BOVen: Zanubrutinib, Obinutuzumab, and Venetoclax Yields 75% OS at 2 Years in High-Risk MCL

Patients with TP53-mutant mantle cell lymphoma (MCL) have historically faced a lack of standard frontline treatment and poor survival prospects; a 2017 study found that chemoimmunotherapy regimens offered patients a median overall survival (OS) of 1.8 years.

Since then, a 2018 study by Tam, et al., in the New England Journal of Medicine that combined ibrutnib, a Bruton tyrosine kinase (BTK) inhibitor, with venetoclax, a therapy to target BCL2 protein, showed promise in relapsed or refractory MCL, even for patients with this high-risk mutation. Following a 2021 study that showed positive results when patients with untreated MCL received ibrutinib (Imbruvica), the CD20-targeting antibody obinutuzumab (Gazyva), venetoclax (Venclexta), investigators from Memorial Sloan Kettering Cancer Center (MSK) and Massachusetts General Hospital (MGH) developed the BOVen study (NCT03824483), which replaced the ibrutinib with the second-generation BTK inhibitor, zanubrutinib (Brukinsa). The triplet is also being studied in chronic lymphocytic leukemia and small lymphocytic lymphoma.

Anita Kumar, MD | Image credit: Memorial Sloan Kettering Cancer Center

In a packed session Monday at the 65th American Society of Hematology Annual Meeting and Exposition in San Diego, California, lead investigator Anita Kumar, MD, an MSK lymphoma specialist in Basking Ridge, New Jersey, presented phase 2 results for 25 patients with TP53 mutations. The primary endpoint was 2-year progression-free survival (PFS), which was achieved after a median follow-up of 23.3 months.

“Based on historical data, we found a 2-year PFS rate of greater than or equal to 55% to be promising and an unacceptable rate to be less than or equal to 30%,” Kumar said. “Therefore, if 11 or more patients were progression-free at 2 years, the treatment regimen will be declared effective.”

Kumar emphasized that BTK-BCL2 inhibition in MCL is well-grounded; she noted that Tuesday’s ASH late-breaking session will bring results from the phase 3 SYMPATICO trial examining use of ibrutinib and venetoclax in relapsed/refractory MCL. Nonetheless, the promise of fewer cardiac effects could make a zanubrutinib-based regimen more attractive to patients and clinicians alike, in light of other evidence that the second-generation therapy is more effective than ibrutinib in patients with TP53 mutations.

Methods. The regimen was administered as follows: 160 mg zanubrutinib (oral) was given daily starting on day 1, 1000 mg obinutuzumab was given (intravenously) starting on day 1 or split on day 1-2, day 8 and day 15 of cycle 1; and on day 1 of cycles 2-8, with venetoclax ramp up starting on day 1 of cycle 3.

Results. Kumar said based on results from the first 25 patients, BOVen is expanding from MSK and MGH to 2 more sites at Northwestern and Emory universities. Results thus far show the following:

• The median age of the study group was 68 years (range 29 to 82); 76% were male.
• 100% of the patients had stage IV disease; 68% were high risk, 28% were intermediate and 4% were low risk based on MCL International Prognostic Index (MIPI) scores.
• 100% of patients had a TP53 mutation; 44% of the patients also had 17p deletion, and 33% had a K-i67 marker of 50%.
• There were 5 progressions, 3 of which occurred in the first year of treatment.
• The study reported 4 deaths; 2 deaths were COVID-19 related, 1 was post-operative pneumonia and 1 was from an unknown cause. All patients who died were in ongoing response at the time of death.
• After 2 cycles of obinutuzumab and venetoclax, as assessed by PET-CTC, overall response rate (ORR) was 76%, with a complete metabolic response rate of 68%.
• Best ORR was 96% (24/25) with 88% achieving a complete response (22/25).
• The 2-year PFS was 72%, and the median was not reached. The 2-year OS was 75%, and the median was not reached.

“Therefore, we have achieved the primary PFS endpoint of this study with 11 patients who are progression-free at 2 years,” Kumar said.

Adverse events (AEs). Overall, the regimen was safe and well-tolerated, Kumar said. The most common AEs were diarrhea, COVID-19 infection, neutropenia, and infusion-related infections. Kumar said grade 3 neutropenia was present in 16% of patients and resolved with granulocyte colony-stimulating factor, and diarrhea was primarily grade 1 and manageable.

“We were interested in characterizing the incidence of clinically significant tumor lysis syndrome (TLS), particularly during the venetoclax ramp up,” she said. However, after 2 cycles of obinutuzumab and zanubrutinib, only 3 patients were at risk of TLS and required initial inpatient venetoclax ramp up.

“BOVen emerges as a promising treatment option for TP53-mutant mantle cell lymphoma,” Kumar said. “We’ve expanded the study to include an additional 25 patients.”

Reference

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. Presented at: 65th American Society of Hematology Annual Meeting & Exposition; San Diego, CA: December 9-12, 2023. Abstr 0738. https://doi.org/10.1182/blood-2023-180069