First-Line Zanubrutinib/Obinutuzumab Shows Efficacy, Safety in Older MCL

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Frontline treatment with the combination of zanubrutinib (Brukinsa) and obinutuzumab (Gazyva) demonstrated efficacy and safety in older patients with newly diagnosed mantle cell lymphoma (MCL), according to data from a phase 2 trial (ChiCTR2300071433).¹

Results presented at the 2024 EHA Congress showed that patients at least 65 years of age with newly diagnosed MCL who completed induction therapy with zanubrutinib plus obinutuzumab (n = 9) achieved an overall response rate (ORR) of 100%, including a complete remission (CR) rate of 88.9% and a partial remission (PR) rate of 11.1%. At a median follow-up of 6 months, no patients experienced disease progression.

“[Older] patients have poor performance status and low tolerance to chemotherapy, so investigators [of the phase 2 study] are looking for chemotherapy-free therapeutic approaches for [older patients with] newly diagnosed MCL,” lead study author Yanan Zhu, MD, of the First Affiliated Hospital of Zhejiang University School of Medicine in Hangzhou, China, and colleagues wrote in a poster presentation of the data.

The covalent BTK inhibitor zanubrutinib received accelerated approval from the FDA in November 2019 for the treatment of patients with MCL who have received at least 1 prior therapy.²

In the open-label, multicenter, single-arm phase 2 study conducted in China, investigators enrolled patients at least 65 years of age with previously untreated MCL. Patients were required to have an ECOG performance status of 0 to 3; measurable lesions or bone marrow/gastrointestinal involvement; serum bilirubin of less than 2mg/dL; aspartate aminotransferase and alanine aminotransaminase less than 2 times the upper limit of normal (ULN), or less than 5 times the ULN for patients with hepatic metastases; and a creatinine clearance rate more than 30mL/min.³

All patients received induction therapy consisting of obinutuzumab at 1000 mg intravenously on days 1, 8, and 15 of the first 28-day cycle, followed by day 1 of cycles 2 through 4, in combination with oral zanubrutinib at 160 mg twice daily starting in cycle 2.1 Maintenance therapy was adjusted based on response: patients with CR following induction therapy transitioned to zanubrutinib monotherapy, and those with a PR continued combination therapy for 2 additional cycles before switching to maintenance with zanubrutinib alone. Zanubrutinib was continued until disease progression, unacceptable toxicity, or other discontinuation criteria were met.

CR rate served as the trial’s primary end point. Secondary end points included ORR, overall survival, progression-free survival, and safety.

The 10 total patients enrolled on the study had a median age of 72 years. Among these patients, 8 had bone marrow involvement. High-risk MCL International Prognostic Index scores were observed in 4 patients at baseline, and 4 patients had a Ki-67 index of at least 30%. One patient had a history of atrial fibrillation.

Among patients who underwent next-generation sequencing (n = 9), ATM mutations were detected in 55.6% of patients, and TP53 mutations were reported in 33.3% of patients.

Safety data from the study showed that most adverse effects (AEs) were grade 1 or 2. Grade 2 infusion-related reactions were observed in 2 patients during the first dose of obinutuzumab dose. Both of these patients experienced grade 3 or 4 thrombocytopenia, which resolved within a week. Importantly, no atrial fibrillation or significant bleeding events were reported during the study, and no patients discontinued therapy due to AEs.

“Obinutuzumab plus zanubrutinib demonstrated a favorable efficacy and a manageable safety profile in [older] patients with untreated MCL,” study authors concluded.

References

1. Zhu Y, Ye X, Wei J, et al. The efficacy and safety of obinutuzumab with zanubrutinib as first-line treatment in older patients with mantle cell lymphoma. Presented at: 2024 EHA Congress; June 13-16, 2024; Madrid, Spain. Abstrasct P2071.
2. FDA grants accelerated approval to zanubrutinib for mantle cell lymphoma. FDA. November 14, 2019. Accessed September 18, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-zanubrutinib-mantle-cell-lymphoma
3. Clinical trial of zanubrutinib with obinutuzumab as first-line treatment in older patients with mantle cell lymphoma. CHICTR.org. Accessed September 18, 2024. https://www.chictr.org.cn/hvshowproject.html?id=239708&v=1.4