FDA ODAC Votes Against the Applicability of STARGLO Data for Glofitamab Plus Chemo for U.S. Patients With R/R DLBCL

FDA

The FDA’s Oncologic Drugs Advisory Committee (ODAC) voted 8 to 1 against the applicability of the patient population and results from the phase 3 STARGLO trial (NCT04408638) to the United States (US) population of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL).1

STARGLO evaluated glofitamab-gxbm (Columvi) in combination with gemcitabine and oxaliplatin (GemOx), and based on data from the study, in December 2024, the FDA accepted a supplemental biologics license application seeking the approval of glofitamab plus GemOx for the treatment of patients with relapsed/refractory DLBCL who have received at least 1 prior line of therapy and who are not candidates for autologous stem cell transplant (ASCT).2

"This was a very tough and close call for me…[The differences in outcomes between Asian and non-Asian populations] could just be a subgroup analysis leading to heterogeneity in treatment effects that can arise from chance, but I would argue that [this] also adds to the uncertainty [about the outcomes for glofitamab plus GemOx in the US population]," Toni Choueiri, MD, of Dana-Farber Cancer Center in Boston, Massachusetts, said following the vote.

In June 2023, the FDA granted accelerated approval to glofitamab for the treatment of adult patients with relapsed/refractory DLBCL not otherwise specified or large B-cell lymphoma arising from follicular lymphoma after at least 2 lines of systemic therapy.3

"I voted no. We’re sitting here at the US FDA, and there were 25 patients on this trial from the US," Daniel Spratt, MD, of University Hospitals Seidman Cancer Center and Case Western Reserve University, said. "It’s imperative—just like the company did [in China] and [what it] sounds like they’re willing to do [in the US]—to ensure that sufficient patients [are enrolled from a given region] in this trial or expansion cohorts. I’m very glad to hear [the company is] actively doing so and willing to do so here in the US. Our patients deserve that."

STARGLO Background and Key Data

The randomized, open-label study enrolled patients at least 18 years of age with histologically confirmed relapsed/refractory DLBCL who had received at least 1 prior line of therapy and were ineligible for ASCT.4 The study included patients enrolled at 62 centers from 13 countries in Asia, Australia, Europe, and North America.

Investigators randomly assigned patients 2:1 to receive glofitamab at step-up dosing to 30 mg in combination with gemcitabine at 1000 mg/m2 and oxaliplatin at 100 mg/m2 for 8 cycles, followed by 4 cycles of glofitamab monotherapy; or rituximab (Rituxan) at 375 mg/m2 plus GemOx for 8 cycles. Overall survival (OS) served as the study’s primary end point.

Findings from the study’s primary analysis demonstrated that at median follow-up of 11.3 months (95% CI, 9.6-12.7), patients treated with glofitamab plus GemOx (n = 183) achieved a median OS that was not estimable (NE; 95% CI, 13.8-NE) compared with 9.0 months (95% CI, 7.3-14.4) for those given rituximab plus GemOx (n = 91; HR, 0.59; 95% CI, 0.40-0.89; P = .011).

An updated analysis showed that at a median follow-up of 20.7 months (95% CI, 19.9-23.3), the median OS was 25.5 months (95% CI, 18.3-NE) for glofitamab plus GemOx vs 12.9 months (95% CI, 7.9-18.5) for rituximab plus GemOx (HR, 0.62; 95% CI, 0.43-0.88).

FDA’s Position

During the meeting, the regulatory agency raised concerns regarding the enrollment of STARGLO, which the FDA said was a multiregional trial with a large Asian population and smaller US representation.5 Additionally, the FDA flagged inconsistent efficacy results in different regional subgroups.

In the intention-to-treat population (n = 274), 9% of patients (n = 25) were from North America, 32% of patients (n = 88) were from Europe, 11% of patients (n = 30) were from Australia, and 48% of patients (n = 131) were from Asia.

A subgroup analysis from the study showed that OS benefits differed for glofitamab plus GemOx among patients from Europe (glofitamab arm, n = 62; rituximab arm, n = 26; HR, 1.09; 95% CI, 0.54-2.18), patients from North America (glofitamab arm, n = 15; rituximab arm, n = 10; HR, 2.62; 95% CI, 0.56-12.34), and patients from the rest of the world (glofitamab arm, n = 106; rituximab arm, n = 55; HR, 0.41; 95% CI, 0.27-0.64).

When assessing outcomes for patients from non-Asian regions, patients treated with glofitamab plus GemOx (n = 99) experienced a median OS of 21.2 months compared with 27.8 months for those given rituximab plus GemOx (n = 44; HR, 1.06; 95% CI, 0.61-1.84). In patients enrolled from Asian regions, the median OS was NE for glofitamab plus GemOx (n = 84) vs 8.2 months for rituximab plus GemOx (n = 47; HR, 0.39; 95% CI, 0.25-0.63).

“The treatment effect across all efficacy end points was inconsistent between the Asian and non-Asian regional subgroups,” Nicole Sunseri, MD, PhD, of the Division of Hematologic Malignancies in the Office of Oncologic Diseases at the FDA, said during the meeting. “Given the size of the Asian subgroup and the magnitude of the treatment effect, it is likely that the overall study results are being driven by the Asian regional subgroup.”

Sunseri explained that when the FDA considers results from a multiregional trial to support a potential approval, the regulatory agency must ensure that the data are applicable for the intended population in the US, and that the treatment aligns with standard oncologic care in the country.

The FDA outlined key differences in baseline characteristics between the Asian and non-Asian regional subgroups. Patients in the Asian subgroup had a median age of 62 years (range, 22-82) compared with 71 years (range, 20-88) among those in the non-Asian subgroup. Additionally, 80% of patients in the non-Asian subgroup were White. Furthermore, 65% of patients in the Asian subgroup refused ASCT, compared with only 7% of patients in the non-Asian subgroup.

In presentations from Genentech, the sponsor for glofitamab, the company argued that the results from the overall population were generalizable to the US population.6 They said that the subgroup point estimate was not a sound assessment of the true treatment benefit in the US population, and that multivariable analysis showed consistency in OS outcomes. They also highlighted that novel lymphoma therapies could explain the performance of rituximab plus GemOx outside of Asia.

References

1. May 20, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC). FDA. https://www.youtube.com/live/iSGFdhMgh1E
2. FDA accepts supplemental biologics license application for Genentech’s Columvi combination for people with relapsed or refractory diffuse large B-cell lymphoma. News release. Genentech. December 4, 2024. Accessed May 20, 2025. https://www.gene.com/media/press-releases/15045/2024-12-04/fda-accepts-supplemental-biologics-licen
3. FDA approves Genentech’s Columvi, the first and only bispecific antibody with a fixed-duration treatment for people with relapsed or refractory diffuse large B-cell lymphoma. News release. Genentech. June 15, 2023. Accessed May 20, 2025. https://www.gene.com/media/press-releases/14994/2023-06-15/fda-approves-genentechs-columvi-the-firs
4. Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet. 2024;404(10466):1940-1954. doi:10.1016/S0140-6736(24)01774-4
5. Glofitamab-gxbm FDA opening remarks. FDA. May 20, 2025. Accessed May 20, 2025. https://www.fda.gov/media/186557/download
6. Glofitamab (Columvi). FDA. May 20, 2025. Accessed May 20, 2025. https://www.fda.gov/media/186558/download