The open-label, randomized BRUIN trial will compare LOXO-305 to investigators choice of either ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa). Approximately 500 patients will be enrolled in the study.

"MCL patients who have been treated with a covalent BTK inhibitor have very few therapeutic options, and outcomes are extremely poor. LOXO-305 has demonstrated a promising efficacy profile in these patients, a setting where we urgently need new therapies," said Michael Wang, MD, Puddin Clarke Endowed professor of Lymphoma and Myeloma at The University of Texas MD Anderson Cancer Center, in a press release.

The primary end point of BRUIN is progression-free survival (PFS), and the secondary end points include event-free survival, time to treatment failure, time to worsening of MCL-related symptoms, comparative tolerability, overall response rate (ORR), duration of response, and overall survival.

A confirmed diagnosis of MCL is required for inclusion in the study as well as being previously treated with at least 1 prior line of systemic therapy for MCL, having measurable disease per Lugano criteria, having an ECOG performance status of 0 to 2, and having adequate laboratory values at baseline.

In the case of prior treatment with an FDA-approved or investigational BTK inhibitor, patients are ineligible to enroll in the study. According to the criteria, patients are also excluded if they have a history of bleeding diathesis, stroke, or intracranial hemorrhage within 6 months of randomization, and prior allogeneic stem cell transplant (ASCT) or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. In addition, patients with significant cardiovascular disease, and other comorbidities that may interfere with study treatment are not eligible to enroll.

Treatment with LOXO-305 has already shown promise for the treatment of 323 patients with previously treated B-cell malignancies. In the phase 1/2 BRUIN study, the use of the agent was investigated in patients with MCL, chronic lymphocytic leukemia/small lymphocytic leukemia, Waldenstroms macroglobulinemia (WM), and other B-cell malignancies. The patients were pretreated with a BTK inhibitor (95%), anti-CD20 antibody (98%), chemotherapy (92%), lenalidomide (Revlimid; 20%), autologous transplant (25%), CAR T-cell therapy (5%), and ASCT.3

According to data presented during the 2020 American Society of Hematology Annual Meeting, the ORR observed with LOXO-305 in 59 efficacy-evaluable patients from the MCL cohort was 52% (95% CI, 38%-65%), which included 14 complete and 15 partial responses. The median time to the first response in these patients was 1.8 months.

In the WM cohort of 19 efficacy-evaluable patients, the ORR observed was 68% (95% CI, 44%-87)%, which notably was similar in patients who were previously treated with a BTK inhibitor (69%; 95% CI, 39%-91%). Further, 4 out of 8 patients with follicular lymphoma had a response to LOXO-305, in addition to 75% of the evaluable Richter's transformation cohort, and 8 out of 35 patients with other B-cell malignancies, including diffuse large B-cell lymphoma and marginal zone lymphoma.

The most commonly reported adverse events (AEs) with LOXO-305 in the phase 1/2 BRUIN study were fatigue (20%), diarrhea (17%), and contusion (13%). Eight percent of patients had dose interruptions due to AEs, while 2.2% had dose reduction, and 1.5% permanently discontinued treatment with LOXO-305.

LOXO-305 was designed to overcome some of the limitations seen with current BTK therapies and we believe the promising efficacy and tolerability data demonstrate its potential to be an important new treatment option for MCL patients, said David Hyman, MD, chief medical officer of Loxo Oncology at Lilly, in a press release.

References:

1. Mato AR, Pagel JM, Coombs CC, et al. 542LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 bruin study. . Presented at: 2020 ASH Annual Meeting and Exposition. December 4-8, 2020; Virtual. Abstract 542.

2. Study of BTK inhibitor LOXO-305 versus approved BTK inhibitor drugs in patients withmantle cell lymphoma(MCL) (BRUIN-MCL-321). Clnicaltrials.gov. Accessed August 17, 2021. https://bit.ly/3CXTgu4

3. Loxo Oncology at Lilly announces updated data from the phase 1/2 BRUIN Clinical Trial for LOXO-305 in mantle cell lymphoma and non-Hodgkin lymphomas at the American Society of Hematology (ASH) Annual Meeting. News release. Loxo Oncology at Lilly. December 5, 2020. accessed August 17, 2021. https://prn.to/37QNw7a

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