Zanubrutinib Combo Earns Accelerated Approval for R/R Follicular Lymphoma

Findings from the ROSEWOOD study (NCT03332017) supported the accelerated approval of zanubrutinib plus obinutuzumab for relapsed/refractory follicular lymphoma.

The FDA has granted accelerated approval to zanubrutinib (Brukinsa) plus obinutuzumab (Gazyva) for the treatment of patients with relapsed/refractory follicular lymphoma following 2 previous lines of treatment, according to a press release from the agency.¹

The approval is based on results from the phase 2 ROSEWOOD trial (NCT03332017), which assessed the efficacy and safety of zanubrutinib plus obinutuzumab compared with obinutuzumab monotherapy in patients with relapsed/refractory follicular lymphoma.²

In the trial, a total of 217 patients were randomly assigned 2:1 to receive either the combination therapy or obinutuzumab alone and were stratified by the number of previous lines of therapy, rituximab (Rituxan)-refractory status, and geographic region. Throughout the 28-day treatment cycles, patients in both arms received intravenous obinutuzumab at 1000 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 to 6, and once every 8 weeks for up to a total of 20 infusions. In the zanubrutinib plus obinutuzumab arm (n = 145), patients received zanubrutinib at 160 mg in addition to obinutuzumab until progressive disease or unacceptable toxicity was reached. Patients from the obinutuzumab arm (n=72) were able to cross over to the combination arm if they experienced progressive disease or stable disease after 1 year of treatment.

The study’s primary end point was overall response rate (ORR) by PET-CT assessment via independent committee review through the Lugano 2014 classification for non-Hodgkin lymphoma. Key secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival (OS), complete response (CR) rate, and safety and tolerability.

At a median follow-up of 20.2 months, the primary end point was met with the ORR for the zanubrutinib/obinutuzumab arm of 69% compared with 46% in the obinutuzumab arm, with a risk difference of 23% (95% CI, 9%-32%; P = .001). The CR rate was 39% in the combination arm compared with 19% in the obinutuzumab arm. In the combination arm, the estimated 18-month CR rate was 87%. The median time to first response was 2.8 months in combination arm (range, 2.0-23.0) and 2.8 months in obinutuzumab arm (2.5-6.5).

The median PFS was 28.0 months (95% CI, 16.1-not estimable [NE]) vs 10.4 months (95% CI, 6.5-13.8) in the combination arm and obinutuzumab arm, respectively (HR, 0.50; 95% CI, 0.33-0.75; P <.001).

Median DOR was not reached in the combination arm and was 14.0 months in the obinutuzumab arm. The estimated 18-month DOR rate in the combination arm was 69%. The estimated OS rates at 24 months were 77% and 71% in the combination and obinutuzumab arms, respectively. The time to next treatment (TTNT) was not estimable in the combination arm and 12.2 months with obinutuzumab. For patients who did not crossover, the median TTNT with obinutuzumab was 32.4 months (95% CI, 21.7-NE). After crossover, ORR was 23%, including 2 patients with CR. Of note, median PFS for these 2 patients was 7.6 months (95% CI, 2.8-16.9), and the median TTNT was 18.2 months (95% CI, 10.7-NE).

Any-grade nonhematologic treatment-emergent adverse effects (TEAEs) that were more common in the combination arm included constipation (13% vs 8%), petechiae (7% vs 0%), and herpes zoster infection (6% vs 0%). Grade 3 or higher TEAEs that were more common in the combination arm included thrombocytopenia (15% vs 7%), pneumonia (10% vs 4%), diarrhea (3% vs 1%), and dyspnea (2% vs 0%). Only pyrexia (13% vs 20%) and infusion-related reactions (3% vs 10%) occurred more frequently in the obinutuzumab arm.

A total of 8% (n=12) of patients in the combination arm and 10% (n=10) in the obinutuzumab arm experienced 1 or more TEAEs that resulted in death. One death was due to anaphylactic reaction after obinutuzumab infusion in the monotherapy arm, and a total of 5 patients (3 in the combination arm and 2 in the obinutuzumab arm) died due to COVID-19.

Eligibility criteria included patients with a diagnosis of grade 1, 2, or 3a follicular lymphoma, patients who received 2 or more previous systemic therapies, and patients who showed a presence of measurable disease. Other eligibility criteria included an ECOG performance status of 0 to 2, the absence of transformation to aggressive B-cell lymphoma, and no previous BTK inhibitor exposure.

References

1. FDA grants accelerated approval to zanubrutinib for relapsed or refractory follicular lymphoma. News release. FDA. March 7, 2024. Accessed March 7, 2024. https://shorturl.at/eILUV
2. Zinzani PL, Mayer J, Flowers CR, et al. ROSEWOOD: A phase II randomized study of zanubrutinib plus obinutuzumab versus obinutuzumab monotherapy in patients with relapsed or refractory follicular lymphoma. J Clin Oncol. 2023;41(33):510 7-5117. doi:10.1200/jco.23.00775