2021 ASCO express Zebutinib combined with PI3Kδ inhibitor Zandelisib for the treatment of relapsed/refractory B-cell malignancies

The 2021 American Society of Clinical Oncology (ASCO) annual meeting will be held online from June 4 to 8.
As one of the most authoritative academic exchange events in the global oncology field, the ASCO annual meeting will show many international frontiers and preparations to scholars around the world.
Scientific research results and clinical data of clinical oncology that are of interest
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Zebutinib (Zanubrutinib) is a new BTK inhibitor independently developed by BeiGene.
It was approved by the U.
S.
FDA in November 2019.
Zebutinib was approved in China on June 3, 2020.
It is used for treatment at least in the past.
Adult MCL and CLL/SLL patients who have undergone one treatment, as a new generation of anti-cancer BTK inhibitors independently developed by China to go abroad, not only achieved good results in the single-agent treatment of MCL, CLL and WM, but also compared with other targeted drugs.
Combination therapy is still being explored and tried
.

This article specially invites Professor Ma Jun, Director of Harbin Institute of Hematology and Tumor, to interpret the preliminary results of Zebutinib combined with Zandelisib in the treatment of relapsed/refractory B-cell malignancies
.

Research background Simultaneous inhibition of PI3Kδ and BTK pathways may overcome the resistance of single pathway targeted drugs
.

Studies have shown that dual inhibition of pathways has shown synergistic effects in cell line experiments2
.

Zandelisib is an oral PI3Kδ inhibitor, and zebutinib is an oral BTK inhibitor.
Based on the efficacy of the two as a single agent in the treatment of B-cell malignancies, the researchers speculate that the combination of Zandelisib and zebutinib can achieve good tolerability, and May further improve the depth and durability of relief
.

Research method This is a multi-cohort phase 1b study, which included patients with FL, CLL, MZL, MCL, DLBCL, or high-grade B-cell lymphoma (HGBCL), who had been treated for ≥1 times, bone marrow and organ function were good, and ECOG≤2 , And have not received PI3Ki or BTKi treatment in the past
.

For this combination therapy, every 28-day cycle is divided into two dose groups, group A: Zandelisib 60 mg once a day for 2 consecutive cycles, and once a day on the first to 7 days in the subsequent 28-day cycle , Zebutinib 160mg 2 times a day
.

Group B: Zebutinib 80 mg twice a day in a 28-day cycle from the first cycle, and Zandelisib 60 mg once a day on days 1-7
.

The dose-limiting toxicity (DLT) observation period of group A was 28 days, and the observation period of group B was extended to 56 days
.

The remission is assessed at 3, 7, and 13 months, and then every 6 months until the disease progresses
.

Study results A total of 20 patients were enrolled at baseline, 7 in group A, and 13 in group B: 8 FL, 5 CLL, 2 DLBCL, 2 HGBCL, 2 MZL, and 1 MCL
.

The median age was 70 years (range 44-85), and the median previous treatment was 2 (1-8)
.

The median follow-up was 2.
9 months (0.
5-17.
4+)
.

Efficacy The remission rate in 16 patients with indolent NHL and MCL was 100% (2 CR, 14 PR), including FL (2 CR, 6 PR), CLL (5 PR), MCL (1 PR) And MZL (2 cases of PR)
.

It is a pity that patients with aggressive B-cell lymphoma have not been relieved from follow-up to the date of publication
.

In terms of safety and safety, there was no DLT in group A, and 4 patients had adverse events (AE) ≥ grade 3 after 28 days, including grade 4 neutropenia (1 case) and grade 3 neutropenia (3 cases) , Fatigue and CMV colitis (1 case), grade 3 AST/ALT and skin rash (1 case) and grade 3 AST/ALT (1 case)
.

In group B, two patients developed grade 3 AST/ALT DLT in the second cycle.
One patient successfully resumed drug treatment, and one patient discontinued treatment due to reappearance of DLT
.

Other grade 3 AEs included: TLS, neutropenia, and thrombocytopenia in 1 patient (CLL), and neutropenia in 2 patients (FL, DLBCL)
.

Research conclusions Zebutinib combined with Zandelisib is well tolerated in the treatment of relapsed/refractory B-cell malignancies, and achieves higher ORR in R/R indolent B-cell malignancies
.

Experts commented that in recent years, due to the emergence of new targeted drugs, the treatment effect and survival of relapsed/refractory B-cell lymphoma have been improved to a certain extent
.

However, there is still a lot of room for exploration, and it is hoped that the survival period and quality of life of patients can be further improved
.

The abnormal activation of the BCR signaling pathway is usually related to the occurrence and development of lymphoma.
As an important part of the BCR pathway, BTK and PI3K have become an important direction for the treatment of B-cell malignant tumors
.

BTK inhibitor single-agent or combined treatment regimens have shown surprising effects in a variety of lymphomas such as MCL, CLL/SLL, WM, FL and DLBCL
.

Previous studies have shown that CD20 monoclonal antibody combined with BTK inhibitors have certain anti-tumor activity in a variety of non-Hodgkin’s lymphomas 3-5, but the study of BTK inhibitors combined with PI3Kδ inhibitors is rarely reported
.

This phase 1b study initially confirmed the efficacy and safety of Zebutinib combined with Zandelisib in the treatment of relapsed/refractory B-cell malignancies
.

Although the median follow-up was short, it achieved a higher remission rate in indolent NHL and MCL patients, and the overall safety was tolerable
.

The research results support the further exploration of Zebutinib combined with Zandelisib in indolent NHL and MCL, and the exploration of more valuable biomarkers for clinical guidance
.

Professor Ma Jun, Director, Chief Physician, Professor, and Doctoral Supervisor of the Harbin Institute of Hematology and Oncology, Chairman of the Supervisory Board of the Chinese Society of Clinical Oncology (CSCO) Vice Chairman of the Asian Society of Clinical Oncology, Chairman of the Chinese Society of Clinical Oncology Against Leukemia, National Health Commission Capabilities Leader of the Expert Group of the Lymphoma Specialist Construction Project of the Construction and Continuing Education Center, Honorary Consultant of the Nursing Group of the Anti-Lymphoma Alliance of the Chinese Society of Clinical Oncology References: 1.
2021ASCO，75532.
Blood.
2015 Apr 2;125(14):2306-9.
3 .
N Engl J Med 2019; 381:432-4434.
Lancet Oncol.
2016 Jan;17(1):48-56.
5.
N Engl J Med.
2018 Jun 21;378(25):2399-2410.
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