New data from cohort 3 of the phase 2 ZUMA-2 trial, presented at the 2024 ASH Annual Meeting, demonstrate that brexucabtagene autoleucel (brexu-cel; Tecartus) yields high overall response rates in patients with relapsed/refractory mantle cell lymphoma (MCL) who have not previously been treated with BTK inhibitors. The study suggests that brexu-cel may be effective as an earlier-line treatment, especially for patients with high-risk disease features.
High Response Rates Across Subgroups
The primary analysis of cohort 3 (NCT04880434) showed an overall response rate (ORR) of 91% (95% CI, 83%-96%) after a median follow-up of 15.5 months. This included a complete response (CR) rate of 73% and a partial response (PR) rate of 17%. Notably, high ORRs were observed in several high-risk subgroups:
- Patients with confirmed TP53 mutations: 100% (15/15)
- Patients with greater than median tumor burden at baseline: 97% (38/39)
- Patients with Ki-67 scores of at least 50%: 94% (17/18)
- Patients with intermediate- or high-risk simplified MCL International Prognostic Index (sMIPI) scores: 89% (56/63)
- Patients with prior bendamustine exposure: 83% (19/23)
These results indicate that brexu-cel is effective across a range of high-risk MCL subtypes, suggesting it could be a valuable treatment option for patients who may not respond well to BTK inhibitors.
Study Design and Patient Population
The phase 2, open-label ZUMA-2 trial enrolled patients with relapsed/refractory MCL who had received between 1 and 5 prior regimens, including anthracycline-, bendamustine-, or high-dose cytarabine-containing chemotherapy, and anti-CD20 monoclonal antibody therapy. A key inclusion criterion was that patients must be BTK inhibitor-naive. Patients underwent leukapheresis, followed by optional bridging therapy. Lymphodepleting chemotherapy consisted of intravenous fludarabine (30 mg/m2) and cyclophosphamide (500 mg/m2) daily for 3 days, followed by brexu-cel infusion at a target dose of 2 × 106 CAR T cells/kg on day 0.
The primary endpoint was ORR by independent radiology review committee assessment per Lugano classification. Secondary endpoints included duration of response (DOR), best objective response, progression-free survival (PFS), overall survival (OS), and safety.
Safety Profile
The safety profile of brexu-cel in this BTK inhibitor-naive cohort was consistent with previous studies. Common treatment-emergent adverse events (TEAEs) included pyrexia (94%), anemia (57%), and hypotension (51%). Grade 3 or higher TEAEs included neutropenia (43%), decreased neutrophil count (42%), and decreased white blood cell count (37%).
Adverse events of special interest included cytokine release syndrome (CRS; any grade, 95%; grade ≥3, 6%) and immune effector cell-associated neurotoxicity syndrome (ICANS; any grade, 66%; grade ≥3, 21%). No new safety signals were detected.
Clinical Implications
The findings from ZUMA-2 cohort 3 support the use of brexu-cel in the relapsed/refractory MCL setting, particularly in patients who are BTK inhibitor-naive. Given the high response rates observed across various high-risk subgroups, brexu-cel may offer a significant benefit for patients with aggressive disease or those who are unlikely to respond to other therapies. Longer follow-up is needed to fully assess the long-term outcomes for these patients.
