Asciminib Moves Toward EU Approval for Ph+ CML in Chronic Phase

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended granting marketing authorization for asciminib (Scemblix) for the treatment of adult patients with Philadelphia chromosome–positive chronic myeloid leukemia in chronic phase (Ph-positive CML-CP) who were previously treated with at least 2 TKIs.¹

The positive opinion is based on findings from the pivotal phase 3 ASCEMBL trial (NCT03106779), which showed an approximate doubling of the 24-week major molecular response (MMR) rate in patients who received asciminib vs bosutinib (Bosulif; 25.5% vs 13.2%, respectively), with a more than three times lower discontinuation rate due to adverse effects (AEs; 5.8% vs 21.1%).

“Although CML treatments have advanced over the last 20 years, many patients continue to experience side effects and resistance to treatment, affecting their quality of life and putting them at risk of disease progression or even death,” Andreas Hochhaus, MD, head of the Department of Hematology and Medical Oncology at Jena University Hospital in Germany, stated in a press release. “If approved, the novel mechanism of action of [asciminib] brings us another option to combat these challenges faced by patients — offering new hope in the management of their disease.”

On October 29, 2021, the BCR-ABL1 inhibitor, which is also known as a STAMP inhibitor (specifically targets the ABL myristoyl pocket), received an accelerated approval from the FDA for the treatment of patients with Ph-positive CML-CP previously treated with at least 2 or more TKIs, and a full approval for adult patients with Ph-positive CML-CP with a T315I mutation.²

In the ASCEMBL trial, 233 patients were randomized 2:1 to receive 40 mg of asciminib twice daily (n = 157) or 500 mg of bosutinib (Bosulif) once daily (n = 76). Patients were stratified based on major cytogenetic response status, and treatment was continued until intolerable toxicity or treatment failure.

The median patient age was 52 years (range, 19-83); 19% of patients were at least 65 years of age, and 2.6% of patients were at least 75 years of age. More than half of patients were female (52%), 75% were White, and 81% had an ECOG performance status of 0. Approximately half of patients (48%) received 2 prior lines of treatment, 31% received 3 prior lines, 15% received 4 prior lines, and 6% received at least 5 prior lines.

The results from the primary analysis were confirmed in longer-term follow-up, where the 96-week MMR rate, a secondary end point of the trial, more than doubled with asciminib at 37.6% (95% CI, 29.99%-45.65%) vs bosutinib at 15.8% (95% CI, 8.43%-25.96%).^1,3

Moreover, deeper molecular response rates measured by reductions in BCR-ABL1 transcript levels were associated with asciminib. The 96-week MR⁴ rate (BCR-ABL1^IS ≤ 0.01%) was 17.2% with asciminib vs 10.5% with bosutinib. The MR^4.5 rate (BCR-ABL1IS ≤ 0.0032%) was 10.8% and 5.3%, respectively.

In this analysis, the median duration of follow-up was 2.3 years from randomization to last contact date.

Notably, asciminib demonstrated benefit across all demographic and prognostic subgroup analyses including lack of efficacy with last TKI (risk difference, 23.1 [95% CI, 11.5-34.7]), intolerance to last TKI (risk difference, 14.5 [95% CI, –9.3 to 38.3]), and at least 5 lines of prior therapy (risk difference, 29.0 [95% CI, 13.1-45.0]).

Regarding BCR-ABL1 mutation status, the risk difference for patients without a detectable mutation was 21.7 (95% CI, 9.3-34.1) and 16.2 (95% CI, –21.9 to 54.2) for those with the mutation. The risk reduction for patients with a baseline BCR-ABL1^IS transcript level of at least 1% was 20.6 (95% CI, 9.4-31.8) and 16.7 (95% CI, –37.8 to 71.2) for those who had transcript levels less than 1%.

The median duration of exposure was 23.7 months for asciminib vs 7 months for bosutinib. At the time of data cutoff, treatment was ongoing in 84 (53.5%) and 15 (19.7%) patients, respectively.

Regarding safety, the rate of discontinuation due to AEs remained low with asciminib.

Treatment-discontinuation rates due to AEs in the 96-week analysis were 7.0% with asciminib vs 25% with bosutinib. The primary reason for treatment discontinuation was lack of efficacy (24.2% vs 35.5%, respectively).

The most common grade 3 or higher AEs with asciminib vs bosutinib were thrombocytopenia (22.4% vs 9.2%), neutropenia (19.9% vs 15.8%), diarrhea (0% vs 10.5%), and increased alanine aminotransferase (0.6% vs 14.5%).

Notably, there was no increased risk of arterial occlusive events over time with asciminib. Most nonhematologic AEs occurred in the first 6 months of treatment and rarely continued beyond the time of onset.

“We are pleased with the recommendation of Scemblix and hope to offer patients living with CML in Europe timely access to this innovative therapy, if approved,” Haseeb Ahmad, president of Europe at Novartis, stated in a press release. “We’ve worked relentlessly to improve CML care over the past two decades, and [we] must seize this opportunity to help patients in need achieve better outcomes. With the strong clinical results seen to-date, we believe we have the potential to transform the standard of care in CML yet again with [asciminib].”

References

1. Novartis receives positive CHMP opinion for Scemblix®, a novel treatment for adult patients with chronic myeloid leukemia. News release. Novartis. June 24, 2022. Accessed June 24, 2022. https://bit.ly/3OGFscq
2. FDA approves asciminib for Philadelphia chromosome-positive chronic myeloid leukemia. FDA. October 29, 2021. Accessed June 7, 2022. bit.ly/3Q6Jexu
3. Rea D, Mauro MJ, Hochhaus A, et al. Efficacy and safety results from ASCEMBL, a phase 3 study of asciminib versus bosutinib (BOS) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) after ≥2 prior tyrosine kinase inhibitors (TKIs): week 96 update. J Clin Oncol. 2022;40(suppl 16):7004. doi:10.1200/JCO.2022.40.16_suppl.7004