Next-Generation Non-Covalent BTK Inhibitor Pirtobrutinib Demonstrates Robust Efficacy in CLL/SLL and MCL Patients Previously Treated with Covalent BTK Inhibitors

December 26, 2021 /BioValleyBIOON/ --Eli Lilly(Eli Lilly) and CompanyTumorR&D department Loxo Oncology recently announced the targeted anticancer drug pirtobrutinib (LOXO-305) for the treatment of chronic lymphocyticLeukemia(CLL), Small Lymphocytic Lymphoma (SLL), Mantle Cell Lymphoma (MCL) Global Phase 1/2 BRUINClinical TrialUpdated clinical data.Pirtobrutinib is an investigational, highly selective, non-covalent Bruton's tyrosine kinase (BTK) inhibitor.

Data shows,In CLL/SLL patients previously treated with a BTK inhibitor, the overall response rate (ORR) was 68%, and in patients followed up for 12 months or longer, the ORR increased to 73%., regardless of the reasons for prior BTK inhibitor discontinuation or BTK mutation status, the ORR was consistent.In MCL patients previously treated with a BTK inhibitor, the ORR was 51%.; In MCL patients who have not previously received BTK inhibitors, the ORR was 82%.

BRUIN is so far the largest group of CLL/SLL patients who have previously received modern standard care (including BTK and BCL2 inhibitors).Clinical Trial。In this real-world population of relapsed/refractory patients, pirtobrutinib continues to demonstrate robust activity, with long-term treatment showing a favorable safety profile. As follow-up time extends, evidence of durable disease control has been observed in this heavily pretreated CLL/SLL population. Currently, there are no evidence-based treatment options for patients who have received covalent BTK and BCL2 inhibitors, and pirtobrutinib has the potential to provide a meaningful new therapy for these CLL/SLL patients as well as those who have received fewer prior regimens.

In terms of MCL, the number of evaluable patients who were previously treated with a BTK inhibitor has doubled since the last data analysis, with nearly identical response rates observed. New treatment options following covalent BTK therapy represent an urgent unmet medical need, and the durable response rates observed with pirtobrutinib suggest that this drug has the potential to provide significant clinical benefit for MCL patients after covalent BTK therapy.

As of July 16, 2021, the study enrolled a total of 618 patients, including 296 CLL/SLL patients, 134 mantle cell lymphoma (MCL) patients, and 188 other B-cell malignancies.TumorPatients. Efficacy data are based on investigator assessments of response. A patient is considered evaluable for efficacy if they have had at least one post-baseline response assessment or discontinued treatment prior to the first post-baseline response assessment.

Among the 296 enrolled CLL/SLL patients, 261 had previously received BTK inhibitor treatment and were the subjects of this analysis. The median number of prior treatments was 3 lines, with 100% having received a BTK inhibitor, 88% an anti-CD20 antibody, 79% chemotherapy, 41% venetoclax, 20% a PI3K inhibitor, 6% CAR-T therapy, and 2%Stem CellsTransplantation.

Among 252 evaluable patients, 171 achieved responses, including 2 complete responses (CR), 137 partial responses (PR), 32 partial responses with lymphocytosis (PR-L), and 62 stable disease (SD), yielding an overall response rate (ORR) of 68% (95% CI: 62-74). Over time, the depth of response continued to improve, with the ORR increasing to 73% (88/119) in patients followed up for 12 months or longer. The ORR remained consistent regardless of prior reasons for BTK discontinuation, types and number of prior therapies, or BTK C481 or PLCG2 mutation status.

Pirtobrutinib demonstrated durable activity in patients who had received at least BTK inhibitor therapy (median prior lines of therapy: 3), with the median progression-free survival (PFS) not yet reached (lower bound of 95% CI: 17.0 months). In patients previously treated with both BTK and BCL2 inhibitors (median prior lines of therapy: 5), the estimated median PFS was 18 months, although these data remain immature and unstable due to a small number of patients experiencing disease progression. As of the data cutoff date, 74% (194/261) of patients previously treated with BTK inhibitors were still receiving pirtobrutinib. The median follow-up time for all patients previously treated with BTK inhibitors was 9.4 months (range: 0.3–27.4 months).

In an exploratory analysis of patients with disease progression previously treated with a BTK inhibitor, pirtobrutinib treatment showed similar PFS in both BTK C481 mutation and BTK C481 wild-type CLL and SLL patients.

Among the 134 MCL patients enrolled, the median number of prior treatments was 3 lines, with 90% having received BTK inhibitors, 97% having received anti-CD20 antibodies, 91% having received chemotherapy, and 22% having receivedStem CellsTransplant, 17% received immunomodulatory (IMiD) drugs, 15% received venetoclax, 13% received proteasome inhibitors, 5% received CAR-T cell therapy, and 4% received PI3K inhibitors.

Among 100 evaluable MCL patients who had previously received BTK inhibitors, 51 patients achieved a response, including 25 with CR and 26 with PR, resulting in an ORR of 51% (95% CI: 41-61). Among 11 MCL patients who had not previously received BTK inhibitor therapy, 9 patients achieved a response, including 2 with CR and 7 with PR, yielding an ORR of 82% (95% CI: 48-98). In those receivingStem CellsMCL relief was observed in patients undergoing transplantation and CAR-T therapy.

The median duration of response was 18 months (with a lower limit of 95% CI at 4.6 months). The median follow-up time for all MCL patients who had a response was 8.2 months (range: 1.0-27.9 months), and as of the data cutoff date, 60% (36/60) remained in response.

In terms of safety, among all 618 patients enrolled in the study, the most commonly reported adverse events, regardless of attribution, were fatigue (23%), diarrhea (19%), neutropenia (18%), and bruising (17%). Additionally, the incidence of adverse events typically associated with covalent BTK inhibitors was low, with most being grade 1 or 2. During the phase 1 dose escalation, no dose-limiting toxicity was reported, and the maximum tolerated dose (MTD) was not reached. One percent (n=6) of patients permanently discontinued the drug due to drug-related adverse events. (Bioon.com)

Source of the original text:Loxo Oncology at Lilly Announces Updated Data from the Phase 1/2 BRUIN Clinical Trial for Pirtobrutinib at the American Society of Hematology Annual Meeting