Significant Responses Seen With Investigational BTK Inhibitor in Pretreated CLL/SLL Population

A high objective response rate was observed in patients with chronic lymphocytic leukemia and small lymphocytic lymphoma treated with LOXO-305, according to results of the phase 1/2 BRUIN trial presented during the 2020 ASH Annual Meeting.

A high objective response rate (ORR) was observed in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) treated with LOXO-305, according to results of the phase 1/2 BRUIN trial presented during the 2020 ASH Annual Meeting.1,2

In the efficacy-evaluable patients with CLL/SLL that were treated across all dose levels (n = 139), 88 patients responded for an ORR of 63% (95% CI, 55%-71%), which included 69 partial responses (PRs) and 19 PRs with ongoing lymphocytosis. Forty-five patients had stable disease (SD), 1 had progressive disease, and 5 discontinued prior to their first response assessment and were considered evaluable.

"The data presented at ASH reveal an incredibly encouraging and consistent safety and efficacy profile for LOXO-305 in heavily pretreated CLL and SLL patients, regardless of previous therapies, reasons for discontinuations of those therapies, or presence of resistance mutations," said presenting author Anthony Mato, MD, director of the CLL Program at Memorial Sloan Kettering Cancer Center. "We are increasingly in need of new therapies for patients that have been previously treated with a covalent BTK inhibitor, and LOXO-305 may allow us to continue treating patients in the same biologic class before attempting more complicated therapeutic approaches."

LOXO-305 is an investigational, highly selective, non-covalent BTK inhibitor that was evaluated in the BRUIN study. The investigators enrolled 323 patients with CLL/SLL (n = 170), mantle cell lymphoma (MCL; n = 61), Waldenström macroglobulinemia (n = 26), and other B-cell lymphomas (n = 66) as of September 27, 2020. Patients with CLL/SLL had received a median 3 prior lines of therapy, including a BTK inhibitor (86%), an anti-CD20 antibody (90%), chemotherapy (82%), venetoclax (Venclexta; 34%), a PI3K inhibitor (21%), chimeric antigen receptor T-cell therapy, and allogeneic transplant (2%).

The trial included a phase 1 dose-escalation phase and a phase 2 dose-expansion portion. The primary end point of the phase 1 portion was maximum-tolerated dose and recommended phase 2 dose; key secondary end points included safety, pharmacokinetics, and anti-tumor activity.

In the phase 2 part of the trial, patients are enrolled across various cohorts based on disease type and prior treatment. Here, the primary end point is ORR, with secondary end points being duration of response (DOR), overall survival (OS), safety, and pharmacokinetics (PK).

Patients were evaluable for efficacy if they had at least 1 post-baseline response assessment, or if they discontinued therapy prior to their first post-baseline response assessment.

Eighty-eight percent of patients with CLL/SLL remain on study treatment as of the data cutoff. Of the 88 patients still responding to treatment, all except 5 remain on treatment. Four patients had disease progression; 1 patient achieved a PR and chose to discontinue pursuit of a transplant. One patient continues on treatment for 17.8 months, which is the longest-followed responding patient.

At a median follow-up for efficacy of 6 months, additional data showed that the ORR was consistent in multiple patient subgroups. In efficacy-evaluable patients who previously received a BTK inhibitor (n = 121), the ORR was 62% (95% CI, 53%-71%); in patients followed for at least 10 months, the response rate increased to 84%.

The ORR was 67% in those who had previously discontinued a covalent BTK inhibitor due to disease progression (n = 79) vs those who stopped the therapy because of toxicity or another reason (52%; n = 42).

The ORR was 69% in patients who received prior chemoimmunotherapy, a covalent BTK inhibitor, and a BCL-2 inhibitor (n = 39). For patients who previously were treated with prior chemoimmunotherapy (n = 39), a covalent BTK inhibitor, a BCL-2 inhibitor, and a PI3K inhibitor, the ORR was 58%.

Moreover, in patients who harbored a BTK C481 mutation (n = 24), the ORR was 71% compared with a 61% ORR in those without the mutation (n = 65). In those with del(17p), TP53 mutation or both (n = 28), the ORR was 79%.

During the dose-escalation portion, pharmacokinetic analyses demonstrated consistent dose-proportional exposures with low inter-patient variability across the full range of doses—25 mg to 300 mg daily. Additionally, daily doses of 100 mg and above exceeded BTK IC90 target coverage for the entirety of the dosing interval. Responses were reported beginning at the first dose level.

Regarding safety, which was evaluable for all 323 patients enrolled on study, the most commonly reported adverse events (AEs) were fatigue (20%), diarrhea (17%), and contusion (13%). Atrial arrythmias and hemorrhage rates were low, as seen in 2 patients and 1 patient, respectively; both were found to not be related to study treatment. Dose interruptions occurred in 8% of patients, reductions in 2.2%, and permanent treatment discontinuations for TRAEs were observed in 1.5% of patients, respectively. There were no dose-limiting toxicities reported and the maximum-tolerated dose was not reached.

At the 2019 ASH Annual Meeting, results of a first-in-human, proof-of-concept trial of LOXO-305 were presented in patients with previously treated B-cell malignancies.3 In those with previously treated CLL, the ORR was 77%; 75% of these patients had received a prior BTK inhibitor. For patients with MCL, the ORR was 50%, and 88% of patients had received a prior BTK inhibitor.

"The LOXO-305 data continue to surpass our expectations, and we are very excited for what these data could mean for patients with CLL and SLL," stated David Hyman, MD, chief medical officer of Loxo Oncology at Lilly, the developer of LOXO-305. "These emerging data further substantiate our thesis that the drug's reversible binding mode, high selectivity, and robust pharmacology offer a differentiated treatment option across B-cell leukemias and lymphomas. We are eager to initiate a phase 3 program in 2021."

LOXO-305 is planned to undergo investigations in phase 3 studies. BRUIN CLL-321, which is expected to start in the first quarter of 2021, is being explored in patients with CLL/SLL who progressed on or were intolerant to a covalent BTK inhibitor. Patients will be randomized to receive LOXO-305 as continuous therapy or investigator’s choice of idelalisib (Zydelig)/rituximab (Rituxan) or bendamustine/rituximab.

BRUINN CLL-322 is expected to enroll patients with CLL/SLL who progressed on or were intolerant to a covalent BTK inhibitor. Patients will be randomized to a fixed-duration treatment of LOXO-305 plus venetoclax/rituximab or venetoclax/rituximab alone. BRUINN CLL-322 is expected to begin in the second quarter of 2021.

Later in 2021, LOXO-305 is also expected to be compared with ibrutinib (Imbruvica) in patients with treatment-naïve in an international, phase 3 trial.


1. 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. Presented at: 2020 ASH Annual Meeting & Exposition; December 4-8, 2020; virtual. Abstract 542.

2. Loxo Oncology at Lilly announces updated data from the phase 1/2 BRUIN clinical trial for LOXO-305 in chronic lymphocytic leukemia and small lymphocytic lymphoma at the American Society of Hematology annual meeting. News release. Eli Lilly and Company. December 7, 2020. Accessed December 7, 2020.

3. Mato AR, Flinn IW, Pagel JM, et al. Results from a first-in-human, proof-of-concept phase 1 trial in pretreated B-cell malignancies for Loxo-305, a next-generation, highly selective, non-Covalent BTK inhibitor. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL; Abstract 501.