A phase Ib/II study demonstrated that mosunetuzumab with polatuzumab vedotin, a combination regimen targeting two biologically relevant B cell targets using a T-cell-engaging bispecific antibody and an antibody–drug conjugate, induced durable responses in patients with relapsed or refractory large B cell lymphoma, including patients with poor clinical and pathologic prognostic features, such as relapse after CAR-T cell therapy.
Despite enrolling patients with poor prognostic features, the regimen has a safety profile that is manageable in an outpatient setting. The findings are presented at ASH 2023 Annual Meeting along with a simultaneous publication in the Nature Medicine by Drs. Lihua E. Budde of the City of Hope Comprehensive Cancer Center in Duarte, CA, US, Julio C. Chavez of the Moffitt Cancer Center in Tampa, FL, US, and colleagues on 10 December 2023.
Large B cell lymphoma, the most common aggressive non-Hodgkin lymphoma (NHL), is managed in the front-line with rituximab-based immunochemotherapy regimens that have curative potential or polatuzumab vedotin in combination with immunochemotherapy. However, approximately 20-40% of patients with large B cell lymphoma are either refractory to front-line therapy or experience subsequent relapse.
Standard of care is evolving in the second-line treatment of large B cell lymphoma and includes traditional salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) or CAR-T cell therapy in patients who are transplant ineligible or those with early disease relapse after front-line therapy or additional immunochemotherapy.
Multiple challenges remain in delivering therapies with durable and curative potential in the relapsed or refractory setting. Approximately half of patients with relpased or refractory large B cell lymphoma are unsuitable for ASCT, and, even after ASCT, only 50% attain a durable remission. For patients suitable for CAR-T cell therapy, there are multiple barriers, including manufacturing challenges, severe life-threatening toxicities, and access to specialist treatment centres. Approximately 50% of patients with large B cell lymphoma do not respond or relapse after CAR-T cell therapy.
Although other treatments are available there is a need to develop new regimens that balance safety, efficacy, and patient access in relapsed or refractory large B cell lymphoma, especially for non-tertiary and community practices.
Initial reports demonstrated safety and efficacy of mosunetuzumab combined with polatuzumab vedotin, supporting development of this combination as a fixed-duration outpatient regimen in second-line, transplant-ineligible large B cell lymphoma.
Mosunetuzumab is an off-the-shelf CD20xCD3 T-cell-engaging bispecific antibody that engages and redirects T cells to eliminate malignant B cells. It is administered in an outpatient setting and is efficacious with a favourable toxicity profile in patients with relapsed or refractory diffuse large B cell lymphoma including patients who had received prior CAR-T cell therapy.
Polatuzumab vedotin is an antibody-drug conjugate that is composed of an anti-CD79b monoclonal antibody conjugated by a protease-cleavable linker to a potent microtubule inhibitor, monomethyl auristatin E. Polatuzumab vedotin in combination with chemoimmunotherapy is approved for the treatment of previously untreated and relapsed or refractory diffuse large B cell lymphoma.
In the article published in the Nature Medicine, the authors explained that the phase II component is a single arm of an ongoing multi-arm trial. The primary endpoint during dose expansion was independent review committee (IRC)-assessed best overall response rate (ORR). Secondary endpoints included investigator-assessed ORR, complete response (CR), duration of response, progression-free survival (PFS) and overall survival (OS). At data cut-off, 120 patients were enrolled of whom 22 in dose escalation and 98 in dose expansion.
The primary endpoint was met during dose expansion, with IRC-assessed best ORR of 59.2% (95% confidence interval (CI) 48.8–69.0) and CR rates of 45.9% (95% CI 35.8–56.3) at median follow-up of 23.9 months.
Median duration of complete response was not reached (95% CI 20.5–not estimable (NE)). Median PFS was 11.4 months (95% CI 6.2–18.7). Median OS was 23.3 months (95% CI 14.8–NE).
Patients who had received prior CAR-T cell therapy and other high-risk subpopulations demonstrated promising efficacy, which is clinically meaningful given the aggressive nature of the disease. However, the authors commented that although the responses in high-risk subgroups are promising, the study is underpowered to assess efficacy in these subgroups.
Across dose escalation and expansion, the most common grade 3 or higher adverse events were neutropenia (25.0%) and fatigue (6.7%). Any-grade cytokine release syndrome occurred in 16.7% of patients.
The study is limited by its single-arm design. Additional translational studies are needed to fully understand mechanisms of resistance to this combination regimen. Limitations of the study also include the lack of patients with prior polatuzumab vedotin exposure and the lack of systematic polatuzumab vedotin retreatment data.
The authors concluded that based on the observed efficacy and safety profile, mosunetuzumab in combination with polatuzumab vedotin holds promise for patients with aggressive relapsed or refractory large B cell lymphoma ineligible for ASCT or aggressive intense immunochemotherapy.
The current results led to the development of the ongoing global, randomised, open-label phase III SUNMO study, which is evaluating the efficacy and safety of mosunetuzumab with polatuzumab vedotin in patients with relapsed or refractory aggressive B-NHL who are ineligible for ASCT, a study that permits prior treatment with polatuzumab vedotin.
The study was sponsored by F. Hoffmann-La Roche, Ltd.
