FDA Grants Breakthrough Therapy Designations for Investigational STAMP inhibitor in CML

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