Zanubrutinib Plus Obinutuzumab Approaches EU Approval in R/R Follicular Lymphoma

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the approval of zanubrutinib (Brukinsa) in combination with obinutuzumab (Gazyva) for use in adult patients with relapsed or refractory follicular lymphoma who have previously received at least 2 lines of systemic treatment.¹

The positive opinion is supported by data from the phase 2 ROSEWOOD trial (NCT03332017), which showed that a median follow-up of 20.2 months, the doublet elicited an overall response rate (ORR) of 69.0% (95% CI, 60.8%-76.4%) vs 45.8% (34%-58%) with obinutuzumab alone (P = .0012), translating to a difference of 22.7%.² Of those who responded to zanubrutinib plus obinutuzumab, 39.3% had a complete response (CR) and 29.7% experienced a partial response (PR); in the obinutuzumab-only arm, these rates were 19.4% and 26.4%, respectively.

“Follicular lymphoma remains an incurable disease and an ongoing challenge for healthcare providers. Despite advances in the treatment landscape, patients often relapse and experience shorter response times to subsequent treatments,” Mehrdad Mobasher, MD, MPH, chief medical officer of Hematology at BeiGene, stated in a press release.¹ “Today’s positive CHMP opinion is a testament to our continued commitment to bringing innovative medicines to patients and demonstrates the value of [zanubrutinib], which—if approved in follicular lymphoma—will become the BTK inhibitor with the broadest label in the European Union.”

Patients with grade 1 to 3A relapsed or refractory follicular lymphoma were enrolled to the ROSEWOOD trial.² To participate, they needed to be at least 18 years of age and have received at least 2 prior systemic therapies, which must have included an anti-CD20 antibody and an alkylating agent. They also were required to have measurable disease, an ECOG performance status ranging from 0 to 2, and acceptable organ function. They could not have had prior BTK inhibition.

Study participants were randomized 2:1 to receive zanubrutinib at 160 mg twice daily in combination with obinutuzumab at 1000 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 to 6, and then every 8 weeks up to a maximum of 20 doses (arm A; n = 145) or single-agent obinutuzumab (arm B; n = 72). Patients received treatment until progressive disease or intolerable toxicity. Those on the monotherapy arm were allowed to cross over to the doublet arm if they experienced disease progression or were not responsive after 1 year of treatment.

They were stratified by number of prior lines of therapy, whether they were refractory to rituximab (Rituxan), and geographic region.

The primary end point of the study was ORR by independent review and Lugano 2014 classification, and other important end points included DOR, PFS, TTNT, OS, and safety.

The median age of patients across the arms 64 years (range, 31-88). An ECOG performance status of 1 or higher was observed in 40.6% and 57% of patients in arms A and B, respectively. A FLIPI score of 3 or higher was seen in 53% and 51.4% of patients, and Ann Arbor stage III to IV disease was observed in 82.1% and 83.3% of patients, respectively. Additionally, 15.9% of those in arm A and 16.7% of those in arm B had bulky disease, and 33.8% and 40.3% of patients, respectively, had high lactate dehydrogenase levels at the time of screening. High tumor burden was observed in 57.2% of those in arm A and 55.6% of those in arm B.

Additionally, the median number of prior lines of therapy was 3 for both arms, with a range of 2 to 11 lines. Rituximab-refractoriness was noted in 53.8% of those in arm A vs 50% of those in arm B; 32.4% and 40.3% of patients, respectively, were refractory to the last line of therapy that they received. Other prior therapies received in arms A and B included chemoimmunotherapy (98.6%; 98.6%), anthracyclines (81.4%; 79.2%), cyclophosphamide (93.8%; 94.4%), and bendamustine (Bendeka; 54.5%; 55.6%).

Long-term data presented at the 17th Annual International Conference on Malignant Lymphoma showed that the median duration of response (DOR) reported with the doublet was not estimable (NE; 95% CI, 25.3-NE) compared with 14 months (95% CI, 9.2-25.1) with the monotherapy. In the doublet and monotherapy arms, the 18-month DOR rates were 69.3% (95% CI, 57.8%-78.2%) and 41.9% (95% CI, 22.6%-60.1%), respectively. Additionally, the duration of CR (DOCR) with zanubrutinib plus obinutuzumab was NE (95% CI, 26.5-NE) vs 26.5 months (95% CI, 2.7-NE) with obinutuzumab alone, and the DOCR rates at 18 months were 87.4% (95% CI, 73.8%-94.2%) and 51.1% (95% CI, 21.0%-74.9%), respectively.

The addition of zanubrutinib to obinutuzumab resulted in a 50% reduction in the risk of disease progression or death compared with obinutuzumab alone, at 28 months (95% CI, 16.1-NE) and 10.4 months (95% CI, 6.5-13.8), respectively (HR, 0.50; 95% CI, 0.33-0.75; P = .0007). The median time to next treatment (TTNT) was NE (95% CI, 33.4-NE) vs 12.2 months (95% CI, 8.5-17.3), respectively. Moreover, the median overall survival (OS) with the doublet was NE (95% CI, NE-NE) vs 34.6 months (95% CI, 29.3-NE) with the monotherapy (HR, 0.62; 95% CI, 0.35-1.07; P = .0845); the 24-month OS rates were 77.3% and 71.4%, respectively.

The doublet was found to be well tolerated overall, with safety findings in line with what has been previously reported with both agents.¹

Higher rates of adverse effects (AEs) were observed with zanubrutinib plus obinutuzumab vs single-agent obinutuzumab, as well as a higher incidence of any-grade petechiae and herpes zoster infection.² However, infusion-related reactions were more commonly experienced with the monotherapy in the overall population.

The any-grade nonhematologic treatment-emergent AEs that were most frequently experienced in arms A and B, respectively, included diarrhea (18.2%; 16.9%), fatigue (15.4%; 14.1%), pyrexia (13.3%; 19.7%), constipation (13.3%; 8.5%), cough (12.6%; 12.7%), asthenia (11.9%; 8.5%), pneumonia (11.9%; 7%), dyspnea (11.2%; 9.9%), back pain (11.5%; 5.6%), COVID-19 (9.8%; 9.9%), nausea (9.1%; 14.1%), abdominal pain (7.7%; 11.3%), pruritis (7%; 9.9%), and IRR (2.8%; 9.9%). Grade 3 or higher nonhematologic AEs comprised pneumonia (9.8%; 4.2%), COVID-19 (5.6%; 2.8%), pneumonia related to COVID-19 (3.5%; 2.8%), diarrhea (2.8%; 1.4%), febrile neutropenia (2.1%; 1.4%), atrial fibrillation (1.4%; 0%), IRR (0.7%; 4.2%), and hypertension (0.7%; 1.4%).

In June 2023, the FDA accepted a supplemental license application seeking the approval of zanubrutinib and obinutuzumab in adult patients with relapsed or refractory follicular lymphoma who received 2 or more prior lines of therapy.³ The sBLA is also supported by ROSEWOOD data, and under the Prescription Drug User Fee Act, the target action date is in the first quarter of 2024.

References

1. BeiGene receives positive CHMP opinion for Brukinsa (zanubrutinib) in relapsed or refractory follicular lymphoma. News release. BeiGene. October 13, 2023. Accessed October 13, 2023. https://ir.beigene.com/news/beigene-receives-positive-chmp-opinion-for-brukinsa-zanubrutinib-in-relapsed-or-refractory-follicular-lymphoma/53e598e8-4a08-4df2-ae1a-c14c0768cb13/
2. Zinzani PL, Mayer J, Trotman J, et al. Zanubrutinib plus obinutuzumab versus obinutuzumab in patients with relapsed or refractory follicular lymphoma: Updated analysis of the ROSEWOOD study. Presented at: 17th International Conference on Malignant Lymphoma; June 13-17, 2023. Lugano, Switzerland. Abstract 81.
3. BeiGene announces FDA acceptance of sNDA for fifth Brukinsa indication. News release. BeiGene. July 12, 2023. Accessed October 13, 2023. https://ir.beigene.com/news/beigene-announces-fda-acceptance-of-snda-for-fifth-brukinsa-indication/5e78f817-3655-4679-ab15-45715fddf585/