Over the past decade, covalent bruton tyrosine kinase (BTK) inhibitors have transformed how chronic lymphocytic leukemia (CLL) is treated, leading to more than a handful of chemo-free treatment options for patients. However, according to researchers in the phase I/ II BRUIN study, treatment failure can occur by developing resistance and discontinuation for adverse events, leaving many patients with fewer treatment options. Also, covalent BTK inhibitors may pose other issues, including reduced or absent activity in the presence of BTK cysteine binding site (C481) mutations and pharmacologic liabilities that may lead to acquired resistance.
According to study results led by New York Lymphoma Rounds Steering Committee member Anthony Mato, MD of Memorial Sloan Kettering Cancer Center, LOXO-305, a highly selective, non-covalent BTK inhibitor, may be an efficacious option for the treatment of heavily pretreated/ poor prognosis relapsed/refractory chronic lymphocytic leukemia.
The study included 186 patients with B-cell non-Hodgkin lymphoma (NHL) — including 94 patients with CLL/ small lymphocytic lymphoma (SLL). The patients were previously treated at least once, with 84 percent previously receiving a BTK inhibitor, 69 percent previously receiving an anti-CD20 antibody, chemotherapy, and BTK inhibitor, 21 percent previously receiving a PI3K inhibitor, and 31 percent previously receiving venetoclax (Venclexta). All patients received seven dose levels, with observed responses at the first dose level and a median follow-up of three months for all patients and 6.7 months for responders. The researchers note an overall response rate (ORR) of 57 percent, with some patients receiving deeper responses of 77 percent with at least six months of follow-up.
This study also included contributions from Scientific Advisory Board member Jennifer R. Brown, MD, PhD of Dana-Farber Cancer Institute; LRF grantee John M. Pagel, MD, PhD of Swedish Cancer Institute; and Philadelphia Lymphoma Rounds Steering Committee Chair Stephen J. Schuster, MD of Abramson Cancer Center/the University of Pennsylvania.
In another BRUIN trial led by LRF Mantle Cell Lymphoma Consortium (MCLC) member Michael Wang, MD of the University of Texas MD Anderson Cancer Center, patients with previously treated mantle cell lymphoma (MCL) treated with LOXO-305 received high response rates with no dose-limiting toxicities or dose reductions during the study follow-up.
A total of 323 patients with advanced B-cell non-Hodgkin lymphoma, including 61 patients with MCL, were enrolled and analyzed for the trial. As in its sister study, patients in this analysis were heavily pretreated with a median of three prior therapies, including previous BTK inhibitors. Approximately 93 percent of MCL patients received a previous BTK inhibitor.
Researchers observed an overall response rate (ORR) of 52 percent for MCL patients and noted that at a median follow-up of six months, 24 of 29 patients with an initial response to LOXO-305 have an ongoing response. Waldenström macroglobulinemia (WM) patients received a promising ORR as well at 68 percent.
Although these are preliminary results, the researchers note that LOXO-305 could be a potentially effective treatment option for difficult-to-treat MCL, as well as WM and other NHLs.
This study also included contributions from LRF grantees Jonathon B. Cohen, MD, MS of Winship Cancer Institute; M. Lia Palomba, MD of Memorial Sloan Kettering Cancer Center; and John M. Pagel, MD, PhD of Swedish Cancer Institute; as well as LRF Mantle Cell Lymphoma Consortium members Timothy S. Fenske, MD of the Medical College of Wisconsin; Ian W. Flinn, MD, PhD of Sarah Cannon Research Institute/ Tennessee Oncology; and New York Lymphoma Rounds Steering Committee member Anthony Mato, MD of Memorial Sloan Kettering Cancer Center.
More Updates from the 2020 American Society of Hematology Annual Meeting
Widely regarded as the premier event in malignant and non-malignant hematology, the virtual ASH Annual Meeting held from December 5-8, 2020 provided a critical forum for leading hematologists /oncologists to present their findings to over 20,000 of their peers.
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