Following the incorporation of rituximab into frontline anthracycline-based chemotherapy for the treatment of diffuse large B-cell lymphoma (DLBCL), the treatment landscape remained relatively stagnant for nearly two decades. However, the past five years have resulted in several new therapies being approved in the relapse setting, with evolution into earlier lines of treatment. An example of this treatment evolution includes the approval of autologous CD19-targeting chimeric antigen receptor T-cell (CAR-T) therapy, first approved after at least two lines of systemic therapy, followed by an expansion of the label to include early-relapse DLBCL, and now being studied in frontline high-risk patients. Despite the enthusiasm surrounding CAR-T therapy, a large portion of patients will still never receive this therapy, either due to disease progression or death while awaiting therapy, or no access. Therefore, there is an unmet need for effective and immediately available treatment, and the T-cell-engaging bispecific antibodies are emerging therapies that seem promising.
Glofitamab is a bispecific monoclonal antibody with a unique configuration of 2-to-1 targeting of CD20 on B cells to CD3 on T cells, leading to engagement and redirection of a patient’s T cells to eliminate malignant B cells. The results of the pivotal single-arm phase II study of glofitamab in patients with relapsed or refractory DLBCL who had received at least two prior lines of therapy suggest we may have another treatment option in third-line DLBCL in the near future. As established in the phase I portion of the study, obinutuzumab 1,000 mg is administered as pretreatment seven days prior to the first dose of glofitamab, which is then administered in a step-up dose of 2.5 mg on day 8, 10 mg on day 15, and 30 mg on day 1 of cycles 2 through 12 (21-day cycles). Demographics of the 154 patients treated with glofitamab suggest the median age was 66 years (range, 21-90 years), 65 percent were men, and all patients had a good performance status (0-1). Most patients (71%) had DLBCL not otherwise specified, 18 percent had transformed from follicular lymphoma, 7 percent had high-grade B-cell lymphoma, and 4 percent had primary mediastinal large B-cell lymphoma. With a median of three prior lines of therapy, 86 percent were refractory to their last therapy, and 30 percent were refractory to CAR-T therapy. At a median follow-up of 12.6 months, 39 percent achieved a complete response (CR), with 52 percent achieving an objective response. The median time to CR was 42 days (first response assessment), which suggests the responses were rapid. The median duration of response was 18.4 months, and progression-free survival was 4.9 months. The most common adverse event was cytokine release syndrome, observed in 63 percent of patients, with grade 3 or higher toxicity observed in 4 percent of patients. Neurologic toxicity was infrequent at 8 percent, with 3 percent being grade 3 or higher. Infections were observed in 38 percent, with 15 percent being grade 3 or higher.
In Brief
It does appear that the T-cell engager glofitamab can be an effective and immediately available therapy for relapsed or refractory DLBCL. The remaining questions center on how we sequence these therapies. In my practice, I will be eager to use this post–CAR-T therapy, and potentially prior to CAR T-cell therapy for those patients at risk of dying from disease progression while awaiting CAR-Ts.
Competing Interests
Dr. Nastoupil indicated no relevant conflicts of interest.
