Asciminib Elicits Significant Major Molecular Responses in Ph+ Chronic-Phase CML

The novel investigational STAMP inhibitor asciminib (ABL001) significantly improved the major molecular response (MMR) rate compared with bosutinib (Bosulif) at 24 weeks in adult patients with Philadelphia chromosome (Ph)–positive, chronic-phase chronic myeloid leukemia (CML) who received prior treatment with 2 or more TKIs, meeting the primary end point of the phase 3 ASCEMBL trial (NCT03106779).¹

Novartis, the drug developer, announced their plan to submit the data from the trial for presentation at an upcoming medical conference. Findings will also be communicated to regulatory authorities.

“Our ability to treat patients with TKIs changed CML care forever. However, the risk of disease progression is a reality for many patients – especially those who experience resistance to sequential TKI therapy or those who cannot adhere to treatment due to the daily impact of intolerable side effects,” John Tsai, MD, head of Global Drug Development and chief medical officer at Novartis, stated in a press release.

“We are incredibly grateful to the patients and investigators around the world who participated in this study,” Tsai added. “These results with asciminib are a testament to our commitment to further transform CML care – this time through STAMP inhibition, by exploiting a natural regulatory mechanism of the ABL kinase.”

Because asciminib specifically targets the ABL myristoyl pocket, the hope is that the agent possesses the potential to address resistance to and intolerance of TKIs in patients with CML who require later lines of treatment, according to Novartis.

In the phase 3, multicenter, open-label ASCEMBL trial, investigators set out to compare with oral STAMP inhibitor with bosutinib in patients with Ph-positive, chronic-phase CML who received prior treatment with a minimum of 2 ATP-binding site TKIs.²

To be eligible for enrollment, patients had to have chronic-phase CML and be 18 years of age or older, must have met certain laboratory values at the time of screening, and have had a BCR-ABL1^IS ratio of greater than 0.1% per central laboratory at the screening examination for those intolerant to the most recent TKI treatment received. Patients also needed to have progressed or been intolerant to the most recent TKI therapy they received at the time of screening.

If patients had a known T315I or V299L mutation at any time prior to study entry; had a history of myocardial infarction, angina pectoris, coronary artery bypass graft within the 6 months before the initiation of study treatment; had clinically significant cardiac arrythmias; or any other specific cardiac or cardiac repolarization abnormality, they were not permitted to participate.

The primary end point of the trial was MMR rate at 24 weeks, while key secondary end points included MMR at 96 weeks, complete cytogenetic response (CCyR) rate, time to MMR, duration of MMR, time to CCyR, duration of CCyR, time to treatment failure, progression-free survival, and overall survival, among others.

In the experimental arm, participants received 40-mg tablets of asciminib to take orally twice daily, while those in the control arm were given 500-mg tablets of bosutinib to take orally once daily.

Data from earlier studies examining the novel investigational STAMP inhibitor were presented at past meetings of the European Hematology Association. In one phase 1 study (NCT02081378), asciminib was evaluated in combination with imatinib (Gleevec) in patients with CML in chronic or accelerated phase who were resistant or intolerant to 2 or more previous TKIs.³

Patients who were intolerant to imatinib or had uncontrolled cardiovascular conditions were excluded from the analysis. In this trial, patients were given continuous 28-day cycles at 1 of 4 doses of the STAMP inhibitor: 40 mg, 60 mg, or 80 mg once daily or 40 mg twice daily.

At a data cutoff date of July 15, 2018, a total of 25 patients with chronic phase CML were enrolled. The median age of participants in the 40-mg-once-daily (n = 9), 60-mg (n = 6), 80-mg (n = 4), and 40-mg-twice-daily (n = 6) subgroups was 51 years, 71 years, 65 years, and 50 years, respectively. Moreover, 44.4%, 50.0%, 25.0%, and 33.3% of patients in those respective subgroups received treatment with 2 prior TKIs. Baseline Y253H and V299L mutations were reported in 1 patient each in the 40-mg-twice-daily subgroup. Notably, 68% of participants received prior treatment with imatinib.

Results showed that among patients with BCR-ABL1^IS of less than 1% at baseline, 60% (n = 9/15) achieved response by 48 weeks. Of evaluable patients without MMR at baseline, 42% achieved MMR and 15% achieved MR. The MMRs at 24 weeks in the 40-mg-once-daily, 60-mg, 80-mg, and 40-mg-twice-daily subgroups were 11.1%, 50.0%, 50.0%, and 66.7%, respectively; at 48 weeks, the rates were 12.5%, 75.0%, 50.0%, and 66.7%, respectively.

With regard to safety, 88% of these heavily pretreated patients experienced any-grade treatment-related adverse effects (AEs); 44% of these toxicities were grade 3/4 in severity. The most commonly reported any-grade AEs included nausea (32%), increased lipase (20%), abdominal pain (16%), peripheral edema (16%), and vomiting (16%).

Dose-limiting toxicities during cycle 1 for each asciminib dose level included decreased neutrophil count (n = 1; 40 mg once daily), abdominal pain and nausea (n = 1 each; 60 mg once daily), pancreatitis and increased lipase (n =1 each; 80 mg once daily), and pancreatitis (n = 1; 40 mg twice daily). Both participants who experienced pancreatitis were able to tolerate treatment following dose reduction and they remained on the trial. One patient progressed to blast phase and they discontinued treatment because of disease progression. No patients died on treatment.

In another phase 1 study, investigators assessed the STAMP inhibitor in combination with either nilotinib (Tasigna) or dasatinib (Sprycel) in patients with CML in chronic or accelerated phase who were resistant or intolerant to 2 or more prior TKIs. Again, those with uncontrolled cardiovascular conditions were not permitted to participate.⁴

In this trial, patients were assigned to treatment in continuous 28-day treatment cycles. Those randomized to the asciminib/nilotinib combination received asciminib at 20 mg or 40 mg twice daily plus nilotinib at 300 mg twice daily. For those in the asciminib/dasatinib arm, patients were given asciminib at 40 mg twice daily or 80 mg once daily plus 100 mg of dasatinib.

At a data cutoff date of July 15, 2018, a total of 17 patients were enrolled to the trial across the cohorts. The median age for participants in the asciminib/nilotinib and asciminib/dasatinib arms was 56 years and 53 years, respectively; 29.4% and 64.7% of patients received 2 prior TKIs, respectively. Moreover, 82.4% and 70.6% of patients in the asciminib/nilotinib and asciminib/dasatinib arms, respectively, received prior imatinib; 70.6% versus 35.3%, respectively, received prior nilotinib; and 94.1% and 70.6%, respectively, received prior dasatinib.

Results showed that of patients without BCR-ABL1^IS of less than 1% at baseline, 43% (n = 6/14) 56% (n = 5/9) pts in the asciminib/nilotinib and asciminib/dasatinib cohorts, respectively, achieved response by 48 weeks.

Among evaluable patients without MMR (BCR-ABL1^IS of less than or equal to 0.1%) at baseline, 31% (n = 4/13) and 36% (n = 5/14) of patients, respectively, achieved MMR by 48 weeks. Notably, in those with MMR at baseline, no MMR loss was observed. Moreover, 14% (n = 2/14) and 7% (n = 1/14) of patients also achieved MR^4.5 (BCR-ABL1^IS of less than or equal to 0.0032%) by 48 weeks with asciminib/nilotinib and asciminib/dasatinib, respectively.

With regard to safety, rates of any-grade AEs and those grade 3/4 in severity were 82% and 53%, respectively, in those who received the asciminib/nilotinib combination. The most commonly observed any-grade toxicities included myalgia (35%), increased lipase (29%), increased amylase (24%), fatigue (24%), and pruritus (24%). One patient experienced a dose-limiting toxicity, maculopapular rash, during cycle 1 of treatment.

For those who received the asciminib/dasatinib combination, rates of any-grade and grade 3/4 AEs were 88% and 29%, respectively. The most common toxicities experienced by this cohort included increased lipase (35%), diarrhea (18%), headache (18%), and nausea (18%). One patient on this arm experienced a dose-limiting toxicity, in the form of increased lipase, during cycle 1.

Asciminib previously received a fast track designation by the FDA, and it is currently being examined in several clinical trials across multiple lines of CML treatment.

References

1. Novartis investigational novel STAMP inhibitor asciminib (ABL001) meets primary endpoint of phase III chronic myeloid leukemia. News release. Novartis. August 26, 2020. Accessed August 26, 2020. https://bit.ly/3hyXf5j.
2. Study of efficacy of CML-CP patients treated with ABL001 versus bosutinib, previously treated with 2 or more TKIs. ClinicalTrials.gov. Updated August 12, 2020. Accessed August 26, 2020. https://clinicaltrials.gov/ct2/show/NCT03106779.
3. Cortes J, Lang F, Kim D-W, et al. Combination therapy using asciminib plus imatinib (IMA) in patients (pts) with chronic myeloid leukemia (CML): results from a phase 1 study. Presented at: 24th Congress of the European Hematology Association. June 13-16, 2019; Amsterdam, The Netherlands. Abstract S883. https://bit.ly/2YCR9JF.
4. Mauro MJ, Kim D-W, Cortes J, et al. Combination of asciminib plus nilotinib (NIL) or dasatinib (DAS) in patients (pts) with chronic myeloid leukemia (CML): results from a phase 1 study. Presented at: 24th Congress of the European Hematology Association. June 13-16, 2019; Amsterdam, The Netherlands. Abstract S884. https://bit.ly/2YCeBqs.