Despite the marked efficacy of ibrutinib, acalabrutinib, and venetoclax in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), treatment failure can occur through the development of resistance. In addition, patients in whom Bruton’s tyrosine kinase (BTK) inhibitors and BCL2 inhibitors fail tend to have a worse prognosis. A new study suggests that the novel agent LOXO-305, a highly potent and selective noncovalent BTK inhibitor, may provide new hope for these heavily pretreated patients with relapsed/refractory CLL/SLL.1 Anthony R. Mato, MD, Director of the CLL Program at Memorial Sloan Kettering Cancer Center, New York, presented the findings at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.
Methods
The aim of the phase I/II BRUIN trial was to determine the safety and early efficacy of LOXO-305 in patients with relapsed/refractory CLL/SLL (n = 170) and other B-cell non-Hodgkin lymphomas (NHL) who had received at least two prior therapies. The primary endpoints were to determine maximum tolerated dose and the recommended phase II dose.
“In terms of baseline characteristics, what is most striking is how heavily pretreated the CLL patient population is,” Dr. Mato noted. The median number of prior therapies in the CLL/SLL cohort was four (range = 1–10). About 86% of CLL/SLL patients had received a prior BTK inhibitor, and 69% had received an anti-CD20 antibody, chemotherapy, and a BTK inhibitor. In addition, 21% had received a phosphatidylinositol-3-kinase (PI3K) inhibitor, and 34% had received venetoclax. This was a high-risk population, with 27% of patients having BTK C481 mutation, 35% having 17p deletion, 30% with a TP53 mutation, and 88% were unmutated for IGHV.
In terms of baseline characteristics, what is most striking is how heavily pretreated the CLL patient population is.— Anthony R. Mato, MD
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Results
At the efficacy cutoff date, 83 of 88 responding patients with CLL/SLL (94%) remained on therapy, and 139 patients with CLL/SLL were evaluable for efficacy. The overall response rate was 63%, which deepened to 83% in patients followed for more than 10 months. There were no complete remissions.
Efficacy was observed in patients regardless of their BTK experience or other prior therapies. The high overall response rate was similar across subgroups, even in the most heavily pretreated patients in whom five prior U.S. Food and Drug Administration–approved therapies (including chemotherapy, CD20 monoclonal antibodies, BTK inhibitors, venetoclax, and PI3K inhibitors) had failed. “A higher overall response rate was seen in patients pretreated with a BTK inhibitor regardless of the reason for discontinuation. Furthermore, overall response was similar in both BTK wild-type and C481-mutant disease,” Dr. Mato noted.
In terms of pharmacokinetics, LOXO-305 demonstrated high oral exposures, with doses ≥ 100 mg daily exceeding the BTK IC90 for the entirety of the dosing interval.
Treatment was well tolerated. There were no dose-limiting toxicities or dose reductions, and the rate of discontinuation due to adverse events was low at 1.5%. However, the treatment-emergent adverse events, regardless of attribution or grade, seen in ≥ 10% of patients (n = 323, including B-cell NHL cohort) were fatigue (20%), diarrhea (17%), and contusion (13%); of these, the only grade 3 toxicity observed was fatigue.
“As few patients have discontinued LOXO-305, we expect the overall response rate to continue to deepen with further follow-up for the entire cohort,” Dr. Mato said.
Clinical Implications
In conclusion, LOXO-305 demonstrated promising efficacy in heavily pretreated, poor-prognosis patients with CLL/SLL following multiple prior lines of therapy including covalent BTK inhibitor and a BCL2 inhibitor, with manageable and minimal adverse events. Follow-up remains short, but the activity of LOXO-305 was not restricted to subjects with BTK C481 mutations. A recommended phase II dose of 200 mg daily was selected for future studies including combinations, which have initiated. However, it is important to remember that patients with CLL that has progressed after treatment with both BTK inhibitors and BCL2 inhibitors have very poor prognosis disease and need to be considered for chimeric antigen receptor T-cell options, and/or allogeneic transplant, which remains the only curative therapy for patients with relapsed/refractory CLL/SLL.
DISCLOSURES: The BRUIN study was sponsored by Loxo Oncology. Dr. Mato has served on a data and safety monitoring board for TG Therapeutics; has received research funding from Genentech, Loxo Oncology, Janssen, Pharmacyclics, Adaptive, AbbVie, AstraZeneca, and TG Therapeutics; and served as a consultant for Genentech, Loxo Oncology, Janssen, Pharmacyclics, Adaptive, AbbVie, BeiGene, AstraZeneca, and TG Therapeutics.
REFERENCE
1. Mato AR, Pagel JM, Coombs CC, et al: LOXO-305: A next generation, highly selective, non-covalent BTK inhibitor in previously pretreated CLL/SLL: Results from the phase 1/2 BRUIN study. 2020 ASH Annual Meeting & Exposition. Abstract 542. Presented December 7, 2020.
