Zanubrutinib Plus Obinutuzumab/Venetoclax Is Safe, Elicits Responses in Older Patients With Untreated MCL

Treatment with zanubrutinib (Brukinsa), obinutuzumab (Gazyva), and venetoclax (Venclexta; the BOVen regimen) was safe and produced responses in older patients with mantle cell lymphoma (MCL), according to data from the phase 2 trial (NCT03824483), which also demonstrated that no new safety signals were reported in this older patient population.¹

Findings presented at the 2024 EHA Congress, demonstrated that at a median follow-up of 11 months (range, 0.8-19.3), the overall response rate (ORR) in efficacy-evaluable patients treated with the BOVen regimen (n = 43) was 98%, including a complete response (CR) rate of 79% and a partial response (PR) rate of 19%.

"The preliminary efficacy is promising with high ORR and high undetectable minimal residual disease [MRD] rates [at 10-5 sensitivity] by cycle 13; however, follow-up is limited,” lead study author Anita Kumar, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, in New York, New York, and colleagues, wrote in a poster presentation of the data.

Notably, at the 2023 ASH Annual Meeting, investigators shared previous data from the phase 2 trial showing that the BOVen combination generated high response rates and 2-year progression-free survival (PFS) rates comparable with historical outcomes for chemoimmunotherapy in high-risk patients with previously untreated, TP53-mutated MCL.²

In this data read-out, investigators shared that at a median follow-up of 23.3 months, the 2-year PFS rate was 72% (95% CI, 56%-92%), and median PFS was not yet reached in the population, meeting the investigation's primary end point of PFS.

In older patients with MCL, chemoimmunotherapy has remained the historical standard-of-care approach; however, chemotherapy-free combinations may represent a new treatment for this patient population. One potential approach is the BOVen regimen.¹

The multicenter, investigator-initiated trial enrolled patients with previously untreated MCL. Patients needed to be at least 65 years of age or have comorbidities precluding them from autologous stem cell transplantation (ASCT), including coronary artery disease; congestive heart failure; pulmonary dysfunction; liver or kidney dysfunction; and expected increased morbidity and mortality due to high-dose therapy/ASCT. Other criteria included an ECOG performance status of 2 or less; an ejection fraction greater than or equal to 35% and less than 45%; impaired pulmonary function test with DLCO less than 50%; absolute neutrophil count greater than 1; platelet count greater than 75; and hemoglobin of 9 or more (unless due to MCL).

All patients received oral zanubrutinib at 160 mg twice daily until the end of treatment or intolerance; intravenous obinutuzumab at 1000 mg with initial dosing on days 1, 8, and 15 during cycle 1, followed by day 1 of cycles 2 through 8; and oral venetoclax at up to 400 mg per day, starting with a 5-week ramp-up period consisting escalating doses of 20 mg per day, 50 mg per day, 100 mg per day, 200 mg per day, and 400 mg per day. Venetoclax was continued until end of treatment or intolerance.

After 24 cycles, the treatment duration was adjusted based on MRD status. Patients achieving CR and undetectable MRD stopped treatment, and those with less than CR and/or detectable MRD continued receiving zanubrutinib and venetoclax. The primary end point was 3-year PFS rate.

Among all patients treated in the older population (n = 46), the median age was 71 years (range, 47-89) and the majority of patients were male (65%). MCL histology included blastoid (9.8%), classic (76%), leukemia phase (15%), or unknown (5%). At baseline, patients had Ki-67 proliferation rates of less than 30% (51%), between 30% and 49% (28%), at least 50% (21%), and unknown (3%). Furthermore, MCL International Prognostic Index classification ranged from low (9.1%), intermediate (20%), high (70%), and unknown (2%).

A total of 83% of patients did not have a 17p deletion per fluorescence in situ hybridization; 28% of patients had TP53-mutated disease by next-generation sequencing; and all patients included in the study were ineligible for transplant due to age (98%) or comorbid disease (2.2%).

Additional data showed that after cycle 3, undetectable MRD at 10^-5 sensitivity occurred in 50% of evaluable patients (n = 21/42), and undetectable MRD at 10^-6 sensitivity was reported in 26% of patients. After cycle 13, these respective rates were 100% (n = 23/23) and 87%.

At data cutoff, 2 patients experienced disease progression, and 1 patient died. One patient was also lost to follow-up.

Regarding safety, any-grade treatment-related adverse effects that occurred in 10% or more of patients included bruising (39%), diarrhea (39%), neutropenia (26%), thrombocytopenia (24%), COVID-19 infection (20%), fatigue (20%), nausea (20%), infusion-related reaction (17%), and anemia (13%).

References

1. Kumar A, Soumerai J, Karmali, R et al. Preliminary safety and efficacy of BOVen (zanubrutinib, obinutuzumab, and venetoclax) for frontline therapy for older patients with mantle cell lymphoma. Presented at: 2024 European Hematology Association Congress; June 13-16, 2023; Madrid, Spain. Abstract P1138.
2. Kumar A, Soumerai J, Abramson JS, et al. A multicenter phase 2 trial of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in patients with treatment-naïve, TP53-mutant mantle cell lymphoma. Blood. 2023;142(Supplement 1):738. doi:10.1182/blood-2023-180069.