Ibrutinib Plus Venetoclax and A CD20 Monoclonal Antibody Increases MRD Negativity in Untreated MCL

Ibrutinib/Venetoclax/CD20 Monoclonal Antibody in MCL

| Image credit: © Bipul Kumar - stock.adobe.com

The addition of venetoclax (Venclexta) to ibrutinib (Imbruvica) plus an anti-CD20 monoclonal antibody demonstrated higher rates of minimal residual disease (MRD) negativity compared with ibrutinib and a CD20 monoclonal antibody alone in patients with previously untreated mantle cell lymphoma (MCL), according to initial results from the randomized phase 2 OASIS II trial (NCT04802590), presented at the 2025 ASCO Annual Meeting.

A total of 101 patients were randomized evenly between the 2 arms. At the end of induction (cycle 6), MRD negativity as assessed by droplet digital PCR (ddPCR) was achieved in 82.1% (80% CI, 71.7%-89.7%) of patients treated with the triplet (n = 39) vs 53.8% (80% CI, 42.4%-65.0%) in the ibrutinib plus CD20 monoclonal antibody group (n = 39), meeting the study’s primary efficacy end point.

The overall response rate (ORR) per Lugano criteria was 80.0% in the triplet arm and 78.5% in the doublet arm. Complete response (CR) rates were 64.0% vs 56.9%, and partial response (PR) rates were 16.0% vs 21.6%, respectively. Stable disease and progressive disease occurred in 3.9% and 2.0% of patients in the ibrutinib/anti-CD20 arm, respectively, with no cases reported in the triplet arm. Non-evaluable responses were reported in 15.7% and 20.0% of patients in the doublet and triplet arms, respectively.

OASIS II Study Breakdown

The OASIS II trial enrolled patients with histologically confirmed, previously untreated, stage II to IV MCL between 18 and 80 years of age at the time of informed consent. An ECOG performance status of 0 to 2 was also required.

Patients were randomized to receive either ibrutinib plus a CD20 monoclonal antibody (Arm A) or ibrutinib, venetoclax, and a CD20 monoclonal antibody (Arm B). The study treatment was administered according to protocol-specific dosing schedules, with therapy continued until disease progression, unacceptable toxicity, initiation of alternative treatment, or withdrawal of consent.

The primary objectives of the study were MRD rate, measured using ddPCR in bone marrow and/or peripheral blood at the end of induction; progression-free survival; and overall survival.

To support correlative analyses, MRD assessments were performed on bone marrow and peripheral blood samples using ddPCR. Stratification factors included age (younger than 66 years vs 66 years or older), country (France, UK, Belgium), and Mantle Cell Lymphoma International Prognostic Index (MIPI) risk category. Analysis populations included the informative MRD set, comprising patients with detectable MRD at baseline; the non-informative MRD set, consisting of patients with noninformative MRD results at baseline; and the safety set, which included all patients who received at least one dose of study drug.

Baseline Patient Demographics

A total of 101 patients were randomized to receive either ibrutinib plus CD20 monoclonal antibody (n = 51) or ibrutinib, venetoclax, and CD20 monoclonal antibody (n = 51).

Within the safety set, the median age was 65 years for the ibrutinib/anti-CD20 arm and 66 years for the triplet arm. Male patients represented 80.4% and 74.0% of the safety population in these respective arms.

Most patients had Ann Arbor stage IV disease, reported in 88.2% of patients in arm A and 88.0% in arm B. Regarding MIPI risk stratification, 27.5% and 26.0% of patients in arms A and B, respectively, were low risk; 43.1% and 46.0% were intermediate risk; and 29.4% and 28.0% were high risk.

Blastoid variant histology was rare, identified in 2.0% of patients in arm A and 6.1% in arm B.

In total, 34.3% of those treated with the doublet and 47.6% of those treated with the triplet met the criteria for greater than 30% Ki-67 positivity at diagnosis. Regarding TP53 mutation status, more than 10.0% of patients displayed P53 mutations at diagnosis, although exact proportions are unclear from the extracted image data.

In the MRD-informative subset (n = 39), the median ages were 67 years in the doublet arm and 63 years with the triplet. Male patients accounted for 79.5% and 71.8% of these respective groups. Stage IV disease was present in 94.9% and 89.7% of patients, and the proportion of patients in the high MIPI risk category was 38.5% in arm A vs 30.8% in arm B. A Ki-67 score over 30% was observed in 34.6% and 50% of patients in the 2 arms, respectively.

Safety Analysis

Regarding safety, a higher incidence of hematologic adverse effects (AEs) was observed in the triplet vs doublet arm.

Among all reported AEs, neutropenia was the most frequently observed (42% in the triplet arm vs 13.7% in the doublet arm). Other common any-grade AEs included diarrhea (32% vs 23.5%), arrhythmia (22.0% vs 7.8%), respiratory tract infection (20.0% vs 5.9%), and lymphopenia (14.0% vs 7.8%). Grade 3 or higher neutropenia was reported in 34% of patients receiving triplet therapy vs 11.8% in the doublet arm. Other grade 3 or higher AEs in the triplet arm included lymphopenia (10.0% vs 3.9%), arrhythmia (10.0% vs 2.0%), hepatitis (6.0% vs 3.9%) respiratory tract infections (6.0% vs 3.9%).

Frequently reported serious adverse effects (SAEs) included arrhythmia (12.0%; 2.0%) and respiratory tract infections (6.0%; 3.9%). Grade 3 or higher SAEs included respiratory tract infection (4.0% vs 3.9%) and arrhythmia (6.0% vs 2.0%).

Reference

Le Gouill S, de Wilde V, Eyre T, et al. Ibrutinib, venetoclax plus CD20 monoclonal Ab: initial results of OASIS II, a prospective randomized phase 2 trial in previously untreated mantle cell lymphoma patients. J Clin Oncol. 2025;43(suppl 16):7044. doi:10.1200/JCO.2025.43.16_suppl.7044