Significant OS Benefit with Glofitamab plus gemcitabine–oxaliplatin (GemOx) in Transplant-Ineligible Patients with Relapsed or Refractory DLBCL (STARGLO study)
Glofitamab is the first CD20 × CD3 bispecific antibody to show overall survival (OS) benefit in patients with diffuse large B-cell lymphoma (DLBCL) in a randomised phase III study.
The results from a global, phase III, open-label, randomised STARGLO study showed a significant benefit with glofitamab plus gemcitabine–oxaliplatin (GemOx) versus rituximab plus GemOx for OS, progression-free survival (PFS), and complete response rate in autologous stem-cell transplant (ASCT)-ineligible patients with relapsed or refractory DLBCL.
Safety profile was consistent with the known risks of the individual agents. The findings were published on 16 November 2024 in The Lancet.
For patients with primary refractory DLBCL after first-line treatment or those who relapse within 12 months of first-line treatment, chimeric antigen receptor (CAR) T-cell therapy has been found to provide superior event-free survival compared with ASCT in two phase III trials, with the ZUMA-7 study of axicabtagene ciloleucel showing OS benefit as well. However, CAR T-cell therapies are not uniformly available to patients due to logistical, geographical, or resource constraints, and are also complex to manufacture or administer, particularly among patients in urgent need of therapy.
Glofitamab is an off-the-shelf T-cell-engaging bispecific antibody with a 2:1 (CD20:CD3) format for bivalent binding to CD20 on B cells and monovalent binding to CD3 on T cells. Glofitamab monotherapy, administered for a fixed duration of 12 cycles, is widely approved for the treatment of patients with relapsed or refractory DLBCL after two or more previous lines of therapy, based on the findings of a phase I/II study, which showed a high rate of and durable complete responses and a manageable safety profile in this patient population.
The phase III, randomised, open-label STARGLO study was done at 62 centres in 13 countries in Asia, Australia, Europe, and North America. The study team recruited transplant-ineligible patients, aged ≥18 years, with histologically confirmed relapsed or refractory DLBCL after one or more previous therapies. Patients were randomly assigned 2:1, stratified by 1 versus ≥2 previous lines of therapy and relapsed versus refractory status to glofitamab plus GemOx or rituximab plus GemOx.
The study independent review committee, which evaluated all response-based endpoints, was masked to treatment assignment. The primary endpoint was OS. Efficacy analyses were by intention-to-treat in all randomly assigned patients. The study team presented results from both, the primary analysis with a cut-off on 29 March 2023 and updated analysis after all patients had completed study therapy with a cut-off on 16 February 2024. Safety analyses included all patients who received any study treatment. This study is ongoing but closed to recruitment.
From 23 February 2021 to 14 March 2023, 274 patients were enrolled and randomly assigned to receive glofitamab plus GemOx (183 patients) or rituximab plus GemOx (91 patients); 158 patients (58%) were male and 116 (42%) were female; median age was 68 years (interquartile range, 58–74). At the primary analysis after a median follow-up of 11.3 months (95% confidence interval [CI] 9.6–12.7), OS was significantly improved with glofitamab plus GemOx versus rituximab plus GemOx with a median not estimable (NE; 95% CI 13.8 months–NE) versus 9.0 months (7.3–14.4) and hazard ratio (HR) of 0.59 (95% CI 0.40–0.89; p = 0.011).
At the updated analysis after a median follow-up of 20.7 months (19.9–23.3), a consistent improvement in OS was observed with glofitamab plus GemOx versus rituximab plus GemOx with a median of 25.5 months (18.3–NE) versus 12.9 months (7.9–18.5) and HR 0.62 (0.43–0.88).
Exploratory analyses suggested OS benefits with glofitamab plus GemOx in several subgroups, including the clinically relevant subgroups defined by number of previous lines of therapy and relapsed or refractory status to last treatment.
In the safety sets, 180 patients (100%) in the glofitamab plus GemOx group and 84 of 88 patients (96%) in the rituximab plus GemOx group had at least one adverse event during the study period. Cytokine release syndrome occurred in 76 of 172 glofitamab-exposed patients (44%) and was predominantly low grade. Deaths related to glofitamab or rituximab occurred in five patients (3%) in the glofitamab plus GemOx group and in one patient (1%) in the rituximab plus GemOx group.
STARGLO was done amid the rapidly changing landscape of the COVID-19 pandemic, which affected different regions at different times. Seven cases of fatal COVID-19 or COVID-19-associated adverse events (all in the glofitamab plus GemOx group) occurred before the widespread availability of effective antivirals such as nirmatrelvir– ritonavir, which has reduced mortality in patients with haematological malignancies and comorbid COVID-19; no patients with fatal COVID-19-associated adverse events in this study received nirmatrelvir–ritonavir. After a protocol modification preventing patients with active or recent COVID-19 infection from starting study therapy (in either group) and requiring discontinuation from study treatment for patients with positive COVID-19 tests while on the study, no additional COVID-19-associated deaths while on study treatment were reported.
The authors commented that enrolment was limited to patients with DLBCL, not otherwise specified, to ensure sufficient homogeneity of the study population, and thus conclusions cannot be drawn for patients with double or triple hit lymphoma (high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements) or high-grade B-cell lymphoma, not otherwise specified.
Due to the evolving global treatment standards for CAR T-cell therapies during the period of study enrolment, patients who were candidates for CAR T-cell therapy at study entry were not excluded from STARGLO. Establishing the relative suitability of CAR T-cell therapies versus glofitamab plus GemOx, in patients who would not otherwise be medically suitable for transplant, is thus a subject for further investigation. Additional data are also needed to investigate glofitamab plus GemOx in patients of Black race, who were under-represented.
The authors concluded that glofitamab plus GemOx had a significant OS benefit compared with rituximab plus GemOx, supporting its use in transplant-ineligible patients with relapsed or refractory DLBCL after one or more previous lines of therapy. The results support the use of glofitamab plus GemOx for the treatment of patients with relapsed or refractory DLBCL, where the need for readily available treatment options remains high.
In an accompanied comment, Dr. Anna Sureda of the Clinical Haematology Department, Institut Català d’Oncologia–L’Hospitalet, IDIBELL, Universitat de Barcelona in Barcelona, Spain and Dr. Astrid Pavlosky of the Pavlovsky Center and Haematology Department, Fundaleu, both in Buenos Aires, Argentina wrote that this option not only broadens the patient population able to access a novel therapy, but might also overcome some of the economic and geographical barriers associated with CAR T-cell therapies, potentially benefiting a notable proportion of patients. Nevertheless, the cost of glofitamab plus GemOx might be a key limitation, particularly in lower-income regions.
Although the long-term durability of clinical responses remains uncertain, the introduction of glofitamab plus GemOx could redefine the treatment approach for a substantial population of patients with relapsed or refractory DLBCL, offering a drug combination that shows an OS benefit. The STARGLO trial positions glofitamab plus GemOx as a potentially pivotal therapy in relapsed or refractory DLBCL. Further studies should explore its long-term durability and comparative effectiveness against CAR T-cell therapies.