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ASH 2020: Early-Phase Study of Noncovalent BTK Inhibitor in CLL

By: Julia Fiederlein
Posted: Thursday, December 10, 2020

Treatment with LOXO-305 appears to be safe and demonstrates antitumor activity in patients with heavily pretreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to Anthony R. Mato, MD, of Memorial Sloan Kettering Cancer Center, New York, and colleagues. The multicenter phase I/II BRUIN trial results were presented during the virtual edition of the 2020 American Society of Hematology (ASH) Annual Meeting and Exposition (Abstract 542).

“Despite the marked efficacy of covalent Bruton’s tyrosine kinase (BTK) inhibitors, treatment failure can occur,” the investigators commented. “To address these limitations, LOXO-305, a highly selective, noncovalent BTK inhibitor that inhibits both wild-type and cysteine 481 (C481)-mutated BTK, was developed.”

The study enrolled a total of 186 patients with B-cell malignancies treated with at least two therapy lines. Of this population, 94 patients had CLL or SLL. Using a 3+3 dose-escalation scheme, LOXO-305 was administered orally in doses ranging from 25 to 300 mg daily. Fatigue and diarrhea were the most frequently reported treatment-emergent adverse events in the overall population. Clinical responses were observed at the first dose level of 25 mg daily. A recommended phase II dose of 200 mg daily was established.

The objective response rate was 57% in the patients with CLL or SLL who were eligible for the efficacy analysis, with 23 partial responses, 14 partial responses with lymphocytosis, 26 cases of stable diseases, 1 progressive disease, and 1 unevaluable response. Among those with at least 6 months of follow-up, the objective response rate was 77%. According to the investigators, the response rate did not seem to be impacted by the BTK C481 mutation status at baseline, reason for BTK inhibitor discontinuation, or other classes of prior therapies received.

Disclosure: For full disclosures of the study authors, visit ash.confex.com.



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