The three-drug regimen of zanubrutinib, obinutuzumab, and venetoclax—dubbed the BOVen regimen—is an effective option for patients with TP53-mutated mantle cell lymphoma (MCL), according to results of a phase II study published in Blood.1
This “chemo-free” regimen combining a BTK inhibitor, BCL2 inhibitor, and an anti-CD20 monoclonal antibody yielded a high overall response rate (ORR), high rates of complete response (CR), and a two-year progression-free survival (PFS) that significantly improved upon the existing standard of care for these patients. Based on these findings, the National Comprehensive Cancer Network (NCCN) added the BOVen regimen as a category 2A recommendation for TP53-mutated MCL.2
“Because standard chemoimmunotherapy is inadequate for TP53-mutated MCL, it was previously recommended that these patients seek enrollment in a clinical trial, if possible,” said study researcher Anita Kumar, MD, of Memorial Sloan Kettering Cancer Center in New York. “Now that the BOVen regimen is included in NCCN guidelines, more patients can access an efficacious front-line treatment option.”
The study included 25 patients with untreated TP53-mutated MCL. Patients received zanubrutinib 160 mg twice daily and obinutuzumab 1,000 mg on cycle days 1, 8, and 15 and day 1 of cycles 2 to 8. After two cycles, venetoclax was added with weekly ramp-up dosing to 400 mg daily.
After 24 cycles of therapy, patients whose disease reached CR with undetectable measurable residual disease (uMRD) were able to discontinue treatment. The primary endpoint was two-year PFS, which allowed comparison with outcomes from similar patients in the Nordic MCL2 and MCL3 trials. If 11 or more patients were free from progression at two years, this regimen would be considered worthy of further exploration.
“We hoped to demonstrate that this novel agent combination had superior PFS compared to chemoimmunotherapy. The two-year PFS was approximately 20% for patients treated with chemoimmunotherapy in the Nordic MCL2 and MCL3 clinical trials,” Dr. Kumar said. “In TP53-mutated MCL, we can see high initial response rates with chemoimmunotherapy and novel agent combinations, but patients often experience relapses. We wanted to use a timepoint that demonstrated durable disease control with this treatment program.”
The three-drug regimen produced a best ORR of 96% and a CR rate of 88%. At cycle 13, uMRD was 95% when measured at 10-5 and 84% when measured to 10-6.
“Based on the biostatistics from the experience with chemoimmunotherapy, we had set an unacceptable two-year PFS of 30% or less, and a two-year PFS that exceeded 55% would represent a significant improvement compared with the prior standard of care,” Dr. Kumar said. “We well exceeded that.”
The two-year PFS was 72%. Two-year disease-specific survival was 91%, and two-year overall survival was 76%.
“For patients with high-risk MCL with TP53 mutation, this two-year PFS was a huge improvement,” Dr. Kumar said.
Patients with uMRD who stopped treatment are undergoing ongoing surveillance for molecular or clinical relapse.
“If a patient has uMRD and then becomes detectable, we can restart treatment even before clinical relapse,” Dr. Kumar said.
Dr. Kumar acknowledged that the study is limited by the small number of patients enrolled. She said the sponsor has agreed to expand the study, and they plan to enroll an additional 25 patients.
In addition, Dr. Kumar said that although TP53 mutation is widely recognized to be a high-risk feature, there is clinical and biologic heterogeneity within the category of patients whose disease has TP53 mutations.
“Hopefully in the future we will be able to better characterize the differences within this patient population to see if certain patients, based on their mutational profile or molecular features, have long-term durable responses with BOVen,” Dr. Kumar said. “We hope to address those questions in the future.”
Any conflicts of interest declared by the authors can be found in the original article.
References
- Kumar A, Soumerai JD, Abramson JS, et al. Zanubrutinib, obinutuzumab, and venetoclax for first-line treatment of mantle cell lymphoma with a TP53 mutation [published online ahead of print, 2024 Oct. 22]. Blood. doi: 10.1182/blood.2024025563.
- National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. B-Cell Lymphomas. Version 3.2024. August 26, 2024. Accessed October 30, 2024. https://www.nccn.org/professionals/physician_gls/pdf/b-cell.pdf.
