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BTK Inhibitor LOXO-305 Shows Promise in Previously Treated Mantle Cell Lymphoma

December 30, 2021

January 2021

In the phase I/II BRUIN trial that included patients with previously treated B-cell malignancies – particularly mantle cell lymphoma (MCL) – treatment with the highly selective non-covalent Bruton tyrosine kinase (BTK) inhibitor LOXO-305 was associated with relatively high response rates. The investigators, led by Michael Wang, MD, of the University of Texas MD Anderson Cancer Center in Houston, added that there were no dose-limiting toxicities or dose reductions during study follow-up.

Overall survival (OS) in MCL after failure of covalent BTK inhibitor therapy is poor, Dr. Wang and researchers noted, and these findings, although preliminary, indicate that LOXO-305 could be a potentially effective treatment option for difficult-to-treat MCL, as well as Waldenström macroglobulinemia (WM), and other non-Hodgkin lymphomas (NHLs). Results from the study were presented during the 2020 ASH Annual Meeting.

A total of 323 patients with advanced B-cell malignancies were enrolled in the phase I/II trial as of September 2020. Dr. Wang reported outcomes from the following disease cohorts:

  • MCL (n=61)
  • WM (n=26)
  • other NHLs, including diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, B-cell prolymphocytic leukemia, and Richter's transformation (n=66)

Patients in this analysis were often heavily pretreated, with a median prior number of therapies of three (range = 1-8), three (range = 2-11), and four (2-10) in the MCL, WM, and other NHLs cohorts, respectively. Approximately 93% of patients with MCL received a prior BTK inhibitor, and more than two-thirds of patients with WM (69%) had received a prior BTK inhibitor. In addition, 5% of patients in the MCL cohort and 14% of those in the other NHLs cohort had progressive disease after undergoing chimeric antigen receptor T-cell therapy.

LOXO-305 was administered orally in 28-day cycles, with dose escalation according to a standard 3+3 design. Responses were evaluated every eight weeks from cycle three, then every 12 weeks starting with cycle 13.

There were no dose-limiting toxicities or dose reductions. "Grade 3/4 adverse events were very rare, and there were no toxicity-related deaths among the [study population] of 323 patients," Dr. Wang reported. The most common treatment-related adverse events (AEs) included bruising (12%), diarrhea (9%), contusion (9%), and fatigue (8%). Only five patients (1.5%) discontinued due to treatment-related AEs, which the investigators attributed to LOXO-305's selectivity.

Among the efficacy-evaluable patients, researchers observed responses at the first dose level of 25 mg once daily, and 200 mg once daily was selected as the recommended phase II dose. The overall response rates (ORRs) varied among the different disease cohorts, from 22% among patients with marginal zone lymphoma in the "other NHLs" group, to 68% in those with WM.

Dr. Wang focused his presentation on those with MCL, where the ORR was 52%. The ORR remained at 52% when researchers looked at the 52 patients with MCL who had received prior BTK inhibitor therapy. Responses in this subgroup included:

  • complete response: 13 (25%)
  • partial response: 14 (27%)
  • stable disease: 9 (17%)

He added that, at a median follow-up of six months, 24 of the 29 patients with MCL that responded to LOXO-305 have an ongoing response.

"LOXO-305 demonstrates promising efficacy in [patients with MCL and other NHLs] previously treated with all classes of available therapy … and across all dose levels," Dr. Wang concluded. However, he said, "longer follow-up is needed to understand the drug's safety profile associated with chronic administration."

Study authors report relationships with Loxo Oncology, which sponsored the trial.


Wang M, Shah NN, Alencar AJ, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated mantle cell lymphoma, Waldenström’s macroglobulinemia, and other non-Hodgkin lymphomas: Results from the phase 1/2 BRUIN study. Abstract 117. Presented at the 2020 ASH Annual Meeting, December 5, 2020.


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