Asciminib Provides MMR Benefits vs SOC TKIs in Newly Diagnosed Ph+ CML

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Asciminib (Scemblix) demonstrated a favorable safety profile and induced statistically significant and clinically meaningful major molecular response (MMR) benefits vs standard-of-care (SOC) TKIs in patients with newly diagnosed, Philadelphia chromosome (Ph)–positive chronic myeloid leukemia (CML) in chronic phase, according to findings from the primary analysis of the phase 3 ASC4FIRST trial (NCT04971226).¹

At week 48, asciminib generated superior MMR rates vs the SOC investigator-selected TKIs nilotinib (Tasigna), imatinib (Gleevec), bosutinib (Bosulif), and dasatinib (Sprycel), meeting a coprimary end point of the trial. Superior MMR rates were observed in patients who received asciminib vs the stratum of patients who received imatinib as a pre-randomization selected TKI, meeting the trial’s other coprimary end point.

Data from ASC4FIRST, the first randomized, head-to-head, multicenter trial of a CML treatment vs approved first- and second-generation SOC TKIs, will be presented at an upcoming medical conference and submitted to regulatory authorities in 2024.

“We are very encouraged by these results given that a significant proportion of patients with newly diagnosed CML do not achieve their treatment goals,” Professor Tim Hughes, MD, of South Australian Health & Medical Research Institute in Adelaide, said in a news release. “There remains a significant need in first-line therapy of CML for tolerable treatment options, allowing [patients] with CML to balance their treatment alongside their quality of life.”

Over 60% of patients with newly diagnosed CML who receive SOC TKIs do not meet molecular response goals at 1 year. Moreover, treatment intolerance and adverse effects (AEs) remain primary reasons for TKI discontinuation, and AE-related discontinuation rates can reach 25% by 5 years.

In ASC4FIRST, asciminib was associated with fewer AEs and treatment discontinuations compared with SOC TKIs. Investigators observed no new safety signals compared with the established safety profile of asciminib.

ASC4FIRST enrolled patients at least 18 years of age with Ph-positive CML that was in chronic phase within 3 months of diagnosis.²

Patients were excluded from the trial if they had received previous CML treatment with other anticancer agents, excepting anagrelide and/or hydroxyurea. Patients were permitted to have received either imatinib, dasatinib, nilotinib, or bosutinib for a maximum of 2 weeks. No treatment with other TKIs was allowed prior to random assignment. Other exclusion criteria included known cytopathologically confirmed central nervous system infiltration; impaired cardiac function or a cardiac repolarization abnormality; a severe and/or uncontrolled medical disease deemed by the investigator to cause unacceptable safety risks or compromise protocol compliance; a history of a significant congenital or acquired bleeding disorder not related to cancer; major surgery within 4 weeks prior to trial enrollment; a history of another active malignancy within 3 years prior to trial enrollment; a history of acute pancreatitis within 1 year prior to random assignment or a medical history of chronic pancreatitis; and a history of chronic liver disease leading to severe hepatic impairment or ongoing acute liver disease.

In ASC4FIRST, 405 patients were randomly assigned 1:1 to receive asciminib at 80 mg daily or an investigator-selected first- or second-generation TKI. Investigator-selected treatments consisted of imatinib at 400 mg daily administered with food, nilotinib at 300 mg twice daily administered under fasting conditions, dasatinib at 100 mg daily administered with or without a meal, or bosutinib at 400 mg daily administered with food.

“We are excited that [asciminib] may help [patients] newly diagnosed with CML achieve their treatment goals [and continue] to live their lives,” Shreeram Aradhye, MD, president of Development and chief medical officer at Novartis, stated in the news release.1 “Given the chronic nature of their condition, patients often need to be on TKI therapy for many years, so treatment options that are well tolerated and highly efficacious are crucial to support adherence. This study outcome builds on our 20-year legacy in CML innovation as we strive to continue to address the remaining unmet needs for [patients] living with this blood cancer.”

The next scheduled data readout of the ongoing ASC4FIRST trial is planned for week 96, and will evaluate the trial’s key secondary end point of MMR at week 96.1 Additional secondary end points assessed in this study include treatment discontinuation because of an AE by week 96; MR4, MR4.5, complete hematological response, and BCR::ABL1 level of 1% or lower by all scheduled data collection time points; duration of and time to first MMR, MR4, and MR4.5; time to treatment failure; event-free survival; failure-free survival; progression-free survival; and overall survival.

References

1. Novartis Scemblix shows superior major molecular response (MMR) rates vs. standard‐of‐care TKIs in phase III trial for newly diagnosed patients with chronic myeloid leukemia. News release. Novartis. January 8, 2023. Accessed January 8, 2023. https://www.novartis.com/news/media-releases/novartis-scemblix-shows-superior-major-molecular-response-mmr-rates-vs-standard-care-tkis-phase-iii-trial-newly-diagnosed-patients-chronic-myeloid-leukemia
2. A study of oral asciminib versus other TKIs in adult patients with newly diagnosed Ph+ CML-CP. ClinicalTrials.gov. Updated November 2, 2023. Accessed January 8, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04971226