Zanubrutinib Plus Obinutuzumab Elicits Improved Responses in Relapsed/Refractory Follicular Lymphoma

The addition of zanubrutinib to obinutuzumab in patients with relapsed/refractory follicular lymphoma demonstrated improved overall response rates, progression-free survival, and overall survival.

The addition of zanubrutinib to obinutuzumab in patients with relapsed/refractory follicular lymphoma resulted in an improved overall response rate (ORR), over a doubling of median progression-free survival (PFS), and better overall survival (OS) vs with obinutuzumab monotherapy, according to findings from the phase 2 ROSEWOOD trial (NCT03332017) presented at the 2022 American Society of Clinical Oncology Annual Meeting.

Data from ROSEWOOD, presented by Pierre Luigi Zinzani, MD, from Institute of Hematology, “Seràgnoli,” University of Bologna, Italy, demonstrated that after a median follow-up of 12.5 months, the median PFS was 27.4 months in the zanubrutinib plus obinutuzumab arm vs 11.2 months in the obinutuzumab monotherapy arm (HR, 0.51; 95% CI, 0.32-0.81; P = .004) and the 18-month OS rate was 85.4% vs 72.6%, respectively (HR, 0.44; 95% CI, 0.22-0.88).1 The study was not powered to detect a difference in OS.

The trial’s primary endpoint, ORR, was 68.3% with zanubrutinib plus obinutuzumab vs 45.8% with obinutuzumab alone (P = .0017), with a complete response (CR) rate of 37.2% vs 19.4% (P = .0083),respectively.1

In the phase 2 DAWN study (NCT01779791), ibrutinib (Imbruvica) was assessed in this same setting, and yielded an ORR of 20.9% and a CR rate was 11%. Additionally, the median PFS was 4.6 months.2 DAWN did not meet its primary endpoint.

No unexpected safety findings were associated with the zanubrutinib plus obinutuzumab combination, leading the study authors to conclude in their poster that “zanubrutinib plus obinutuzumab has a favorable benefit-risk profile and represents a potential combination therapy for patients with relapsed/refractory follicular lymphoma,” as approved treatment options are limited and associated with significant toxicities.

Patients eligible for the ROSEWOOD trial had relapsed/refractory follicular lymphoma and received 2 or more prior systemic treatments, including an anti-CD20 antibody and an alkylator-based combination therapy. A total of 217 patients enrolled and were randomized 2:1 to receive either zanubrutinib plus obinutuzumab or obinutuzumab monotherapy. Obinutuzumab was given in both arms on days 1, 8, and 15 of cycle 1; day 1 of cycles 2 through 6; and then every 8 weeks (up to 20 doses maximum). Zanubrutinib was administered at 160 mg twice daily until progressive disease or unacceptable toxicity.

Patients with confirmed progressive disease or no response at 12 months in the obinutuzumab arm were allowed to crossover to the combination regimen. Primary analysis cutoff was October 8, 2021. In the combination arm, 50% of patients were still on treatment at data cutoff. In the obinutuzumab arm, 26% of patients were still on treatment, with the major reason for discontinuation being disease progression followed by crossover to combination therapy.

The median number of prior lines of therapy was 3 in each treatment arm, and about one fourth in each arm had 3 or more prior lines. Approximately one third of patients (34.5%) in the combination arm and 40.3% in the obinutuzumab monotherapy arm had an elevated level of lactate dehydrogenase at screening. Approximately half of patients in each arm were refractory to rituximab (Rituxan); 32.4% in the combination arm vs 40.3% in the obinutuzumab alone arm were refractory to their most recent line of therapy.

The superiority of zanubrutinib plus obinutuzumab over obinutuzumab alone with regard to the ORR was consistent across the subgroups. The 18-month duration of response rate was 70.9% in the combination arm and 54.6% in the obinutuzumab alone arm. The ORR by investigator after crossover was an exploratory endpoint. The ORR for 29 patients who crossed over to zanubrutinib plus obinutuzumab was 24.1%.

The median time to next anti-lymphoma treatment was not estimable in the zanubrutinib plus obinutuzumab arm vs 12.1 months in the obinutuzumab alone arm (HR, 0.37; 95% CI, 0.23-0.60; P< .0001).

“I believe that in order to understand where this combination fits in the follicular lymphoma treatment landscape, we should test it against established second-line regimens, such as lenalidomide-based regimens,” discussant Juan P. Alderuccio, MD, from the Sylvester Comprehensive Cancer Center, University of Miami, concluded.

References
1. 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): abstr 7510.
2. Gopal AK, Schuster SJ, Fowler NH, et al. Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study. J Clin Oncol. 2018;36(23):2405-2412. doi:10.1200/JCO.2017.76.8853.