Zanubrutinib plus obinutuzumab versus obinutuzumab in patients with relapsed/refractory follicular lymphoma: Updated analysis of the ROSEWOOD study.
Authors: Flowers Christopher , Zinzani Pier Luigi , Mayer Jiří , Bijou Fontanet , de Oliveira Ana C. , Song Yuqin , Zhang Qingyuan , Merli Michele , Bouabdallah Krimo , Ganly Peter S. , Zhang Huilai , Yuen Sam , Kingsley Ed , Assouline Sarit E. , Auer Rebecca , Kim Pil , Greenbaum Adam , Huang Sha , Delarue Richard , Trotman Judith 
Published: June 2023

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Background: In an early-phase study, the combination of zanubrutinib plus obinutuzumab (ZO) was well tolerated and associated with an early signal of efficacy in patients (pts) with follicular lymphoma (FL) (Tam et al. Blood Adv 2020). ROSEWOOD (NCT03332017) is a phase 2, randomized study designed to assess efficacy and safety of ZO vs obinutuzumab (O) in pts with relapsed/refractory (R/R) FL. Here, we present an updated analysis with a median follow-up of 20.2 mo. Methods: Pts with R/R FL (grade 1–3a) who received ≥2 lines of therapy including an anti-CD20 antibody and alkylating agent were randomized 2:1 to receive ZO or O. Zanubrutinib was given at 160 mg twice daily until progression or unacceptable toxicity. The primary endpoint was overall response rate (ORR) by independent central review. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and safety. Results: A total of 217 pts were randomized (145 for ZO; 72 for O). Median age was 64 years. Of the 217 pts, 114 (52.5%) had a high Follicular Lymphoma International Prognostic Index (FLIPI) score at screening and 123 (56.7%) pts had high tumor burden criteria according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Median number of prior lines of therapy was 3 (range, 2–11). A total of 114 (52.5%) pts were refractory to rituximab; 214 (98.6%) pts received prior immunochemotherapy. Prior exposure to anticancer drugs included anthracyclines (80.6%), cyclophosphamide (94.0%), and bendamustine (54.8%). ORR was 69.0% (ZO) vs 45.8% (O) ( P = 0.0012). Complete response rate was 39.3% (ZO) vs 19.4% (O); 18-mo DOR rate was 69.3% (ZO) vs 41.9% (O); median PFS was 28.0 mo (ZO) vs 10.4 mo (O) (hazard ratio [HR], 0.50 [95% CI: 0.33, 0.75]; P = 0.0007). Median TTNT was not evaluable for ZO and 12.2 mo for O (HR, 0.34 [95% CI: 0.22, 0.52]; P < 0.0001). Estimated OS rate at 24 mo was 77.3% (ZO) and 71.4% (O), with median OS not reached in either arm. Nonhematologic treatment-emergent adverse events of any grade that occurred more frequently for ZO vs O ( > 5% difference) were petechiae (6.3% vs 0%) and herpes zoster infection (6.3% vs 0%); in contrast, pyrexia (13.3% vs 19.7%) and infusion-related reaction (2.8% vs 9.9%) occurred more frequently in pts on O. When adjusted for duration of treatment exposure, incidences of infection and cytopenia were similar, and incidence of all grades of hemorrhage was 2.4 (ZO) vs 1.3 (O) persons per 100 person-months. Two pts in each treatment group reported major hemorrhage. Incidences of atrial fibrillation and hypertension were low and similar in both treatment arms. Conclusions: ZO demonstrated meaningful activity and a manageable safety profile in pts with heavily pretreated R/R FL, representing a potential novel therapy. Clinical trial information: NCT03332017 .