FDA Grants Breakthrough Therapy Designations for Investigational STAMP inhibitor in CML
The BTD designations for asciminib were based on the phase 3, multicenter, open-label, randomized ASCEMBL trial and a phase I trial that included patients with Ph+ CML, some of them harboring the T315I mutation.
Officials with the FDA have granted Breakthrough Therapy designation (BTD) to a novel investigational treatment for treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) in chronic phase (CP), previously treated with 2 or more tyrosine kinase inhibitors (TKIs). The drug, Novartis’ asciminib (ABL001), specifically targets the ABL myristoyl pocket (STAMP).1
Asciminib was also granted BTD for the treatment of adult patients with Ph+ CML in CP harboring the T315I mutation.1
According to Novartis, some patients with Ph+ CML in CP, previously treated with 2 or more TKIs struggle to meet treatment goals due to resistance and intolerance, and patients in later lines of care may be at risk of progression.1
The BTD designations for asciminib were based on the phase 3, multicenter, open-label, randomized ASCEMBL trial, in which asciminib was compared to bosutinib (Bosulif; Pfizer) in patients with Ph+ CML in CP previously treated with 2 or more TKIs; and a phase I trial that included patients with Ph+ CML, some of them harboring the T315I mutation.1
Data from these trials were shared at the 2020 Annual Meeting of the American Society of Hematology (ASH).1,2
Results from the ASCEMBL study demonstrate that, at 24 weeks, asciminib nearly doubled the major molecular response (MMR) rate compared to bosutinib (25.5% vs. 13.2%, respectively ([95% CI, 2.19-22.3]; 2-sided P=0.029) in patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) previously treated with 2 or more tyrosine-kinase inhibitors (TKIs).2
In the ASCEMBL trial, 233 patients were randomized to receive asciminib 40 mg twice daily (n=157) or bosutinib 500 mg once a day (n=76). Data showed that, at 24 weeks, more patients achieved a CCyR in the asciminib arm (40.8%) than in the bosutinib arm (24.2%); and deep molecular response (DMR) rates were higher for patients in the asciminib arm than in the bosutinib arm—with 10.8% and 8.9% patients achieving MR and MR on asciminib, respectively, vs. 5.3% and 1.3% on bosutinib.2
Grade ≥3 adverse events (AEs) occurred in 50.6% and 60.5% of patients treated with asciminib and bosutinib, respectively. Treatment discontinuation due to AEs in the asciminib arm was 5.8% compared to 21.1% for patients taking bosutinib. Similarly, AEs requiring dose interruption and/or dose adjustments were reported less frequently with asciminib than with bosutinib (37.8% vs. 60.5%, respectively). At data cutoff, more patients were still on treatment in the asciminib arm vs. the bosutinib arm (61.8% vs. 30.3%, respectively).2
The most common grade ≥3 AEs occurring in 10% or less of patients treated with asciminib were thrombocytopenia (17.3%) and neutropenia (14.7%), while for bosutinib they were increased alanine aminotransferase (ALT) (14.5%), neutropenia (11.8%) and diarrhea (10.5%). On-treatment deaths on the asciminib arm occurred in 2 (1.3%) patients (ischemic stroke and arterial embolism); there was one (1.3%) death on bosutinib (septic shock). The most frequent AEs (all grades; ≥20%) were thrombocytopenia (28.8%) and neutropenia (21.8%) in the asciminib arm, compared to diarrhea (71.1%), nausea (46.1%), increased ALT (27.6%), vomiting (26.3%), rash (23.7%), increased aspartate aminotransferase (21.1%), neutropenia (21.1%) and thrombocytopenia (18.4%) in the bosutinib arm.2
The FDA previously granted Fast Track designation to asciminib,1,2 and Novartis plans for a submission in the first half of 2021 for review under the FDA Oncology Center of Excellence Real-Time Oncology Review program.1
REFERENCES
- Novartis receives FDA Breakthrough Therapy designations for investigational STAMP inhibitor asciminib (ABL001) in chronic myeloid leukemia [news release]. Basel, Switzerland; February 8, 2021: Novartis. Accessed February 9, 2021. https://www.novartis.com/news/media-releases/novartis-receives-fda-breakthrough-therapy-designations-investigational-stamp-inhibitor-asciminib-abl001-chronic-myeloid-leukemia
- Novartis investigational STAMP inhibitor asciminib (ABL001) shows superior MMR rate to Bosulif®* in chronic myeloid leukemia trial [news release]. Basel, Switzerland; December 8, 2020: Novartis. Accessed February 9, 2021. https://www.novartis.com/news/media-releases/novartis-investigational-stamp-inhibitor-asciminib-abl001-shows-superior-mmr-rate-bosulif-chronic-myeloid-leukemia-trial
