FDA Issues Complete Response Letter for Glofitamab in DLBCL Treatment

On July 21, 2025, the U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) regarding the approval of glofitamab-gxbm (Columvi) in combination with gemcitabine and oxaliplatin (GemOx) for the treatment of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant and have received at least one prior line of therapy. This decision follows an 8-to-1 vote by the FDA's Oncology Drug Advisory Committee (ODAC) indicating that the results from the phase 3 STARGLO trial were insufficient to support the proposed treatment regimen in the U.S. population.

The STARGLO trial, identified by ClinicalTrials.gov identifier NCT04408638, was designed to evaluate the efficacy of the glofitamab and GemOx combination in patients with relapsed/refractory DLBCL. Although the trial showed promising results, the FDA expressed concerns regarding the applicability of the trial's findings to the U.S. patient population due to substantial differences in treatment effects observed among various regional subgroups. For instance, the hazard ratios (HR) for overall survival (OS) in North America and Europe were notably less favorable compared to the results from the Asia Pacific region.

Dr. Jeremy Abramson, director of the Jon and Jo Ann Hagler Center for Lymphoma at Massachusetts General Hospital, who served as the principal investigator for the STARGLO study, emphasized the critical need for effective treatments for patients with this aggressive form of lymphoma. He stated, “The STARGLO study showed that [glofitamab plus] GemOx significantly improves overall survival and could have a positive impact for patients earlier in their treatment journey.” The trial's two-year follow-up analysis indicated a median OS that was not evaluable (NE) with the glofitamab combination, compared to 13.5 months observed with rituximab plus GemOx.

Despite the CRL, glofitamab remains under accelerated approval for DLBCL patients in third-line or later treatment stages. This regulatory path highlights the ongoing commitment to making this treatment available to those who have exhausted other options. Levi Garraway, MD, PhD, chief medical officer at Genentech, expressed disappointment over the CRL but maintained confidence in the data supporting glofitamab's potential. “We are committed to bringing [glofitamab] to more people living with lymphoma and are actively exploring its potential in additional treatment settings, including as frontline therapy,” he remarked.

The ODAC meeting brought to light significant concerns regarding the trial's data, particularly the inconsistent treatment effects across different demographics, disease burdens, and treatment histories. The FDA noted these discrepancies raised questions about the robustness of the trial results and their generalizability to the intended U.S. patient population. As stated in the ODAC briefing document, “These observed differences and their potential contributing factors raise substantial concerns regarding both the robustness of the trial results and their applicability.”

With over 35 countries having already approved the combination treatment, the implications of the FDA's decision are significant. Patients in the U.S. with relapsed/refractory DLBCL may face limited options as they navigate post-relapse treatment, underscoring the urgency for further research and potential alternative strategies to address this challenging aspect of lymphoma management. As the medical community continues to explore this landscape, the future of glofitamab as a treatment option remains uncertain yet pivotal for many patients awaiting new therapies to combat their disease.