Results Show Promising Efficacy in MCL With Next-Generation BTK Inhibitor LOXO-305

Investigators on the BRUIN trial reported impressive response rates across multiple B-cell malignancies with the use of the Bruton tyrosine kinase inhibitor LOXO-305, especially in those with heavily pretreated mantle cell lymphoma.

Results of a phase 1/2 trial that were presented at the 2020 American Society of Hematology Annual Meeting and Exposition showed that patients with mantle cell lymphoma (MCL) and other B-cell malignancies had promising response rates when treated with LOXO-305.

A highly selective Bruton tyrosine kinase (BTK) inhibitor that targets both wild-type and C481-mutant BTK, LOXO-305 could be a viable treatment option for patients with difficult-to-treat hematologic malignancies, such as MCL and Waldenström macroglobulinemia (WM).

“LOXO-305 demonstrates promising efficacy in [patients with MCL and other non-Hodgkin lymphomas (NHLs)] previously treated with all classes of available therapy,” Michael Wang, MD, professor in the Department of Lymphoma & Myeloma at The University of Texas MD Anderson Cancer Center, said during a presentation of the data. “Responses were observed across all dose levels and efficacy was independent of prior therapy.”

The agent’s use in patients with various B-cell malignancies, including those with chronic lymphocytic leukemia/small lymphocytic lymphoma, was examined in the dose-escalation, dose-expansion BRUIN trial (NCT03740529). Patients had to have received at least 2 prior regimens, given as a combination or sequentially, or 1 prior BTK inhibitor–containing regimen. LOXO-305 was administered orally in cycles of 28 days according to a 3 + 3 design, with a starting dose of 25 mg daily.

The primary end points of the trial were determining the maximum tolerated dose in the phase 1 portion and preliminary antitumor activity and safety in phase 2. In total, 323 patients were enrolled as of the September 2020 cutoff, 61 of whom had MCL, 26 with WM, and 66 with other NHLs.

The median number of prior therapies for patients with MCL and WM was 3, of whom 93% and 69%, respectively, previously received a BTK inhibitor. Those with other NHLs received an average of 4 prior therapies. Interestingly, progressive disease following chimeric antigen receptor (CAR) T-cell therapy was seen in 5% of patients with MCL and 14% of those with other NHLs.

Overall response rates (ORR) varied by disease cohort. Of note, those with MCL who were evaluable for response (n = 56) had an ORR of 52%, and this remained true when the cohort of patients was reduced to just those who had prior BTK inhibitor therapy (n = 52). Complete responses accounted for 25% of both groups, as well. In those with prior stem cell transplant (n = 14) or prior CAR T-cell therapy (n = 2), ORRs were 64% and 100%, respectively. At a median follow-up of 6 months, most of those with MCL who responded to therapy (83%; 24 of 29 patients) had an ongoing response.

In response-evaluable patients with WM (n = 19), the ORR was 68% and was consistent when only those with prior BTK inhibitor therapy were examined (n = 13; 69%). Responses in both groups were comprised exclusively of partial responses and 77% of patients overall had an ongoing response at data cutoff. ORRs in other NHL subtypes included 75% for Richter transformation (RT), 50% for follicular lymphoma, 24% for diffuse large B-cell lymphoma, and 22% for marginal zone lymphoma. A large majority of patients with RT (83%) had an ongoing response at the median follow-up of 6 months.

Of note, there were no dose-limiting toxicities noted in the study and the maximum-tolerated dose was not reached. Only 5 patients (1.5%) discontinued treatment due to treatment-related adverse events and 200 mg was selected as the recommended phase 2 dose.

“Longer follow-up is needed to better understand the LOXO-305 safety profile associated with chronic administration,” Wang said.


1. 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. Blood. 2020;136(suppl 1):8-10. Abstract 117. doi:10.1182/blood-2020-134314

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