Long-Term ROSEWOOD Data Confirm Efficacy of Zanubrutinib Plus Obinutuzumab in R/R Follicular Lymphoma

The addition of zanubrutinib (Brukinsa) to obinutuzumab (Gazyva) produced superior clinical activity, prolonged survival, and had a favorable toxicity profile compared with obinutuzumab alone in heavily pretreated patients with relapsed/refractory follicular lymphoma, according to updated findings from the phase 2 ROSEWOOD trial (NCT03332017) presented at the 17th Annual International Conference on Malignant Lymphoma (ICML).¹

At a median follow-up of 20.2 months, zanubrutinib plus obinutuzumab induced an overall response rate (ORR) of 69% (95% CI, 60.8%-76.4%) vs 45.8% (95% CI, 34%-58%) with obinutuzumab alone (P = .0012), translating to a 22.7% difference. Among those who responded to the doublet, 39.3% achieved a complete response (CR) and 29.7% had a partial response (PR); these rates were 19.4% and 26.4%, respectively, with the monotherapy (P = .0035).

The median duration of response (DOR) with the combination was not estimable (NE; 95% CI, 25.3-NE) vs 14 months (95% CI, 9.2-25.1). The 18-month DOR rates were 69.3% (95% CI, 57.8%-78.2%) with the combination and 41.9% (95% CI, 22.6%-60.1%) with the monotherapy. The duration of CR (DOCR) was NE (95% CI, 26.5-NE) with zanubrutinib plus obinutuzumab vs 26.5 months (95% CI, 2.7-NE) with obinutuzumab alone; the 18-month DOCR rates were 87.4% (95% CI, 73.8%-94.2%) and 51.1% (95% CI, 21.0%-74.9%), respectively.

Moreover, the median progression-free survival (PFS) was longer with the combination vs the monotherapy, 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 anti-lymphoma treatment (TTNT) was NE (95% CI, 33.4-NE) with the doublet vs 12.2 months (95% CI, 8.5-17.3) with the monotherapy. Regarding overall survival (OS), the median OS was NE (95% CI, NE-NE) vs 34.6 months (95% CI, 29.3-NE), respectively (HR, 0.62; 95% CI, 0.35-1.07; P = .0845), with 24-month OS rates of 77.3% and 71.4%, respectively.

“This longer follow-up analysis provides evidence of the significant CR rate, [and] longer PFS and TTNT, with zanubrutinib plus obinutuzumab vs obinutuzumab alone,” said lead study author Pier Luigi Zinzani, MD, of the Institute of Hematology, “Seràgnoli,” at the University of Bologna, Italy, in a presentation of the data.

The ROSEWOOD trial enrolled patients with grade 1 to 3A relapsed or refractory follicular lymphoma who were 18 years of age or older had received 2 or more prior systemic treatments, including an anti-CD20 antibody and an alkylating agent.1 Patients were also required to have measurable disease, an ECOG performance status of 0 to 2, and adequate organ function. Patients could not have previous exposure to BTK inhibitors.

Patients were randomly assigned 2:1 to receive either zanubrutinib at a twice daily dose of 160 mg plus obinutuzumab at 1000 mg on days 1, 8, and 15 of cycle 1, day 1 of cycles 2 through 6, and then every 8 weeks up to a maximum of 20 doses (arm A) or obinutuzumab monotherapy (arm B). Treatment continued until progressive disease or unacceptable toxicity. Notably, patients in arm B were allowed to cross over to arm A if they developed centrally confirmed progressive disease or did not respond by 12 months of treatment.

Key stratification factors included number of previous lines of therapy, rituximab (Rituxan)-refractory status, and geographic region.

The study’s primary end point was ORR by independent review and Lugano 2014 classification. Other key end points included DOR, PFS, OS, TTNT and safety.

As of June 2021, 217 patients enrolled onto the study at 127 sites across 17 countries; this was the intent-to-treat (ITT) analysis set. Of these, 145 were assigned to arm A and 72 were assigned to arm B.

The median age of patients in arm A was 63 years (range, 31-84) and 65.5 years (range 32-88) in arm B. An ECOG performance status of 1 or higher was seen in 40.6% of patients in arm A and in 57% of those in arm B. In arm A, 53% of patients had a FLIPI score of 3 or more and 82.1% had Ann Arbor stage III to IV disease; these percentages were 51.4% and 83.3%, respectively, in arm B. Moreover, 15.9% and 16.7% of patients, respectively, had bulky disease. High lactate dehydrogenase levels at screening were seen in 33.8% of those in arm A and 40.3% of those in arm B. Per GELF criteria, 57.2% and 55.6% of patients, respectively, had high tumor burden.

The median number of prior lines of therapy was 3 in both arms (range 2-11). Over half (53.8%) of those in arm A were refractory to rituximab and 32.4% were refractory to their most recent line of therapy; in arm B, these rates were 50% and 40.3%, respectively. The percentage of patients who developed PD up to 2 years after first-line treatment was 34.5% in arm A and 41.7% in arm B. Prior therapies administered included chemoimmunotherapy (arm A and B, 98.6%), anthracyclines (81.4%; 79.2%) cyclophosphamide (93.8%; 94.4%), or bendamustine (Bendeka; 54.5%; 55.6%).

As previously reported at the 2022 ASCO Annual Meeting, data from the primary analysis of this trial showed that the combination regimen elicited a superior ORR vs obinutuzumab monotherapy, meeting the primary end point of the trial.2 After a median follow-up of 12.5 months, patients who received the combination achieved an ORR of 68.3% (95% CI, 60%-75.7%) vs 45.8% (95% CI, 34%-58%) with obinutuzumab alone (P = .0017); the CR rates were 37.2% and 19.4%, respectively (P = .0083).

At the data cutoff, 46 patients in arm A and 6 patients in arm B were still on study treatment; 97 and 65 patients, respectively, discontinued treatment. The main reasons for discontinuation included disease progression (arm A, n = 53; arm B, n = 11), adverse effects (AEs; n = 27; n = 9), investigator decision (n = 7; n = 3), and withdrawal of consent (n = 5; n = 2). Seven patients in arm A and 1 patient in arm B discontinued treatment for another unspecified reason. In arm B, 4 patients completed treatment and 35 crossed over to the doublet arm.

Of the patients who received zanubrutinib plus obinutuzumab, the median treatment exposure was 12.2 months (range, 0.5-44.1) vs 6.5 months (range, 0.1-28.7) with obinutuzumab alone. Twelve or more cycles of the combination were completed by 56.7% of patients, and the median relative dose intensity was 98.9% (range, 30.7%-100%). The median number of infusions was 11 in arm A and 9 in arm B (range, 30-20).

Additional data showed that the benefit observed with the combination in terms of responses was consistent regardless of age, number of prior lines of therapy, bulky disease status, FLIPI risk category, refractory status, whether patients progressed up to 6 months after completion of the previously administered line of therapy, or whether they progressed up to 2 years after starting first-line chemotherapy.

Zanubrutinib plus obinutuzumab did not have any unexpected safety signals. The combination was associated with numerically higher rates of most AEs vs obinutuzumab alone, although pyrexia and infusion-related reactions (IRR) were more frequently observed (>5% difference) with the monotherapy in the overall population. Conversely, there was a higher incidence of petechiae and herpes zoster infection of any grade in the combination arm.^1,3

Common any-grade nonhematologic treatment-emergent AEs (TEAEs) included diarrhea (arm A, 18.2%; arm B, 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%).

Nonhematologic TEAEs that were grade 3 or higher included 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%).

Exposure-adjusted incidence rates for TEAEs of special interest were mostly comparable between the treatment arm A and B. These included anemia (0.8%; 1.0%), neutropenia (2.6%; 3.5%), thrombocytopenia (3.5%; 2.9%), atrial fibrillation (0.1%; 0.1%), hypertension (0.3%; 0.6%), infections (5.6%; 5.6%), opportunistic infections (0.2%; 0%), major hemorrhage (0.1%; 0.3%), second primary malignancies (0.4%; 0.4%), skin cancers (0.2%; 0.3%), and tumor lysis (0%; 0.1%). However, differences in any-grade hemorrhage were observed (2.4%; 1.3%).

“Zanubrutinib demonstrated a favorable risk-benefit profile and may represent a potential novel combination therapy for patients with relapsed/refractory follicular lymphoma,” Zinzani concluded.

Based on these findings, the combination of zanubrutinib plus obinutuzumab is being compared with lenalidomide (Revlimid) plus rituximab (Rituxan) in patients with previous exposure to 1 or more lines of systemic therapy in the ongoing phase 3 MAHOGANY trial (NCT05100862).³ 

Editor’s Note: Dr Zinzani reports serving as a consultant or in anadvisory role for Secura Bio, Celltrion, Gilead, Janssen-Cilag, BMS, Servier, Sandoz, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, ADC Therapeutics, Incyte, and BeiGene. He has received other remuneration or served on a Speakers Bureau for Celltrion, Gilead, Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, Eusa Pharma, Kyowa Kirin, Novartis, Incyte, and BeiGene.

References

1. 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.
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 BeiGene highlights significant Brukinsa (zanubrutinib) data at the 17th International Conference on Malignant Lymphoma. Press Release.
3. Beigene. June 15, 2023. Accessed June 21, 2023. https://ir.beigene.com/news/beigene-highlights-significant-brukinsa -zanubrutinib-data