FDA Grants Accelerated Approval to Asciminib for Newly Diagnosed Ph+ Chronic-Phase Chronic Myeloid Leukemia

FDA

The FDA has granted accelerated approval to asciminib (Scemblix) for the treatment of adult patients with newly diagnosed, Philadelphia chromosome (Ph)–positive chronic myeloid leukemia in chronic phase (CP-CML).¹

The regulatory decision was supported by data from the phase 3 ASC4FIRST trial (NCT04971226), which showed that patients treated with asciminib (n = 201) experienced a 48-week major molecular response (MMR) rate of 68% (95% CI, 61%-74%) compared with 49% (95% CI, 42%-56%) for those given investigator's choice of TKI (n = 204), which included imatinib (Gleevec), nilotinib (Tasigna), dasatinib (Sprycel), or bosutinib (Bosulif; difference, 19%; 95% CI, 10%-28%; P < .001).^1,2 In the imatinib stratum, the MMR rate was 69% (95% CI, 59%-78%) for those in the asciminib arm (n = 101) vs 40% (95% CI, 31%-50%) in the TKI arm (n = 102; difference, 30%; 95% CI, 17%-42%; P < .001).^1,2

“While there are a range of effective TKIs currently available for newly diagnosed patients, clinicians frequently have had to weigh sacrificing either efficacy or tolerability,” Jorge Cortes, MD, director of the Georgia Cancer Center, stated in a news release.³ “In the first-of-its-kind ASC4FIRST trial, [asciminib] achieved impressive results across all 3 parameters of efficacy, safety, and tolerability vs all standard-of-care TKIs. This [asciminib] data has the potential to be practice-changing.”

ASC4FIRST evaluated asciminib vs standard-of-care TKIs in patients at least 18 years of age with newly diagnosed Ph-positive CP-CML who received no prior TKIs.² However, patients were allowed to receive imatinib, nilotinib, dasatinib, or bosutinib for up to 2 weeks prior to randomization. Additionally, a TKI was selected for each patient prior to randomization in the event they were assigned to the control arm. The TKI was selected by the treating physician in consultation with the patient.

Patients (n = 405) were randomly assigned 1:1 to receive 80 mg of asciminib once per day or investigator's choice of TKI at label doses. Each cohort featured an imatinib stratum and a second-generation TKI stratum.

Key stratification factors included pre-randomization TKI selection (imatinib vs second-generation TKI) and European Treatment and Outcome Study long-term survival score (high vs intermediate vs low).

The MMR rate at week 48 for asciminib vs all TKIs and asciminib vs TKIs in the imatinib stratum served as the trial's primary end points.

Additional data presented at the 2024 ASCO Annual Meeting demonstrated that the MMR benefit was consistent for asciminib across all demographic and prognostic subgroups compared with all investigator-selected TKIs.

In the overall population, the 12-week early molecular response (EMR), 48-week MR⁴, and 48-week MR^4.5 rates were 89.6%, 38.8%, and 16.9%, respectively, for those given asciminib. These respective rates were 70.1%, 20.6%, and 8.8% for those given any investigator-selected TKI.

In the imatinib stratum, the 12-week EMR, 48-week MR⁴, and 48-week MR^4.5 rates were 88.1%, 42.6%, and 17.8%, respectively, for those given asciminib. These respective rates were 59.8%, 14.7%, and 4.9% for those in the control arm.

For the second-generation TKI stratum, the respective 12-week EMR, 48-week MR⁴, and 48-week MR^4.5 rates for asciminib were 91.0%, 35.0%, and 16.0%. These rates were 80.4%, 26.5%, and 12.7%, respectively, for second-generation TKIs.

Regarding safety, grade 3 or higher adverse effects (AEs) occurred in 38.0% of evaluable patients treated with asciminib (n = 200), 44.4% of evaluable patients given imatinib (n = 99), and 54.9% of evaluable patients treated with a second-generation TKI (n = 102). The rates of AEs leading to treatment discontinuation were 4.5%, 11.1%, and 9.8% in the asciminib, imatinib, and second-generation TKI groups, respectively. The respective rates of AEs leading to dose adjustment or interruption were 30.0%, 39.4%, and 52.9%.

Safety data from a pooled population of patients with newly diagnosed and previously treated Ph-positive CP-CML showed that the most common adverse effects reported in at least 20% of patients treated with asciminib included musculoskeletal pain, rash, fatigue, upper respiratory tract infection, headache, abdominal pain, and diarrhea.¹

The most common laboratory abnormalities that occurred in at least 40% of patients with newly diagnosed Ph-positive CP-CML consisted of decreased lymphocyte count, decreased leukocyte count, decreased platelet count, decreased neutrophil count, and decreased calcium.

Asciminib is recommended at a dose of 80 mg once per day or 40 mg twice per day in approximate 12-hour intervals.

“Many patients who are newly diagnosed with CML struggle to navigate this chronic condition and may switch or even stop treatment because of side effects that interrupt their daily lives,” Lee Greenberger, PhD, chief scientific officer at The Leukemia & Lymphoma Society, stated in a news release.³ “That’s why approvals of new first-line treatment options are so important. For patients, finding a medicine that’s right for them at the very beginning of treatment may lead to better long-term disease control with fewer side effects.”

References

1. FDA grants accelerated approval to asciminib for newly diagnosed chronic myeloid leukemia. FDA. October 29, 2024. Accessed October 29, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-asciminib-newly-diagnosed-chronic-myeloid-leukemia
2. Hughes TP, Hochhaus A, Takahashi N, et al. ASC4FIRST, a pivotal phase 3 study of asciminib (ASC) vs investigator-selected tyrosine kinase inhibitors (IS TKIs) in newly diagnosed patients (pts) with chronic myeloid leukemia (CML): primary results. J Clin Oncol. 2024;42(suppl 17):LBA6500. doi:10.1200/JCO.2024.42.17_suppl.LBA6500
3. Novartis Scemblix FDA approved in newly diagnosed CML, offering superior efficacy, and favorable safety and tolerability profile. News release. Novartis. October 29, 2024. Accessed October 29, 2024. https://www.novartis.com/us-en/news/media-releases/novartis-scemblix-fda-approved-newly-diagnosed-cml-offering-superior-efficacy-and-favorable-safety-and-tolerability-profile