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
"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
"We are very excited to share this update on LOXO-305 in MCL with the hematology community and look forward to sharing data on chronic lymphocytic leukemia and small lymphocytic lymphoma patients in the coming days," said
Additional data from the BRUIN Phase 1/2 trial in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) will be presented in an oral presentation at ASH (abstract 542) on
Key Data Presented at ASH
Pharmacokinetic analyses during dose escalation demonstrated consistent dose-proportional exposures with low inter-patient variability across the entire dosing range of 25mg to 300mg daily. Doses of 100mg QD and greater exceeded BTK IC90 target coverage for the entirety of the dosing interval. Responses were observed starting at the first dose level.
The efficacy data presented at ASH are based on investigator response assessments. Patients were considered efficacy-evaluable if they had at least one post-baseline response assessment or if they discontinued treatment prior to their first post-baseline response assessment.
- In the 56 efficacy-evaluable patients with MCL, 29 responded to treatment including 14 complete responses (CR) and 15 partial responses (PR) resulting in an overall response rate (ORR) of 52% (95% CI: 38-65). Among the 52 patients who had received a prior covalent BTK inhibitor, the ORR was also 52% (95% CI: 38-66). Responses in MCL were observed in patients who received prior cellular therapy, including 64% (9/14) of patients with prior autologous or allogeneic transplant, and 100% (2/2) with prior CAR-T. Responses were also observed in two of four patients with blastoid variant MCL, an aggressive subtype associated with worse prognosis. Median time to first response was 1.8 months, corresponding with the first response assessment. Median follow-up for the 56 efficacy-evaluable MCL patients was six months. Of the 29 responding MCL patients, all except five remain on therapy (four for progressive disease and one who achieved a CR and electively discontinued treatment to undergo allogeneic stem cell transplant). The longest-followed responding patient continues on treatment at 18.3 months.
- In 19 efficacy-evaluable Waldenström's macroglobulinemia patients, 13 responded including 9 PR and 4 minor responses (MR), resulting in an ORR of 68% (95% CI: 44-87). Among the 13 patients who had received a prior covalent BTK inhibitor, the ORR was 69% (95% CI: 39-91, 5 PR, and 4 MR). Ten of 13 WM responders are ongoing on LOXO-305 treatment at a median follow-up of 4.6 months.
- Among eight efficacy-evaluable patients with follicular lymphoma, responses were observed in four patients.
- Among eight patients with Richter's transformation identified prior to enrollment, responses were observed in six, resulting in an ORR of 75%.
- Of the remaining 39 efficacy evaluable patients, eight responses were observed (6/25 patients with Diffuse large B-cell lymphoma (DLBCL), 2/9 patients with marginal zone lymphoma (MZL)).
Safety data were presented for the entire enrolled BRUIN population. Across all 323 patients enrolled in the study, the most commonly reported adverse events, regardless of attribution, were fatigue (20%), diarrhea (17%), and contusion (13%). In addition, rates of two adverse events commonly associated with BTK inhibitors, atrial arrythmias and hemorrhage, were low, experienced by two patients and one patient respectively, and considered by investigators as unrelated to LOXO-305. Dose interruptions, reductions and permanent discontinuations for drug-related adverse events were observed in 8%, 2.2%, and 1.5% of patients, respectively. No dose limiting toxicities were reported and a maximum tolerated dose (MTD) was not reached.
LOXO-305 Development Program Update
LOXO-305 is an investigational, oral, highly selective, non-covalent Bruton's tyrosine kinase (BTK) inhibitor. BTK plays a key role in the B-cell antigen receptor signaling pathway, which is required for the development, activation and survival of normal white blood cells, known as B-cells, and malignant B-cells. BTK is a validated molecular target found across numerous B-cell leukemias and lymphomas including chronic lymphocytic leukemia, mantle cell lymphoma, Waldenström macroglobulinemia, and marginal zone lymphoma. Currently available BTK inhibitors irreversibly inhibit BTK and the long-term efficacy of these therapies can be limited by acquired resistance, most commonly through BTK C481 mutations. In rapidly growing tumors with inherently high rates of BTK turnover, resistance to covalent BTK therapies may be the result of incomplete target inhibition. LOXO-305 was designed to reversibly bind BTK, deliver consistently high target coverage regardless of BTK turnover rate, preserve activity in the presence of the C481 acquired resistance mutations, and avoid off-target kinases that have complicated the development of both covalent and investigational non-covalent BTK inhibitors. Interested patients and physicians can contact the
About the BRUIN Trial
This first-in-human, global, multi-center Phase 1/2 trial evaluates LOXO-305 as a single agent in patients with previously treated chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), or non-Hodgkin's lymphomas (NHL). The trial includes a Phase 1 dose escalation phase and a Phase 2 dose expansion phase. The Phase 1 dose escalation enrolls patients with CLL/SLL or NHL who have received at least two prior lines of therapy and have progressed or are intolerant to standard of care. The dose escalation phase followed a "3+3" design with LOXO-305 dosed orally in 28-day cycles. As dose cohorts were cleared, additional patients could enroll in cleared cohorts and intra-patient dose escalation was permitted. The primary objective of the Phase 1 portion of the trial is to determine the maximum tolerated dose and recommended Phase 2 dose. Key secondary objectives include measures of safety, pharmacokinetics, and anti-tumor activity (i.e. Overall Response Rate (ORR) and Duration of Response, as determined by appropriate histology-specific response criteria). In the Phase 2, patients are enrolled across various cohorts, depending on disease type and prior therapy. The primary endpoint for Phase 2 is ORR. Secondary endpoints include duration of response (DOR), overall survival (OS), safety, and pharmacokinetics (PK).
This press release contains forward-looking statements (as that term is defined in the Private Securities Litigation Reform Act of 1995) about
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