Glofitamab-gxbm Approved for Relapsed/Refractory Large B-Cell Lymphomas

Diffuse large B-cell lymphoma.

The FDA has approved glofitamab-gxbm (Columvi™, Genentech, Inc.) for treatment of relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified or large B-cell lymphoma (LBCL) arising from follicular lymphoma. Patients are required to have undergone two or more previous lines of systemic therapy.

Why it matters: "The prognosis is poor for patients who are unsuitable candidates for second-line treatment with aggressive salvage chemotherapy and for those who have received at least two therapies previously," wrote Michael J. Dickinson, MBBS, Leader of the Aggressive Lymphoma Disease Group at Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Australia, and colleagues, in their published results of the NP30179 trial (NCT03075696), on which approval was based. "Glofitamab is distinct in the emerging class of CD20×CD3 bispecific monoclonal antibodies because it has a novel 2:1 tumor–T-cell binding configuration that confers bivalency for CD20 (B cells) and monovalency for CD3 (T cells), leading to the engagement and redirection of patients' existing T cells to eliminate malignant B cells."

What they studied: Safety and efficacy were evaluated in the phase 2, multicenter, open-label, single-arm trial in which 132 patients were pretreated with obinutuzumab to mitigate cytokine release syndrome (CRS) and followed by 12, 21-day cycles of glofitamab monotherapy. Patients had either DLBCL, not otherwise specified (80%) or LBCL arising from follicular lymphoma (20%). As well, patients were required to have undergone at least two prior lines of systemic therapy. Patients with active or previous central nervous system lymphoma or disease were excluded from the trial. The primary end points measured were objective response rate and duration of response, determined by an Independent Review Committee using the 2014 Lugano criteria.

What they found:

• At a median follow-up of 11.6 months, the median time to response was 42 days
• The objective response rate with glofitamab was 56%, with 43% of patients achieving a complete response
• The median duration of response was 18.4 months, and the nine-month Kaplan-Meier estimate for duration of response was 68.5%

Adverse events: The most common adverse events in ≥20% of patients receiving glofitamab, excluding laboratory abnormalities, were CRS, musculoskeletal pain, rash, and fatigue. The most common grade 3 or 4 laboratory abnormalities in ≥20% of patients were decreases in lymphocyte counts, phosphate, neutrophil counts, and fibrinogen, and increase in uric acid.

What's next: Further investigation of glofitamab's safety will be conducted in comparative studies. The novel mechanism of action and unique 2:1 tumor–T-cell binding structure of glofitamab, along with the efficacy demonstrated in the trial, make it a strong candidate for combinations with other treatments.

Conclusion: "The efficacy of glofitamab therapy, its novel mechanism of action, and unique 2:1 structure provide a strong rationale for combinations with other treatments," concluded Dr. Dickinson and colleagues. "In this phase 2 study involving patients with DLBCL, we found that a fixed course of glofitamab therapy induced durable complete responses and is a new active therapy for patients with this disease."

Instructions: The recommended administration of glofitamab-gxbm is throughout 12, 21-days cycles. Pretreatment with 1,000 mg of obinutuzumab via intravenous infusion should be given seven days prior to the initiation of glofitamab-gxbm treatment to deplete circulating and lymphoid tissue B cells. On Day 8 of Cycle 1, patients should be given the first step-up dose of glofitamab-gxbm at 2.5 mg, followed by the second step-up dose of 10 mg on Day 15 of Cycle 1 and 30 mg of glofitamab-gxbm on Day 1 of each subsequent cycle, for a maximum of 12 cycles.

Due to the risk of CRS and other severe reactions, glofitamab-gxbm should be administered and managed by a health care professional with appropriate medical support. Due to the risk of CRS, patients should be hospitalized during and for 24 hours after the first step-up dose, and again for the second step-up dose if any grade CRS occurs with the 2.5 mg dose. Patients who experience grade ≥2 CRS with their previous infusion should be hospitalized during and for 24 hours after the completion of the next infusion.

Please refer to the prescribing information for complete dosing information.

For More Information

US Food and Drug Administration (2023). FDA grants accelerated approval to glofitamab-gxbm for selected relapsed or refractory large B-cell lymphomas. Available at: https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-glofitamab-gxbm-selected-relapsed-or-refractory-large-b-cell

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