FDA Grants Breakthrough Therapy Designation to Asciminib for 2 CML Indications

The FDA has granted breakthrough therapy designation (BTD) to the novel investigational first-in-class STAMP inhibitor asciminib (ABL001) for the treatment of adult patients with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase who have been previously treated with 2 or more tyrosine kinase inhibitors (TKIs), according to the agent’s developer, Novartis.¹

In addition, asciminib was also granted BTD for the treatment of adult patients with chronic phase Ph+ CML harboring the T315I mutation.

These FDA designations were based on the results observed in 2 trials, including the pivotal phase 3 ASCEMBL trial (NCT03106779) and a phase 1 trial which included patients with Ph+ CML, some of whom harbored the T315I mutation. Data from these trials were shared at the 2020 Annual Meeting of the American Society of Hematology (ASH) Annual Meeting and Exposition.^2,3

In the ASCEMBL trial, 233 adults with CML in chronic phase who were previously treated with at least 2 TKIs were randomized to receive either asciminib twice daily (n = 157) or bosutinib (Bosulif) once daily (n = 76). At 24 weeks, more patients achieved a complete cytogenetic response in the asciminib arm (40.8%) than in the bosutinib arm (24.2%). Moreover, rates of molecular response and deep molecular response were also revealed to be higher for those in the asciminib arm, at 10.8% and 8.9%, respectively, versus 5.3% and 1.3% of patients in the bosutinib arm.

Grade 3 or higher adverse events (AEs) occurred in 50.6% of patients treated with asciminib and 60.5% of those treated with bosutinib. The most frequent AEs (all grades; ≥20%) were thrombocytopenia (28.8%) and neutropenia (21.8%) in the asciminib arm, compared with diarrhea (71.1%), nausea (46.1%), increased alanine aminotransferase (ALT; 27.6%), vomiting (26.3%), rash (23.7%), increased aspartate aminotransferase (AST; 21.1%), neutropenia (21.1%), and thrombocytopenia (18.4%) in the bosutinib arm.

“These important comparative data are impressive, and they reinforce the critical role asciminib may play, if approved, in overcoming the treatment challenges we face in later treatment lines of chronic-phase CML,” lead study author Michael J. Mauro, MD, leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center and professor at Weill Cornell Medicine, said in a press release.⁴ “While the advent and expansion of TKI therapies has resulted in tremendous progress for patients living with CML over the last decades, many of our patients in later treatment lines still face inadequate response, disease progression and intolerable side effects.”

In the phase 1 study of asciminib, adults with CML in chronic or accelerated phase who were resistant or intolerant to at least 2 TKIs were enrolled. Notably, patients with the T315I mutation were also eligible after receiving at least 1 TKI if no other effective therapy was available.

A total of 52 patients with T315I received asciminib, 35 (67.3%) of whom had ongoing treatment at the data cutoff; 17 patients (32.7%) discontinued treatment. Of those who were still on treatment, 31 (88.6%) had received treatment for over 48 weeks.

Among evaluable patients not in major molecular response (MMR) at baseline, 23 of 49 (46.9%) achieved MMR and 21 of these responders were still in MMR at the time of data cutoff; 40.8%, 42.9%, 44.9%, and 46.9% had MMR by 24, 48, 72, and 96 weeks, respectively.

Treatment-related AEs were reported in 45 of the total 52 patients (86.5%) and were mainly mild in severity; grade 3 or greater AEs were reported in 17 patients (32.7%). Further, all-grade serious AEs were reported in 12 patients (23.1%), with 2 (3.8%) deemed treatment related. The most frequent any-grade AEs of clinical interest (occurring in ≥10% of patients) were gastrointestinal toxicity (48.1%), hypersensitivity (26.9%), myelosuppression (25.0%), pancreatic toxicity (25.0%), hepatotoxicity (23.1%), thrombocytopenia (21.2%), hemorrhage (17.3%), leukopenia (15.4%), and edema and fluid retention (13.5%).

Notably, asciminib was previously granted fast track designation by the FDA, and Novartis indicated it plans for a submission to the FDA in the first half of 2021 for review under the FDA Oncology Center of Excellence Real-Time Oncology Review program.

References:

1. Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia. News release. Novartis. Published February 8, 2021. Accessed February 8, 2021. https://www.novartis.com/news/media-releases/novartis-receives-fda-breakthrough-therapy-designations-investigational-stamp-inhibitor-asciminib-abl001-chronic-myeloid-leukemia

2. Hochhaus A, Boquimpani C, Rea D, et al. Efficacy and safety results from ASCEMBL, a multicenter, open-label, phase 3 study of asciminib, a first-in-class STAMP inhibitor, vs bosutinib (BOS) in patients (Pts) with chronic myeloid leukemia in chronic phase (CML-CP) previously treated with ≥2 tyrosine kinase inhibitors (TKIs). Presented at the 62nd ASH Annual Meeting and Exposition, held December 5-8, 2020. Abstract LBA4.

3. Cortes JE, Hughes TP, Mauro MJ, et al. Asciminib, a first-in-class STAMP inhibitor, provides durable molecular response in patients (pts) with chronic myeloid leukemia (CML) harboring the T315I mutation: primary efficacy and safety results from a phase 1 trial. Presented at the 62nd ASH Annual Meeting and Exposition, held December 5-8, 2020. Abstract 650.

4. Novartis investigational STAMP inhibitor asciminib (ABL001) shows superior MMR rate to Bosulif in chronic myeloid leukemia trial. News release. Novartis. Published December 8, 2020. Accessed February 8, 2021. https://www.novartis.com/news/media-releases/novartis-investigational-stamp-inhibitor-asciminib-abl001-shows-superior-mmr-rate-bosulif-chronic-myeloid-leukemia-trial