ORLANDO – A phase 1 trial of the next-generation Bruton tyrosine kinase (BTK) inhibitor LOXO-305 has demonstrated safety and provided evidence of its efficacy in heavily pretreated patients with B-cell malignancies, including some with acquired resistance to other BTK inhibitors and venetoclax, according to an investigator.
The antitumor activity of this highly selective investigational oral BTK inhibitor was significant in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), with a rapid onset of action and resolution of lymphocytosis “consistent with effective BTK target inhibition,” said, of the Center for CLL at Memorial Sloan Kettering Cancer Center in New York.
Responses were also seen in patients with BTK C481 mutations, the primary cause of progressive CLL after BTK inhibitor use, Dr. Mato said at the annual meeting of the American Society of Hematology.
The safety and tolerability profile of LOXO-305 is “consistent with highly selective drug design,” with no evidence of off-target effects, he said. “Collectively, these data demonstrate that BTK remains a highly actionable target despite progression on covalent BTK inhibitors.”
While BTK inhibitors have transformed treatment of B-cell malignancies, resistance remains a major problem, said Dr. Mato, citing 5-year ibrutinib discontinuation rates of 41% in the front line setting and 53.7% in the relapsed/refractory setting.
Key reasons for discontinuation are intolerance, events such as atrial fibrillation and major bleeding, progression of disease, and the appearance of BTK C481 mutations, which prevent covalent BTK inhibitors from achieving effective target inhibition, he said. In contrast, LOXO-305 is designed to non-covalently bind to BTK, regardless of C481 status.
Dr. Mato described results of the phase 1 BRUIN trial, in which 28 adult patients with CLL or B-cell non-Hodgkin lymphomas received once daily oral LOXO-305 at doses ranging from 25 mg to 200 mg. All patients had received at least two lines of prior therapy and had active disease in need of treatment.
For 13 evaluable CLL patients, the overall response rate was 77% (10 patients), Dr. Mato reported. Overall response rates for MCL and other B-cell malignancies were 50%, or three out of six MCL patients and two of four patients with Waldenström macroglobulinemia, diffuse large B-cell lymphoma, or marginal zone lymphoma.
Though only a small subset of CLL patients have had multiple response assessments, the available data suggest that responses “deepen over time” with continued LOXO-305 treatment, Dr. Mato said.
With the median follow-up of 2.7 months, 24 of 28 patients remain on therapy, including all responders. “Some of the responses appear to be quite durable,” Dr. Mato said.
There have been no dose-limiting toxicities, the maximum tolerated dose has not been reached, and there have been no notable adverse events characteristic of covalent BTK inhibitors – namely atrial fibrillation or major bleeding – despite frequent monitoring, according to Dr. Mato.
There were two grade 3 events (leukocytosis and neutropenia), but the remaining treatment-emergent adverse events have been grade 1-2. “Having managed many of these patients, I can tell you that these adverse events were quite manageable,” Dr. Mato told attendees.
BRUIN is a global trial that continues to enroll patients at 18 sites in 3 countries, with a plan in 2020 to incorporate “rational combinations” of agents, according to the investigator.
Dr. Mato reported disclosures related to Gilead, Pharmacyclics, AstraZeneca, AbbVie, Sunesis, Johnson & Johnson, TG Therapeutics, LOXO, DTRM Biopharma, Genentech, Janssen, Acerta, Pharmacyclics, and Celgene.
SOURCE: Mato AR et al. ASH 2019, Abstract .