance to 2 or more TKIs are limited due to modest efficacy and/or safety concerns. Although ponatinib is an effective therapy in pretreated patients, it is also linked with increased cardiovascular risk. Bosutinib is a second-generation TKI with efficacy in patients with CML who have received at least 2 TKIs.

Asciminib is a first-in-class inhibitor specifically targeting the ABL myristoyl pocket (STAMP). In August 2020, Novartis, the manufacturer of asciminib, announced that the FDA had granted the agent a fast track designation.²

In the phase 3 study, investigators sought to determine the efficacy and safety of asciminib versus bosutinib in 233 patients with CP-CML who have received at least 2 prior TKIs. Patients were randomized 2:1 to receive asciminib at 40 mg twice daily (n = 157) or bosutinib at 500 mg once daily (n = 76) for at least 96 weeks. Patients were stratified by major cytogenetic response (MCyR) status at baseline.

Based on an amendment to the study protocol, switching to asciminib was permitted only for patients who met treatment failure criteria on bosutinib.

To be eligible for enrollment, previously treated patients with CML-CP must have received 2 or more TKIs, could not harbor T3151 or V299L mutations, had failed or were intolerant to their most recent TKI, and those with intolerance must have had BCR-ABL1^IS greater than 0.1% at screening.

The primary end point of the trial was MMR rate at 24 weeks while on study treatment without meeting any treatment failure criteria before 24 weeks. Secondary end points included MMR rate at 96 weeks while on study treatment without meeting any treatment failure criteria before 96 weeks, safety and tolerability, and complete cytogenetic response (CCyR) and MMR rates at and by scheduled data collection time points, time to and duration of MMR, time to and duration of CCyR, time to treatment failure, progression-free survival, overall survival, and pharmacologic parameters.

The data cutoff data was May 25, 2020, at which point all patients completed their week 24 visit or had previously discontinued treatment.

The median age was 52.0 years (range, 19-83) and 51.5% of patients were female. MCyRs had occurred in 29.3% of patients. Patients discontinued their last TKI due to lack of efficacy (63.9%), lack of tolerability (34.8%), or other (1.3%). Patients had received either 2 (48.1%) or 3 or more (51.9%) lines of therapy. The BCR-ABL^IS at baselines were not applicable. However, 14.2% of patients had a BCR-ABL1 mutations; 1.7% of patients had multiple BCR-ABL1 mutations.

At the time of data cutoff, treatment was ongoing in 61.8% of patients on the asciminib arm vs 30.3% of those on bosutinib. In the asciminib arm and bosutinib arms, patients discontinued treatment due to lack of efficacy (21.0% vs 31.6%, respectively), adverse event (AE; 5.1% vs 21.1%), physician decision (6.4% vs 7.9%), patient decision (2.5% vs 3.9%), death (0.6% vs 0%), lost to follow-up (0.6% vs 1.3%), progressive disease (0.6% vs 3.9%), or protocol deviation (0.6% vs 0%). Twenty-two patients (28.9%) had switched over from bosutinib to receive asciminib.

At a median follow-up of 14.9 months, the median duration of exposure was 43.4 weeks (range, 0.1-129.9) for asciminib and 29.2 weeks (range, 1.0-117.0) for bosutinib. The MMR benefit was observed across key patient subgroups, including MCyR (27.5%), female sex (20.4%), failure on prior TKI (15.5%), and regardless of whether it was the third (9.3%), fourth (11.2%), and fifth (16.1%) line of therapy. Patients benefitted from asciminib regardless of whether they were BCR-ABL1 unmutated at week 1, day 1 (13.5%) or mutated (15.3%).

To understand the potential impact of asciminib when compared with bosutinib, Hochhaus said a logistic regression model was designed. When adjusted by MCyR, the odds ratio for asciminib versus bosutinib was 2.35 (95% CI, 1.08-5.12). When adjusted by MCyR and other important variables, the odds ratio was similar, at 2.38 (95% CI, 1.06-5.35).

“This indicates that the treatment effect is still significant while accounting for imbalances,” Hochhaus said.

Moreover, the cumulative incidence of MMR was 25.0% with asciminib compared with 11.9% with bosutinib, with a difference between the 2 arms becoming evident around 12 weeks, according to Hochhaus. The rate of CCyR at 24 weeks was 40.8% and 24.2% with asciminib and bosutinib, respectively, with a common risk difference of 17.3% (95% CI, 3.62-31.0%).

Data also showed that the molecular response (MR)⁴ at 24 weeks was 10.8% and 5.3% with asciminib and bosutinib, respectively. These rates were 8.9% and 1.3% for MR^4.5. The rates of BCR-ABL1^IS at 1% or less at week 24 among patients with i^IS more than 1% at baseline were 44.5% with asciminib and 22.2% with bosutinib.

Regarding safety, all-grade and grade 3 or higher AEs were similar between arms (all-grade, 89.7% with asciminib vs 96.1% with bosutinib; grade ≥3 50.6% vs 60.5%, respectively). Two deaths occurred on the asciminib arm due to arterial embolism and ischemic stroke (n = 1 each), which was not considered related to study treatment, and 1 on the bosutinib arm due to septic shock after disease progression. Two additional patients who were randomized to asciminib died during survival follow-up due to CML.

The most common AEs that led to treatment discontinuation on asciminib (5.8%) included thrombocytopenia (3.2%) and neutropenia (2.6%). On bosutinib, the AEs that led to patients discontinuing treatment (21.1%) included increased alanine aminotransferase (5.3%) and increased alanine aminotransferase (2.6%). All-grade and grade 3 or higher AEs that led to dose adjustments/interruptions occurred in 37.8% and 34.0% of patients on asciminib and 60.5% and 48.7% on bosutinib, respectively. All-grade AEs that required additional therapy occurred in 66.0% of patients on asciminib and 88.2% of those on bosutinib; grade 3 or higher AEs that led to additional therapy occurred in 28.2% and 40.8% of patients, respectively.

The most frequent all-grade AEs occurring in at least 20% of patients in either arm were thrombocytopenia (28.8% with asciminib vs 18.4% with bosutinib), neutropenia (21.8% vs 21.1%, respectively), diarrhea (11.5% vs 71.1%, respectively), nausea (11.5% vs 46.1%), rash (7.1% vs 23.7%), vomiting (7.1% vs 26.3%), increased ALT (3.8% vs 27.6%), and increased AST (3.8% vs 21.1%).

Arterial-occlusive events occurred in 3.2% of patients on asciminib compared with 1.3% of those on bosutinib. On the asciminib arm, this comprised myocardial ischemia (n = 2) and coronary artery disease (n = 1).

Patients on asciminib with mutations at baseline also developed newly emerging BCR-ABL1 mutations; these occurred at the ATP binding site (n = 3). Emerging mutations were reported in patients without mutations at baseline, at the ATP binding site (n = 2) and the myristoyl binding pocket (n = 2). No patients on bosutinib had mutations at baseline and none had emerged following treatment.

“Conclusions on the impact of mutations cannot be made, due to their low incidence and heterogeneity,” Hochhaus said.

Investigations are planned to evaluate asciminib in earlier lines of therapy of CML, Hochhaus said in a press briefing during the meeting.

“This study is designed to get approval,” he said, adding that Novartis is planning to submit regulatory applications for approval of asciminib to the FDA and European Medicines Agency in early 2021. “Third-line treatment will not be the only indication for asciminib, but it will certainly be the first indication for this drug. My personal expectation is that first-line response [to asciminib] will be even strong, even better.”

The ongoing, 4-arm, phase 2 CMLXI trial (NCT03906292) is evaluating the combination of asciminib with various TKIs in the frontline setting of patients with CP-CML. In the study, asciminib is administered at varying daily doses (40 mg, 60 mg, and 80 mg) and at the twice-daily 20-mg dose in combination with imatinib (Gleevec), nilotinib (Tasigna), and dasatinib (Sprycel).

References

1. Hochhaus A, Boquimpani B, Réa D, et al. 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). Presented at: 2020 ASH Annual Meeting & Exposition; December 5-8, 2020; Virtual. Abstract LBA-4.
2. Novartis investigational novel STAMP inhibitor asciminib (ABL001) meets primary endpoint of Phase III chronic myeloid leukemia study. News release. Novartis. August 26, 2020. Accessed December 7, 2020. https://bit.ly/33RwIeV.