Zanubrutinib (BRUKINSA) is a small molecule inhibitor of Bruton’s tyrosine kinase (BTK) discovered by BeiGene scientists that is currently being evaluated globally in a broad clinical program as a monotherapy and in combination with other therapies to treat various B-cell malignancies. Because new BTK is continuously synthesized, BRUKINSA was specifically designed to deliver complete and sustained inhibition of the BTK protein by optimizing bioavailability, half-life, and selectivity. With differentiated pharmacokinetics compared to other approved BTK inhibitors, BRUKINSA has been demonstrated to inhibit the proliferation of malignant B cells within a number of disease-relevant tissues.
Updated data from the Phase II ROSEWOOD study (NCT03332017), of zanubrutinib in combination with obinutuzumab were presented in a poster session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting. The study’s primary endpoint was the 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.
A total of 217 patients were randomized (145 for ZO; 72 for O). The median age was 64 years. Of the 217 patients, 114 (52.5%) had a high Follicular Lymphoma International Prognostic Index (FLIPI) score at screening, and 123 (56.7%) patients had high tumor burden criteria according to Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. The median number of prior lines of therapy was 3 (2–11). In zanubrutinib plus obinutuzumab combination arm ORR was 69.0% (ZO) vs. 45.8% in obinutuzumab arm. Complete response rate was 39.3% with zanubrutinib plus obinutuzumab (ZO) vs 19.4% with obinutuzumab (O) only, the 18-month duration of response rate was 69.3% with zanubrutinib plus obinutuzumab (ZO) vs 41.9% with obinutuzumab (O); median PFS was 28.0 month with ZO vs 10.4 months with obinutuzumab. The Estimated OS rate at 24 months was 77.3% with zanubrutinib plus obinutuzumab (ZO) and 71.4% with obinutuzumab only, with median OS not reached in either arm.
As far as safety is concerned the 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 patients on obinutuzumab. When adjusted for duration of treatment exposure, incidences of infection and cytopenia were similar, and the incidence of all grades of hemorrhage was 2.4 (ZO) vs 1.3 (O) persons per 100 person-months. Two patients in each treatment group reported major hemorrhage. Incidences of atrial fibrillation and hypertension were low and similar in both treatment arms.
“I believe that in order to understand where this combination fits in the follicular lymphoma treatment landscape, we should test it against established second-line regimens, such as lenalidomide-based regimens.”–Expert Opinion.
The ROSEWOOD study revealed that the combination of zanubrutinib and obinutuzumab exhibited significant effectiveness and manageable safety in heavily treated patients with relapsed/refractory follicular lymphoma (R/R FL). Further analysis with a longer follow-up period demonstrated a notable increase in the complete response rate and extended progression-free survival (PFS) and time to next treatment (TTNT) when compared to obinutuzumab alone. This favorable outcome was consistently observed across important subgroups. The combination of zanubrutinib and obinutuzumab showcases a promising risk-benefit profile and has the potential to serve as an innovative combination therapy for patients with R/R FL. Currently, a Phase III study known as MAHOGANY (NCT05100862) is underway, investigating zanubrutinib plus obinutuzumab in patients who have previously received ≥1 lines of systemic therapy