Zanubrutinib Combined with R-CHOP in Previously Untreated Non-Germinal Center B-Cell (GCB) Diffuse Large B-Cell Lymphoma (DLBCL) Patients with BCL2 and MYC Protein Co-Expression: A Multicenter, Phase II Study

Introduction: DLBCL is the most common subtype of lymphoma, accounting for up to 40% of lymphoma cases worldwide and can be classified into GCB and non-GCB by immunohistochemistry (IHC). R-CHOP is the standard first-line treatment of DLBCL. Patients with non-GCB DLBCL or co-expression of BCL2 and MYC have a worse outcome with R-CHOP treatment. This study aimed to investigate the efficacy and safety of the new-generation BTKi zanubrutinib combined with R-CHOP in previously untreated non-GCB DLBCL patients with BCL2 and MYC protein co-expression. At 2023 ASH, preliminary efficacy and safety results of 27 patients were reported. As of cut-off date, all 44 patients have been enrolled, and here, we report the updated results. Methods: Eligible patients were previously untreated non-GCB DLBCL confirmed by Hans' algorithm, aged 18 years or older, MYC positive (defined as ≥40%) and BCL-2 positive (defined as ≥50%) determined by IHC, and ECOG PS of 0-2. Patients were treated with R-CHOP combined with zanubrutinib (160 mg, PO, BID) of each 21-day cycle for 6 cycles. After 4 cycles, response was assessed by CT per Lugano 2014 criteria, and patients who had PD would discontinue the treatment. After completion of 6 cycles treatment, patients who were assessed with CR (by PET-CT) would proceed to zanubrutinib (160 mg, PO, BID) maintenance treatment for up to one year, or until PD, intolerance of toxicity, or death. The primary endpoint was 3-year EFS rate assessed by investigator, defined as the time from the start of treatment until disease progression, relapse after CR, initiation of subsequent systemic anti-tumor treatment due to PET-positive or biopsy-confirmed residual disease after 6 cycles of treatment, or death from any cause. Secondary endpoints included ORR, CR rate, 3-year PFS rate, 3-year OS rate and safety. The safety analysis set (SAS) included all subjects who received at least one dose of R-CHOP plus zanubrutinib. The efficacy analysis set (EAS) consisted of all subjects in SAS who had at least one post-baseline efficacy evaluation. Results: From Jan 2022 to Jun 2024, 44 patients were enrolled with a median age of 60.2 (33.2-79.1), 50% (22/44) were male, and 54.5% (25/44) were with IPI ≥3. At the data cut-off date of 30 Jun 2024 (median follow-up: 14.88 mo), SAS included 44 patients, EAS included 40 patients. Thirty-nine patients received 4 treatment cycles and were assessed by CT with CR (n=15) or partial response (n=24); 1 patient experienced symptomatic progression and was confirmed PD by CT at cycle 2, and thus discontinued study treatment. Among the 39 patients, 37 patients completed 6 cycles of treatment and achieved objective response (37/37), with 34 CRs (CR and complete metabolic response) and 3 PRs. Patients with CR proceeded to zanubrutinib maintenance treatment, while 3 patients with PR received salvage therapy decided by the investigator. The median maintenance treatment period was 6.57 (range, 0.33-17.41) mo, and the response was well maintained with CR for all the 34 patients. Eight patients have completed the study treatment and have entered the follow-up phase. The most common hematologic TEAEs were neutropenia (grade 1-2: 21/44, 47.7%; grade ≥3: 1/44, 2.3%) and thrombocytopenia (grade 1-2: 11/44, 25.0%; grade ≥3: 3/44, 6.8%), and non-hematologic TEAEs included alanine aminotransferase increased (grade 1-2: 9/44, 20.5%), aspartate aminotransferase increased (grade 1-2: 5/44, 11.4%), hypokalemia (grade 1-2: 6/44, 13.6%; grade ≥3: 1/44, 2.3%), anemia (grade 1-2: 7/44, 15.9%), infectious pneumonia (grade 1-2: 5/44 11.4%; grade ≥3: 3/44, 6.8%) and hemorrhage (grade 1-2: 8/44, 18.2%; grade ≥3: 1/44, 2.3%). Patients with grade 1/2 AEs were recovered without any special treatment. One patient had hypertension of grade 2 and recovered. No atrial fibrillation/flutter or other cardiovascular events were observed during the treatment. Twelve patients experienced SAEs of thrombocytopenia (n=6), neutropenia (n=2), infectious pneumonia (n=3), and hyperglycemia (n=1), and were recovered. Conclusions: Zanubrutinib plus R-CHOP followed by zanubrutinib maintenance was well tolerated and showed promising responses in untreated non-GCB double-expression DLBCL patients. The study is ongoing and further survival results will be continuously released.