Durable Efficacy With LOXO-305 in Heavily Pretreated CLL/SLL

LOXO-305, a highly selective noncovalent Bruton tyrosine kinase (BTK) inhibitor, was associated with promising response and efficacy rates in patients with heavily pretreated and poor-prognosis chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). This is according to findings from the phase I/II BRUIN study presented by Anthony Mato, MD, from the Memorial Sloan Kettering Cancer Center in New York, at the 2020 ASH Annual Meeting.

A total of 186 patients with advanced B-cell malignancies who had received two or more prior therapies were included in the BRUIN trial. Diagnoses among the patient population included: CLL/SLL (n=94); mantle cell lymphoma (n=38); diffuse large B-cell lymphoma (n=19); Waldenström macroglobulinemia (n=17); follicular lymphoma (n=6); marginal zone lymphoma (n=5); and other, including Richter transformation (n=7).

Patients in the study were treated with one of seven dose levels of LOXO-305, ranging from 25 mg to 300 mg, all of which were administered orally in 28-day cycles. Identification of the maximum tolerated dose and the recommended phase II dose (RP2D) comprised the primary endpoint.

In his presentation, Dr. Mato focused on the 94 patients with CLL/SLL. Median age was 69 years and the median number of prior therapies was four. Most patients (84%) received a prior BTK inhibitor, while 69% of patients previously received an anti-CD20 antibody, chemotherapy, and BTK inhibitor. Approximately 21% and 31% of patients previously received a phosphoinositide 3-kinase (PI3K) inhibitor and venetoclax, respectively. A large portion of patients had high-risk features, such as del17p (21%), TP53 mutation (30%), and unmutated IGHV (84%).

The efficacy-evaluable population included 64 patients with CLL/SLL who had undergone the first response evaluation or had discontinued therapy. The researchers evaluated response every eight weeks from cycle three, then every 12 weeks from cycle 12.

There were no reports of dose-limiting toxicities or dose reductions in patients treated with LOXO-305. Fatigue (16%) and diarrhea (15%) were the only treatment-emergent adverse events seen in 10% or more of patients treated with LOXO-305, the authors observed.
In terms of efficacy, 200 mg once-daily was selected as the RP2D, though the researchers noted that the first dose level of 25 mg elicited a response.

Eighty-eight patients with CLL/SLL (94%) remained on therapy at the efficacy cutoff date. The overall response rate was 57%, which included 23 partial responses (PRs), 14 patients with PR with lymphocytosis, 26 patients with stable disease, one patient with progressive disease, and one patient who was not evaluable.

Median follow-up times were three months for the overall cohort, compared with 6.7 months for responding patients. Responses deepened over time, which the investigators suggested was consistent with covalent BTK inhibitors.

The researchers indicated that the absence or presence of a pretreatment BTK C481 mutation did not influence the response rate, and that responding patients with BTK C481 mutations had reductions in mutant disease burden as assessed with droplet digital polymerase chain reaction.

“LOXO-305 demonstrated promising efficacy in [patients with] heavily pretreated, poor-prognosis CLL/SLL following multiple prior lines of therapy including covalent BTK inhibitor and a BCL2 inhibitor,” Dr. Mato and researchers concluded. They noted that, in addition to its “well tolerated” safety profile, LOXO-305 also exhibited a wide therapeutic index.
LOXO-305 is being evaluated in a variety of B-cell malignancies, including mantle cell lymphoma. In other research presented at the meeting, the agent was associated with an overall response rate of 52%.

Study authors report relationships with Loxo Oncology, which sponsored the trial.


Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, A next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: Results from the phase 1/2 BRUIN study. Abstract #542. Presented at the 2020 American Society of Hematology Annual Meeting, December 7, 2020.