The FDA's Oncologic Drugs Advisory Committee (ODAC) voted 8-to-1 against the applicability of the phase 3 STARGLO trial results to US patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), despite the trial demonstrating significant survival benefits for glofitamab (Columvi) in combination with gemcitabine and oxaliplatin (GemOx).
The STARGLO study, a global randomized phase 3 trial, showed that glofitamab-GemOx reduced the risk of death by 41% compared to rituximab-GemOx in transplant-ineligible patients with R/R DLBCL. The median overall survival reached 25.5 months with glofitamab-GemOx versus 12.9 months with rituximab-GemOx (HR = 0.59; 95% CI: 0.40–0.89; P = 0.011).
Trial Design and Patient Population
The STARGLO trial enrolled 274 patients across 62 sites in 13 countries, randomizing them 1:1 to receive either glofitamab-GemOx (n = 183) or rituximab-GemOx (n = 91). Eligible patients had R/R DLBCL and were either ineligible for autologous stem cell transplant (ASCT) or had failed at least two prior lines of therapy.
The trial population distribution raised concerns at the FDA meeting, with 161 patients from the Asia Pacific region, 88 from Europe, and only 25 from North America. The FDA briefing document highlighted "differential treatment effects on outcomes such as OS, PFS, CR rate, and ORR across regional subgroups," noting that outcomes were "largely driven by the trial's Asian population."
Efficacy Outcomes
Despite the committee's concerns about regional applicability, the efficacy data from STARGLO was compelling:
- Overall Survival: Median OS of 25.5 months for glofitamab-GemOx vs. 12.9 months for rituximab-GemOx (HR = 0.62; 95% CI: 0.43-0.88)
- Progression-Free Survival: 63% reduction in the risk of disease progression or death (HR = 0.37; 95% CI: 0.25–0.55; P < 0.000001)
- Complete Response Rate: 50.3% with glofitamab-GemOx vs. 22.0% with rituximab-GemOx (P < 0.0001)
These results mark glofitamab-GemOx as the first bispecific antibody-based regimen to demonstrate a survival benefit in a phase 3 study for transplant-ineligible patients with R/R DLBCL.
Safety Profile
The safety profile of glofitamab-GemOx was consistent with the known toxicities of the individual agents:
- Cytokine Release Syndrome (CRS): Occurred in 44.2% of patients receiving glofitamab-GemOx, with most cases being low-grade (grade 1: 31.4%, grade 2: 10.5%, grade 3: 2.3%) and typically occurring in cycle 1
- Treatment Exposure: Patients in the glofitamab-GemOx arm received a median of 11 cycles, compared to 4 in the rituximab-GemOx arm, largely due to disease progression in the control group
Mechanism of Action and Clinical Significance
Glofitamab is a CD20xCD3 T-cell-engaging bispecific antibody with a unique 2:1 format that includes two CD20-binding domains and one CD3-binding domain. This design brings T cells into close proximity with malignant B cells to promote immune-mediated cytotoxicity.
Unlike CAR T-cell therapies, glofitamab-GemOx offers a fixed-duration, off-the-shelf therapy that can be administered in outpatient settings with appropriate monitoring—a significant advantage for patients ineligible for cellular therapies.
Regulatory Status and Future Direction
Glofitamab monotherapy received accelerated approval in the US in June 2023 for R/R DLBCL following two or more prior lines of therapy. The STARGLO study was intended as a confirmatory trial to support full approval.
The FDA's decision on the supplemental biologics license application (sBLA) for glofitamab in combination with GemOx is expected by July 20, 2025. The regimen has already been approved in more than 30 countries and has a National Comprehensive Cancer Network (NCCN) Category 1 preferred recommendation in the US for second-line transplant-ineligible DLBCL.
FDA Committee Concerns
The ODAC's negative vote centered on concerns about the applicability of the STARGLO results to US patients. The FDA briefing document noted imbalanced prognostic factors between treatment arms among North American patients, with the glofitamab arm having more patients with primary refractory disease (80.0% vs 40.0%), higher International Prognostic Index scores (66.6% vs 50.0%), and more advanced stage disease (80.0% vs 66.7%).
"This imbalance underscores the difficulties with interpreting data from small subgroups, where the effectiveness of randomization in terms of balancing prognostic factors between treatment arms was essentially lost," the FDA briefing document stated.
Implications for Clinical Practice
For oncology pharmacists and clinicians, the STARGLO results offer important insights for managing treatment-refractory aggressive B-cell lymphomas:
- Toxicity Management: CRS, although mostly low-grade, requires readiness with antipyretics, corticosteroids, and tocilizumab protocols
- Patient Selection: Appropriate selection based on prior therapy lines, performance status, and transplant ineligibility criteria will be crucial for optimizing outcomes
- Alternative to CAR T: Given its fixed-duration and immediate availability, glofitamab-GemOx may serve as an important option for patients unable to receive or access CAR T-cell therapy
Glofitamab is also being studied in earlier lines of DLBCL, including in combination with polatuzumab vedotin and R-CHP in the SKYGLO phase 3 study (NCT06047080). The oncology community awaits full presentation of two-year follow-up data from STARGLO at the ASCO 2025 Annual Meeting, which may further inform practice patterns and regulatory decision-making.
