FDA grants accelerated approval to zanubrutinib (Brukinsa) + Grayva (obinutuzumab) for relapsed or refractory follicular lymphoma

The regulatory decision was supported by data from the phase II ROSEWOOD trial (NCT03332017), which showed that at a median follow-up of 20.2 months, patients treated with the combination (n = 145) experienced an overall response rate (ORR) of 69% (95% CI, 60.8%-76.4%) compared with 46% (95% CI, 34%-58%) for those given obinutuzumab alone (n = 72; two-sided P = .0012). The complete response (CR) rates were 39.3% and 19.4%, respectively (P = .0035). The 18-month duration of response (DOR) rates were 69.3% (95% CI, 57.8%-78.2%) for zanubrutinib plus obinutuzumab vs 41.9% (95% CI, 22.6%-60.1%) for obinutuzumab monotherapy. The median DOR was not estimable (NE; 95% CI, 25.3 months–NE) with the combination vs 14.0 months (95% CI, 9.2-25.1) for obinutuzumab alone.

The median duration of CR (DOCR) was NE (95% CI, 26.5-NE) in the combination arm and 26.5 months (95% CI, 2.7-NE) in the control arm. 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 study enrolled patients with grade 1 to 3a relapsed/refractory follicular lymphoma who received at least 2 prior lines of therapy that included an anti-CD20 antibody and an alkylating agent. Patients were also required to have measurable disease, an ECOG performance status of 0 to 2, and adequate organ function. Prior treatment with a BTK inhibitor was not permitted.

Patients were randomly assigned in a 2:1 fashion to receive oral zanubrutinib at 160 mg twice per day plus obinutuzumab, or obinutuzumab alone. In both arms, obinutuzumab was administered at 1000 mg on days 1, 8, and 15 of cycle 1, then on day 1 of cycles 2 to 6, and then once every 8 weeks thereafter for up to a maximum of 20 doses. ORR per independent review committee (IRC) assessment served as the trial's primary end point. Secondary end points included IRC-assessed DOR and progression-free survival (PFS); overall survival (OS); time to next treatment (TTNT); and safety. Additional data showed that zanubrutinib plus obinutuzumab elicited a median PFS of 28.0 months (95% CI, 16.1-NE) vs 10.4 months (95% CI, 6.5-13.8) for obinutuzumab alone (HR, 0.50; 95% CI, 0.33-0.75; P = .0007). The median OS was NE (95% CI, NE-NE) and 34.6 months (95% CI, 29.3-NE), respectively (HR, 0.62; 95% CI, 0.35-1.07; P = .0845). The 24-month OS rates were 77.3% for the combination and 71.4% for obinutuzumab monotherapy.

Patients in the experimental arm experienced a median TTNT that was NE (95% CI, 33.4-NE) vs 12.2 months (95% CI, 8.5-17.3) for those in the control arm (HR, 0.34; 95% CI, 0.22-0.52; P < .0001).

Regarding safety, the most common any-grade nonhematologic treatment-emergent adverse effects (TEAEs) consisted of diarrhea (zanubrutinib/obinutuzumab, 18.2%; obinutuzumab, 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 infusion-related reaction (2.8%; 9.9%). Grade 3 or higher nonhematologic TEAEs included pneumonia (zanubrutinib/obinutuzumab, 9.8%; obinutuzumab, 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%), infusion-related reaction (0.7%; 4.2%), and hypertension (0.7%; 1.4%).