SUMMARY: The FDA on June 15, 2023, granted accelerated approval to Glofitamab-gxbm (COLUMVI®) for Relapsed or Refractory Diffuse Large B-Cell Lymphoma, Not Otherwise Specified (DLBCL, NOS) or Large B-Cell Lymphoma (LBCL) arising from Follicular Lymphoma, after two or more lines of systemic therapy.
The American Cancer Society estimates that in 2023, about 80,550 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,180 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphomas in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.
DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using Gene Expression Profiling: Germinal Center B-cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher 5-year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype. Approximately 30-40% of patients experience disease progression or relapse, during the first 2 years and attempts to improve on R-CHOP regimen have not been successful. Maintenance treatment strategy following R-CHOP, to better control the disease, delay disease progression and improve long term survival, have included Autologous Stem Cell Transplantation, CAR T-cell therapy, maintenance treatment with agents such as oral protein kinase inhibitor Enzastaurin and Everolimus. Outcomes for transplant-ineligible patients with Relapsed/Refractory DLBCL patients remain poor. There is a critical unmet need for this patient group.
Glofitamab is a CD20-directed CD3 T-cell engager bispecific antibody, designed to target CD20 on the surface of B cells and CD3 on the surface of T cells. This dual targeting activates and redirects a patient’s existing T cells to engage and eliminate target B cells by releasing cytotoxic proteins into the B cells. Glofitamab differs from other CD20-directed CD3 T-cell engager bispecific antibodies in that it has two anti-CD20 binding domains. It is therefore bivalent for the tumor antigen and monovalent for the T-cell CD3 protein. Further, it is a time-limited therapy.
The present FDA approval was based on positive data from the NP30179 study, which is a Phase I/II, multicenter, open-label, dose-escalation and expansion study, evaluating the safety, efficacy and pharmacokinetics of Glofitamab in patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL). Once the recommended Phase II dose of Glofitamab was established, patients with DLBCL who had previously received at least two lines of therapy were enrolled in the expansion cohorts. This expansion cohort included 154 patients (N=154), who had Relapsed or Refractory disease, and had received at least two previous lines of therapy including at least one anti-CD20 antibody-containing regimen and at least one anthracycline-containing regimen.
Eighty percent of patients had Relapsed or Refractory DLBCL, and 20% had LBCL arising from Follicular Lymphoma. Approximately 85% of patients were refractory to their most recent therapy and 33% had received prior CAR T-cell therapy. This study excluded patients with active or previous Central Nervous System lymphoma or disease. Treatment consisted of a single dose of Obinutuzumab 1,000 mg IV on Cycle 1 Day 1, to deplete circulating and lymphoid tissue B cells and to mitigate Cytokine Release Syndrome, followed by fixed-duration Glofitamab monotherapy administered by IV infusion according to a step-up dosing schedule (2.5 mg on Day 8 of Cycle 1 and 10 mg on Day 15 of Cycle 1), then 30 mg on Day 1 of each subsequent cycle for a maximum of 12 cycles. The cycle length was 21 days. Patients were hospitalized for the first dose of Glofitamab and subsequent doses were administered in the outpatient setting unless Cytokine Release Syndrome of Grade 2 or higher was reported after the first dose. The Primary end point was Complete Response (CR) rate according to assessment by an Independent Review Committee. Key Secondary end points included Duration of Response, Progression Free Survival, and Safety. The efficacy analysis included 132 patients.
The Overall Response Rate (ORR) was 56% with a Complete Response rate of 43%. With an estimated median follow up of 11.6 months among responders, the estimated median Duration of Response was 18.4 months. Further, 68.5% of patients who achieved a response continued to respond for 9 months or longer. The median Time to Response was 42 days. The most common adverse reactions, excluding laboratory abnormalities were Cytokine Release Syndrome (CRS), musculoskeletal pain, rash, and fatigue. CRS occurred in 70% (with 4.1% Grade 3 or higher CRS), Immune Effector Cell-Associated Neurotoxicity (ICANS) in 4.8%, serious infections in 16%, and tumor flare in 12%. The most common Grade 3 to 4 laboratory abnormalities were lymphopenia and neutropenia, decrease in serum phosphate and fibrinogen levels, and increase in serum uric acid.
It was concluded that a fixed duration treatment of off-the-shelf therapy with Glofitamab induced durable Complete Responses, among patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma.
Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. Dickinson MJ, Carlo-Stella C, Morschauser F, et al. N Eng J Med. 2022;387:2220-2231.