September 25, 2022

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Eli Lilly and Merck announces latest data on BTK C481S inhibitor



 

The effect is amazing! Eli Lilly and Merck announces latest data on BTK C481S inhibitor.

 

At present, a variety of BTK small molecule inhibitors have been successfully applied to the treatment of B-cell lymphoma in clinical practice.

The currently marketed BTKi mainly produces enzyme inhibition by forming a covalent bond with the cysteine ​​residue in the active site of BTK.

However, covalent binding easily produces drug-resistant mutations, which has become a major problem in clinical treatment.

The C481S mutation is a known resistance mechanism of the first generation of irreversible BTKi.

 

On December 12th, Loxo and Merck, a subsidiary of Eli Lilly, announced their oral, highly selective, non-covalent (reversible) BTK C481S inhibitors pirtobrutinib and MK-1026 at the 63rd Annual Meeting of the American Society of Hematology (ASH).

Efficacy data in hematological tumors (reply to the official account “ASH” to download the research PPT).

 


Phase I/II study of Pirtobrutinib in the treatment of CLL/SLL and MCL

At the conference, Loxo announced the updated data of the global phase I/II BRUIN clinical trial of pirtobrutinib in patients with chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL).

 

BRUIN is the largest clinical trial conducted so far. As of July 16, 2021, 618 patients participated in the study, including 296 CLL/SLL, 134 MCL, and 188 other B-cell malignancies.

 

Among the 252 CLL/SLL patients who had previously received BTKi treatment and whose curative effect was assessable, 171 had a response, including 2 CR, 137 PR, 32 partial remission with persistent lymphocytosis (PR-1), 62 SD, ORR Is 68%.

Over time, the remission continued to deepen, and the ORR of patients with a follow-up of 12 months or more rose to 73% (88/119).

For patients who have previously received BTKi treatment, pirtobrutinib has shown a strong therapeutic effect whether it is due to disease progression or safety and other reasons.

 

The effect is amazing! Eli Lilly and Merck announces latest data on BTK C481S inhibitor.

 

Patients who received at least one BTKi treatment before (median treatment line: 3) have not yet reached the median PFS, and patients who have received at least one BTKi and BCL2 inhibitor (median treatment line: 5 lines) have an estimated median PFS of 18 moon. Pirtobrutinib has similar PFS in BTK C481 mutant and BTK C481 wild-type CLL/SLL patients.

 

The effect is amazing! Eli Lilly and Merck announces latest data on BTK C481S inhibitor.

 

Among 100 patients with MCL who have received BTKi treatment and whose efficacy can be evaluated, 51 responded, including 25 CRs and 26 PRs, with an ORR of 51% (95% CI: 41-61).

Among the 11 patients with MCL who were not treated with BTKi, 9 had remission, including 2 CRs and 7 PRs, with an ORR of 82%.

Remission was observed in MCL patients who had received stem cell transplantation and CAR-T treatment.

 

The effect is amazing! Eli Lilly and Merck announces latest data on BTK C481S inhibitor.

 

Among all the 618 patients participating in the study, the most common adverse events (regardless of attribution) included fatigue (23%), diarrhea (19%), neutropenia (18%), and contusion (17%) .

In addition, the incidence of adverse events related to covalent BTK inhibitors is very low, most of which are grade 1 or 2. During the phase I dose escalation phase, no dose-limiting toxicity was reported and the maximum tolerated dose (MTD) was not reached.

1% (n=6) patients permanently discontinued the drug due to drug-related adverse events.

 

The effect is amazing! Eli Lilly and Merck announces latest data on BTK C481S inhibitor.

 

Phase II study of MK-1026 in the treatment of CLL/SLL

Merck announced the Phase II dose extension study data of MK-1026 in CLL/SLL patients.

 

 

A total of 51 CLL/SLL patients received the MK-1026 phase II recommended dose (65 mg, once daily) treatment, 43 (84%) patients had previously received BTKi treatment, and 32 patients (63%) had C481S BTK mutations.

The ORR of 38 patients with evaluable efficacy was 57.9% (22 cases), CR was 2.6% (1 case), PR was 31.6% (12 cases), 9 cases (23.7%) PR-1, 15 cases (39.5%) disease stability.

 

 

In terms of safety, among all treated patients, the incidence of treatment-related TEAEs was 66%, 26.3% (31 cases) had grade 3 and above TEAEs, and 9 (8%) discontinued due to drug-related TEAEs.

 

The effect is amazing! Eli Lilly and Merck announces latest data on BTK C481S inhibitor.

 

 

 

The effect is amazing! Eli Lilly and Merck announces latest data on BTK C481S inhibitor.

(source:internet, reference only)


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