Eli Lilly's Next-Generation Non-Covalent BTK Inhibitor LOXO-305 Demonstrates Robust Efficacy in Patients with Covalent BTK Inhibitor-Resistant B-Cell Malignancies

December 14, 2019 News /BioValleyBIOON/ -- U.S. pharmaceutical giantEli Lilly(Eli Lilly) recently announced interim data from the global Phase I/II BRUIN dose-escalation study of the targeted anticancer drug LOXO-305 at the American Society of Hematology (ASH) Annual Meeting. LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. The data showed that across all doses studied, LOXO-305 demonstrated efficacy in B-cellLeukemiaObjective responses were observed in patients with lymphoma, including those with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) who were resistant to BTK inhibitors, intolerant to BTK inhibitors, or resistant to BCL2 inhibitors.

Data presented at the ASH annual meeting were based on patients who received treatment as of September 27, 2019, with follow-up conducted on November 5, 2019. A total of 28 patients were enrolled across five dose-escalation cohorts: 25 mg once daily (n=5), 50 mg once daily (n=6), 100 mg once daily (n=9), 150 mg once daily (n=5), and 200 mg once daily (n=3). Among these patients, there were 16 cases of chronic lymphocytic leukemia (CLL), 8 cases of mantle cell lymphoma (MCL), 2 cases of Waldenström macroglobulinemia, 1 case of diffuse large B-cell lymphoma, and 1 case of marginal zone lymphoma. The CLL patients had received a median of four prior systemic therapy regimens, and 75% of them had been treated with at least one Bruton tyrosine kinase (BTK) inhibitor. The MCL patients had received a median of three prior systemic therapy regimens, and 88% of them had been treated with at least one BTK inhibitor.

Pharmacokinetic analysis during the dose-escalation phase indicated that LOXO-305 exposure increased in a dose-dependent and linear manner with increasing doses. Starting at a once-daily dose of 50 mg, the target coverage of LOXO-305 for both wild-type and C481S-mutant BTK exceeded the IC90, based on estimates derived from cellular potency.

Efficacy data presented at the ASH annual meeting were based on response assessments by study investigators, with responses observed across all dose levels: (1) Among 16 patients with chronic lymphocytic leukemia (CLL), 10 of the 13 patients evaluable for response assessment were responders (8 with partial response and 2 with partial response with persistent lymphocytosis), yielding an overall response rate (ORR) of 77%. All CLL patients showedTumorTumor burden decreased, and the depth of response increased over time. Therapeutic responses were observed in patients who had acquired resistance to prior BTK therapy (with or without the C481S mutation), patients who were intolerant to prior BTK therapy, and patients who had acquired resistance to prior BCL-2 therapy (including one case with a known BCL2 G101V mutation). As expected, LOXO-305 treatment induced acute lymphocytosis, which gradually resolved over time; this is a favorable pharmacodynamic response associated with effective BTK inhibition. Among three CLL patients who did not meet the criteria for response assessment (one of whom harbored the BTK C481S mutation), all three developed lymphocytosis early in Cycle 1. All CLL responders maintained their response, and all CLL patients remain on study.

Among 8 patients with mantle cell lymphoma (MCL): Of the 6 patients evaluable for response assessment, 3 were responders (1 complete response and 2 partial responses), yielding an overall response rate (ORR) of 50%. Two of the responders had experienced disease progression after prior BTK inhibitor therapy (with no documented C481X mutations). All responding MCL patients remained in remission and continued in the study. Three MCL patients discontinued treatment due to progressive disease during Cycle 1.

The majority of treatment-emergent adverse events were Grade 1 in severity. The most frequently reported events (regardless of attribution) were fatigue (total 25%: 21% Grade 1, 4% Grade 2) and diarrhea (total 18%: 14% Grade 1, 4% Grade 2). Two adverse events of Grade ≥3 were attributed to LOXO-305 (Grade 3 leukocytosis and Grade 3 transient neutropenia). No dose-limiting toxicities were reported, and the maximum tolerated dose (MTD) was not reached.

Dr. Anthony Mato, Director of the CLL Program at Memorial Sloan Kettering Cancer Center and lead presenter of the BRUIN study data, stated: “We are pleased to report that LOXO-305 demonstrates activity in patients who are resistant or intolerant to covalent BTK inhibitors, as well as in those resistant to BCL2 inhibitors. We observed highly compelling response rates in patients with chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). Notably, treatment responses were independent of C481 mutation status, a potential mechanism of resistance to covalent BTK inhibitors. Objective responses were observed in dose cohort 1, and the maximum tolerated dose was not reached. These data suggest that LOXO-305 achieves the desired selective engagement and target coverage in humans to maximize the full potential of this molecular target, whether used in combination with other agents or moved into earlier lines of therapy.””

LOXO-305 is an investigational, highly selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor. BTK plays a pivotal role in the B-cell antigen receptor signaling pathway and is essential for the development, activation, and survival of normal leukocytes (B cells) as well as malignant B cells. BTK is an effective molecular target found in many B-cell leukemias and lymphomas, including chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia, mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL).

Currently available BTK inhibitors irreversibly inhibit BTK, and the long-term efficacy of these therapies is limited by acquired resistance, most commonly through the BTK C481 mutation, as well as intolerance due to off-target inhibition of other cellular targets. LOXO-305 is designed to reversibly bind BTK, maintaining activity in the presence of the acquired C481 resistance mutation while avoiding off-target kinases implicated in the development of other covalent and non-covalent BTK inhibitors.

By the United StatesTumorPrecision drug developer Loxo Oncology was acquired by Eli Lilly for $8 billion in early January this year. In addition to LOXO-305,Eli LillyIt also acquired multiple targeted drugs from Loxo, including: (1) the “broad-spectrum” anticancer drug Vitrakvi (larotrectinib), andBayerco-developed, this is a tropomyosin receptor kinase (TRK) inhibitor approved for the treatment of NTRK gene fusion-positive solid tumors; (2) LOXO-195, co-developed with Bayer, is a next-generation TRK inhibitor designed to overcome potential acquired resistance; (3) selpercatinib (also known as LOXO-292), an oral RET kinase inhibitor for patients with RET alterationsTumor; (4) FGFR project, in preclinical development, for the treatment of cancers with abnormal alterations in fibroblast growth factor receptors (FGFR). (Bioon.com)

Original source:Lilly Presents Interim Clinical Data from LOXO-305 Dose Escalation Trial in B-Cell Leukemias and Lymphomas at the American Society Hematology Annual Meeting