FDA Issues Complete Response Letter for Glofitamab in R/R DLBCL Combination Therapy

The FDA has issued a complete response letter (CRL) regarding the supplemental biologics license application (sBLA) for glofitamab (Columvi) in combination with gemcitabine and oxaliplatin (GemOx) for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). The CRL indicates that data from the phase 3 STARGLO study (NCT04408638) did not provide sufficient evidence to support the proposed second-line DLBCL indication within the US patient population.¹

This decision means that, while the sBLA for the combination therapy was not approved for this specific second-line indication, glofitamab retains its existing accelerated approval in the US for adult patients with R/R DLBCL not otherwise specified or with large B-cell lymphoma arising from follicular lymphoma after 2 or more lines of systemic therapy. The FDA's action underscores the stringent regulatory scrutiny applied to novel oncology therapies, particularly when seeking expanded indications based on specific patient subsets and treatment lines.

In May 2025, the FDA's Oncologic Drugs Advisory Committee (ODAC) voted that the results were not applicable to a US patient population, with a total of 9% of patients enrolled in the US and 48% in Asian regions.²

“We’re sitting here at the US FDA, and 25 patients were enrolled from the US,” said Daniel Spratt, MD, ODAC member and chairman and professor of radiation oncology at University Hospital Seidman Cancer Center, when explaining the reason why he voted no.

The STARGLO study was a global, multicenter, open-label, randomized phase 3 trial that evaluated the efficacy and safety of glofitamab plus GemOx compared with rituximab (Rituxan) plus GemOx in adult patients with R/R DLBCL who had received 1 prior line of therapy and were ineligible for autologous stem cell transplant. The trial demonstrated a statistically significant and clinically meaningful 41% reduction in the risk of death for patients treated with the glofitamab combination, corresponding to a hazard ratio of 0.59.¹ These compelling results were published in The Lancet and presented at the 61st American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting the therapeutic potential of glofitamab in a challenging patient population.

Despite the FDA's recent CRL for the second-line indication in the US, the glofitamab-GemOx combination has garnered regulatory approvals in over 35 countries globally for the treatment of R/R DLBCL after 1 prior line of therapy. Furthermore, glofitamab monotherapy is approved in more than 60 countries for R/R DLBCL after 2 or more prior lines of therapy. Its clinical utility is also recognized within key US clinical practice guidelines, including the National Comprehensive Cancer Network (NCCN) Guidelines® for B-Cell Lymphomas, which recommend glofitamab as an option for specific subsets of patients with R/R DLBCL. This broad international acceptance and inclusion in clinical guidelines underscore the global medical community's recognition of glofitamab as a valuable therapeutic option.

Looking ahead, discussions are ongoing with the FDA regarding a potential new postmarketing requirement involving the phase 3 SKYGLO study (NCT06047080). This trial is designed to investigate glofitamab in combination with polatuzumab vedotin (Polivy), rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) for individuals with previously untreated large B-cell lymphoma. The outcome of these discussions and the potential for new clinical data will be crucial in defining the future landscape for glofitamab's role in earlier lines of therapy.

The development of new therapies for R/R DLBCL remains a critical area of unmet need in oncology. While the recent CRL for the expanded second-line indication in the US represents a setback, glofitamab continues to offer a treatment option for heavily pretreated patients, and ongoing research aims to further define its role across the DLBCL treatment paradigm.

REFERENCES:

1. Genentech provides update on supplemental biologics license application for Columvi combination for people with relapsed or refractory diffuse large B-cell lymphoma. News release. Genentech. July 21, 2025. Accessed July 21, 2025. https://tinyurl.com/2bbtwdpa
2. Meeting of the Oncologic Drug Advisory Committee. FDA. May 20, 2025. Accessed July 21, 2025. https://tinyurl.com/5n7mwvjt