Background: Although advanced stage follicular lymphoma (FL) is incurable, a majority of newly diagnosed patients achieve long-term, durable remissions with immunochemotherapy. However, the toxicity burden of immunochemotherapy is inevitable. Zanubrutinib plus Obinutuzumab, a novel “chemo-free regimen”, showed promising efficacy and a reasonable safety profile in relapsed/refractory (R/R) follicular lymphoma (FL) (Zinzani PL et al, JCO 2023). Given non-overlapping toxicities and motivation to spare patients from conventional chemotherapy, we conducted a phase II study of Zanubrutinib plus Obinutuzumab as first-line systemic therapy for patients with advanced stage FL. Here, we report initial safety and efficacy data from this ongoing Phase II study (NCT06553352).

Methods: Patients with previously untreated FL 1-3a, advanced disease (stage III or IV, or stage II with non-contiguous disease), Eastern Cooperative Oncology Group performance status 0 to 2, and high tumor burden according to Groupe d'Étude des Lymphomes Folliculaires (GELF) criteria will be enrolled. All subjects received Zanubrutinib 160mg BID on days 1-28 of a 28-day cycle for 12 cycles or until disease progression or withdrawal from the trial. Obinutuzumab was received at a dose of 1000 mg on days 1, 8, and 15 of cycle 1 and on day 1 of 2-6 cycles, followed by Obinutuzumab maintenance therapy every 2 months for 2 years. The primary endpoint was complete remission (CR) rate at 12 months, and the secondary endpoint were PFS and OS at 2 years, objective response rate (ORR) and toxicity.

Results: As of September 10, 2024, 26 pts had been enrolled. Median age of all pts was 56 (range: 29-73) years, 46% (12/26) were male, 88% (23/26) had Ann Arbor stage III/IV disease, and 58% (15/26) had a FLIPI score ≥2 at study entry. Median follow-up was 4.9 months (range: 1.2-11.1). All patients underwent safety assessment, with 15% (4/26) Grade 1-2 infusion-related reactions (IRRs）related to Obinutuzumab. Serious AEs were gr 2 pneumonitis (n=1), gr 2 thrombocytopenia (n=1), and intestinal obstruction which was unrelated to treatment (n=1). Ten patients received more than 6 cycles and underwent at least one post-baseline tumor assessment after Cycle 6, with 100% (10/10) achieving an objective response, including 80% (8/10) who achieved CR. Six pts who achieved CR underwent ctDNA assessment at baseline and after Cycle 6, with 67% (4/6) achieved MRD negative.

Conclusion: Zanubrutinib plus Obinutuzumab is well-tolerated and induces high CR rates in pts with previously untreated FL.

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2025
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