FDA Accepts sBLA for Zanubrutinib Plus Obinutuzumab for R/R Follicular Lymphoma

FDA

The FDA has accepted a supplemental biologics license application (sBLA) seeking the approval of zanubrutinib (Brukinsa) in combination with obinutuzumab (Gazyva) in the treatment of adult patients with relapsed/refractory follicular lymphoma who received at least 2 prior lines of therapy.¹

The sBLA is supported by data from the phase 2 ROSEWOOD trial (NCT03332017). Data from the primary analysis showed that at a median follow-up of 12.5 months, patients with pretreated follicular lymphoma administered zanubrutinib plus obinutuzumab (n = 145) experienced an overall response rate (ORR) of 68.3% (95% CI, 60.0%-75.7%) compared with 45.8% (95% CI, 34.0%-58.0%) for those treated with obinutuzumab alone (n = 72; P = .0017).² The complete response (CR) rate was 37.2% (95% CI, 29.4%-45.7%) in the combination arm vs 19.4% (95% CI, 11.1%-30.5%) in the monotherapy arm (P = .0083). The 18-month duration of response (DOR) rate in the experimental arm was 70.9% vs 54.6% for the control arm.

Updated data showed that at a median follow-up of 20.2 months, the combination elicited an ORR of 69.0% (95% CI, 60.8%-76.4%) compared with 45.8% (95% CI, 34.0%-58.0%) for obinutuzumab monotherapy (P = .0012). The CR rates were 39.3% and 19.4%, respectively (P = .0035), and the median duration of CRs (DOCR) were not estimable (NE; 95% CI, 26.5-NE) and 26.5 months (95% CI, 2.7-NE), respectively.³ Moreover, the median DOR was NE (95% CI, 25.3-NE) and 14.0 months (95% CI, 9.2-25.1), respectively, and the 18-month DOR rates in the investigative and control arms were 69.3% (95% CI, 57.8%-78.2%) and 41.9% (95% CI, 22.6%-60.1%). The 18-month DOCR rates were 87.4% (95% CI, 73.8%-94.2%) and 51.1% (95% CI, 21.0%-74.9%), respectively.

The target action date is in the first quarter of 2024 under the Prescription Drug User Fee Act.¹

“Follicular lymphoma is the most common slow-growing non-Hodgkin lymphoma, but there are limited treatment options for patients whose condition has progressed after 2 lines of therapy. We are therefore pleased that [zanubrutinib] is the first BTK inhibitor to demonstrate efficacy in follicular lymphoma and plan to continue worldwide regulatory submissions based on the ROSEWOOD results,” Mehrdad Mobasher, MD, MPH, chief medical officer, Hematology, at BeiGene, stated in a news release.¹ “Importantly, we are grateful to the people living with relapsed or refractory follicular lymphoma who chose to participate in the ROSEWOOD study.”

The randomized, open-label ROSEWOOD study enrolled patients with relapsed/refractory grade I to IIIA follicular lymphoma who received at least 2 prior lines of treatment that included an anti-CD20 antibody and an alkylating agent.^2,3 Patients were also required to have measurable disease, an ECOG performance status of 0 to 2, adequate organ function, and no prior exposure to a BTK inhibitor.

Patients were randomly assigned 2:1 to receive 160 mg of oral zanubrutinib twice per day plus 1000 mg of intravenous obinutuzumab on days 1, 8, and 15 of cycle 1, then on day 1 of cycles 2 to 6, then once every 8 weeks for up to 20 doses, or the same regimen of obinutuzumab alone.

Treatment in the experimental arm continued until disease progression or unacceptable toxicity. Notably, patients in the control arm were allowed to cross over to receive the combination if progressive disease was centrally confirmed or no response was achieved within 12 months.

Stratification factors included number of prior lines of treatment, rituximab (Rituxan)-refractory status, and geographic region.

ORR per 2014 Lugano classification served as the primary end point. Secondary end points included DOR and progression-free survival (PFS) per independent review committee, as well as overall survival (OS), time to next treatment, and safety.

Additional updated data presented at the 2023 ASCO Annual Meeting showed that treatment with zanubrutinib plus obinutuzumab resulted in a median PFS of 28.0 months (95% CI, 16.1-NE) vs 10.4 months (95% CI, 6.5-13.8) with obinutuzumab alone (HR 0.50; 95% CI 0.33-0.75; P = .0007).³ The median OS was NE (95% CI, NE-NE) in the combination arm vs 34.6 months (95% CI, 29.3-NE) in the control arm (HR, 0.62; 95% CI, 0.35-1.07; P = .0845). The 24-month OS rates were 77.3% and 71.4% for the experimental and control arms, respectively.

Safety findings from the primary analysis showed that the most common treatment-emergent adverse effects (TEAEs) included diarrhea (zanubrutinib/obinutuzumab, 18.2%; obinutuzumab, 16.9%), fatigue (15.4%; 14.1%), and pyrexia (13.3%; 9.7%).² The rates for all 3 TEAEs were the same for both arms in the updated analysis.³

References

1. BeiGene announces FDA acceptance of sNDA for fifth Brukinsa indication. News release. BeiGene. July 12, 2023. Accessed July 12, 2023. https://ir.beigene.com/news/beigene-announces-fda-acceptance-of-snda-for-fifth-brukinsa-indication/5e78f817-3655-4679-ab15-45715fddf585/
2. Zinzani PL, Mayer J, Auer R, et al. Zanubrutinib plus obinutuzumab (ZO) versus obinutuzumab (O) monotherapy in patients (pts) with relapsed or refractory (R/R) follicular lymphoma (FL): Primary analysis of the phase 2 randomized ROSEWOOD trial. J Clin Oncol. 2022;40(suppl 16):7510. doi:10.1200/JCO.2022.40.16_suppl.7510
3. Flowers C, Zinzani PL, Mayer J, et al. Zanubrutinib plus obinutuzumab versus obinutuzumab in patients with relapsed/refractory follicular lymphoma: Updated analysis of the ROSEWOOD study. J Clin Oncol. 2023;41(suppl 16):7545. doi:10.1200/JCO.2023.41.16_suppl.7545