LOXO-305 in Previously Treated CLL/SLL: Safety and Early Efficacy Data from the BRUIN Trial

Although covalent Bruton’s tyrosine kinase (BTK) inhibitors have been transformative in the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), they can present some limitations. Treatment failure can occur due to resistance and toxicity. LOXO-305 is a novel, highly selective, noncovalent BTK inhibitor developed to address these limitations. Researchers reported safety and early efficacy data of LOXO-305 in patients with previously treated CLL/SLL participating in the BRUIN trial.

The BRUIN multicenter phase 1/2 trial is enrolling patients with advanced B-cell malignancies who have received at least 2 prior therapies.¹ Patients receive LOXO-305 monotherapy dose escalation in 28-day cycles. Response is assessed every 8 weeks from cycle 3 and every 12 weeks from cycle 13.

As of September 27, 2020, 323 patients with B-cell malignancies received LOXO-305. Of the enrolled patients, 170 had CLL/SLL, with a median age of 69 years. Patients had received a median of 3 prior therapies. Of enrolled patients with CLL/SLL, 85% had received prior BTK inhibitor treatment and 90% had received treatment with an anti-CD20 antibody, chemotherapy, and a BTK inhibitor. In addition, 21% had received a phosphoinositide 3-kinase (PI3K) inhibitor and 34% had received venetoclax. Molecular characterization for high-risk features included 17p deletion in 25% of patients with CLL/SLL, TP53 mutation in 30%, and unmutated IGHV in 88%.

Of the 170 patients with CLL/SLL enrolled in the study, 139 patients were evaluable for efficacy. Median follow-up time was 6 months. The overall response rate was 63%. Responses deepened over time; among the 79 patients with at least 6 months of follow-up, the overall response rate was 68% and among 29 patients with at least 10 months of follow-up, the response rate was 86%. Response rate was not influenced by BTK C481 mutation status, reason for prior BTK inhibitor discontinuation, or other classes of prior therapy received. Of the 88 responding patients, 83 remain on therapy, with 4 ending therapy due to disease progression and 1 electively discontinuing treatment to undergo an allogeneic stem-cell transplant.

Overall, LOXO-305 was well-tolerated. Dose-limiting toxicity and dose reductions did not occur. The only treatment-emergent adverse events seen in at least 10% of patients were fatigue (12%), diarrhea (14%), and contusion (12%).

The researchers conclude that in patients with heavily pretreated CLL/SLL and poor prognosis, treatment with LOXO-305 demonstrated promising efficacy. The activity of LOXO-305 was observed in patients both with and without BTK C481 mutation. LOXO-305 was well-tolerated and demonstrated a wide therapeutic index.

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Reference

1. Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, A Next Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results from the Phase 1/2 BRUIN Study. American Society of Hematology 62nd Annual Meeting and Exposition. Abstract 542.