FDA Approves SCEMBLIX® for Chronic Myeloid Leukemia

SUMMARY: The FDA on October 29, 2021, granted accelerated approval to SCEMBLIX® (Asciminib), for patients with Philadelphia chromosome-positive Chronic Myeloid Leukemia (Ph-positive CML) in Chronic Phase, previously treated with two or more Tyrosine Kinase Inhibitors (TKIs), and approved SCEMBLIX® for adult patients with Ph-positive CML in Chronic Phase with the T315I mutation.

The American Cancer Society estimates that about 9,110 new CML cases will be diagnosed in the United States in 2021 and about 1,220 patients will die of the disease. Chronic Myeloid Leukemia (CML) constitutes about 15% of all new cases of leukemia and the average age at diagnosis of CML is around 64 years. The hallmark of CML, the Philadelphia Chromosome (Chromosome 22), is a result of a reciprocal translocation between chromosomes 9 and 22, wherein the ABL gene from chromosome 9 fuses with the BCR gene on chromosome 22. As a result, the auto inhibitory function of the ABL gene is lost and the BCR-ABL fusion gene is activated resulting in cell proliferation and leukemic transformation of hematopoietic stem cells.

The presently available Tyrosine Kinase Inhibitors (TKI’s) approved in the United States share the same therapeutic target, which is the ATP-binding site of BCR-ABL1 kinase. Close to 50% of clinical resistance is associated with the acquisition of mutations in this region of the kinase, resulting in conformational changes that render TKIs inactive. Therefore resistance to one of the TKIs, will likely result in resistance to the others as well. Further, the “gatekeeper” T315I mutation, which has been reported in 20% of patients with mutations, confers resistance to all clinically available TKIs except ICLUSIG® (Ponatinib).

SCEMBLIX® is a novel, first-in-class, potent and specific, oral BCR-ABL1 inhibitor that does not bind to the ATP-binding site of the kinase. Instead, it specifically targets the ABL1 myristoyl pocket, also known as a STAMP (Specifically Targeting the ABL Myristoyl Pocket) inhibitor, with activity against native unmutated BCR-ABL1, and all clinically observed ATP-site mutants, including T315I. In a Phase I study, SCEMBLIX® was active in heavily pretreated patients with CML who had resistance to or unacceptable side effects from TKIs, including patients in whom ICLUSIG® had failed, and those with a T315I mutation.

The present FDA approval was based on data from the Phase III ASCEMBL trial which evaluated this agent in patients with Ph-positive CML who previously received 2 or more TKIs, and the Phase I CABL001X2101 trial, which evaluated its use in patients with Ph-positive CML in Chronic Phase harboring a T315I mutation.

ASCEMBL is a multicenter, randomized, active-controlled, open-label, Phase III trial, which evaluated SCEMBLIX® in patients with Ph-positive CML in Chronic Phase, previously treated with two or more TKIs. In this study, a total of 233 patients were randomized (2:1) to receive either SCEMBLIX® 40 mg twice daily (N=157) or BOSULIF® (Bosutinib) 500 mg once daily (N=76). Patients were stratified by Major Cytogenetic Response (MCyR; Ph-positive metaphases 35% or less at baseline). Patients intolerant of their most recent TKI were eligible if they had BCR-ABL1 International Scale more than 0.1% at screening. Treatment was continued until unacceptable toxicity or treatment failure occurred. The median patient age was 52 years and 48% of patients had received 2 prior lines of treatment, 31% received 3 prior lines of therapy. The Primary endpoint was Major Molecular Response (MMR) rate at 24 wks.

In this study, the MMR rate was 25.5% in patients treated with SCEMBLIX® compared with 13.2% in those receiving BOSULIF®, meeting the primary objective of this study (P=0.029). At a median follow up of 20 months, the median duration of MMR has not yet been reached. Among those pts who achieved MMR, the median time to MMR was 12.7 weeks among those who achieved MMR with SCEMBLIX®, and 14.3 weeks with BOSULIF®. At 24 wks, more patients on SCEMBLIX® (19.7%)] achieved Deep Molecular Response (MR4 and MR4.5), compared with 6.6% with BOSULIF®. The Complete Cytogenetic Response rate at 24 weeks was 40.8% with SCEMBLIX® compared with 24.2% for BOSULIF®. Additionally, preplanned subgroup analysis showed that the MMR rate at 24 weeks was superior with SCEMBLIX® compared to BOSULIF® across most major demographic and prognostic subgroups, including among patients who received 3 or more prior TKIs, in those who discontinued the prior TKI due to treatment failure, and regardless of baseline Cytogenetic Response.

CABL001X2101 is a multicenter, open-label clinical trial, in which the efficacy of SCEMBLIX® was evaluated in patients with Ph-positive CML in Chronic Phase, with the T315I mutation. In this study, 45 patients with the T315I mutation received SCEMBLIX® 200 mg twice daily and treatment was continued until unacceptable toxicity or treatment failure. The main efficacy outcome measure was MMR.

MMR was achieved by 24 weeks in 42% of the patients, and 49% of the patients achieved MMR by 96 weeks. The median duration of treatment was 108 weeks.

The most common adverse reactions included upper respiratory tract infections, musculoskeletal pain, fatigue, nausea, rash, diarrhea, and cytopenias. Patients also were noted to have increased triglycerides, increased creatine kinase, alanine aminotransferase, lipase, and amylase.

It can be concluded from these two studies that SCEMBLIX®, a first-in-class STAMP inhibitor, demonstrated statistically significant and clinically meaningful superiority in efficacy, compared with BOSULIF®, among patients with Chronic Phase CML previously treated with two or more TKIs. SCEMBLIX® is also a new treatment option for patients with Ph-positive CML in Chronic Phase, harboring a T315I mutation.

A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After ≥2 Prior TKIs. Rea D, Mauro MJ, Boquimpani C, et al. Blood. 2021 Aug 18;blood.2020009984. doi: 10.1182/blood.2020009984. Online ahead of print.