In lieu of an 8-to-1 ODAC ruling against the applicability of the phase 3 STARGLO results in US patients, a CRL has been issued for glofitamab in relapsed/refractory DLBCL.
The FDA has issued a complete response letter (CRL) for glofitamab-gxbm (Columvi) with gemcitabine and oxaliplatin (GemOx) as a treatment for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem cell transplant and received at least 1 prior line of therapy, according to a release from the developer, Genentech.1
The FDA found that results from the phase 3 STARGLO trial (NCT04408638) were insufficient to support the combination in the proposed patient population. The treatment will continue to remain under accelerated approval for patients with DLBCL in the third-line or later stage of treatment.
In December 2024, the FDA accepted a supplemental biologics license applicationfor the agent in this indication.2 More recently, in May 2025, the FDA’s Oncology Drug Advisory Committee (ODAC) voted 8-to-1 against the applicability of the supporting trial’s population and results to the proposed US population.3
Results evaluating the glofitamab combination in patients with relapsed/refractory DLBCL came from the STARGLO trial. Updated results from the trial were shared at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting.4
“For patients with this aggressive form of lymphoma, effective treatment after relapse is paramount. The STARGLO study showed that [glofitamab plus] GemOx significantly improves overall survival [OS] and could have a positive impact for patients earlier in their treatment journey. This regimen is already approved in over 35 countries, which underscores the urgent need it addresses,” stated Jeremy Abramson, MD, director of the Jon and Jo Ann Hagler Center for Lymphoma at the Massachusetts General Hospital Cancer Center, and principal investigator of the STARGLO study, in the press release.1
STARGLO Data
At the 2-year follow-up analysis, the median OS was not evaluable (NE; 95% CI, 19.2 months-NE) with glofitamab plus GemOx vs 13.5 months (95% CI, 7.9-13.5) with rituximab (Rituxan) plus GemOx (HR, 0.60; 95% CI, 0.42-0.85; P = .003). The 24-month OS rate was 54.4% (95% CI, 46.8%-62.0%) vs 33.6% (95% CI, 22.9%-44.2%), respectively.
The median progression-free survival (PFS) was 13.8 months (95% CI, 8.8-30.0) with gemcitabine vs 3.6 months (95% CI, 2.5-7.1) with rituximab (HR, 0.41; 95% CI, 0.29-0.58; P <.001). The 18-month PFS rates were 46.5% (95% CI, 38.5%-54.5%) vs 23.0% (95% CI, 11.5%-34.4%). The overall response rate (ORR) was 68.3% (95% CI, 61.0%-75.0%) vs 40.7% (95% CI, 30.5%-51.5%), respectively; the complete response (CR) rate was 58.5% (95% CI, 51.0%-65.7%) vs 25.3% (95% CI, 16.8%-35.5%), and the median duration of CR was NE (95% CI, 27.2 months-NE) vs 24.2 months (95% CI, 6.9-NE).
The landmark analysis by response at end-of-treatment in those treated with glofitamab plus GemOx revealed a median OS of NE and a 12-month OS rate of 89.3% (95% CI, 82.3%-96.4%); the median PFS was NE and the 12-month PFS rate was 82.4% (95% CI, 72.2%-92.5%). It was noted that more than 80% of patients with a CR at end-of-treatment were progression-free and alive 12 months after treatment ended.
ODAC Meeting
In a document briefing from the ODAC meeting, the primary issues regarding the STARGLO trial results were the inconsistent treatment effects between regional subgroups and the applicability of these trial results to a US patient population.5
The FDA noted that there were considerable differences between subgroups regarding efficacy for OS, PFS, CR, and ORR; regarding patient and disease-related factors for demographics, disease burden and histology, and treatment history; and regarding treatment and data capture for exposure, concordance in response assessments, timing of efficacy assessments, and use of new anti-lymphoma therapy.
For patients enrolled in Europe (n = 88) and North America (n = 25), the HRs for OS were 1.09 (95% CI, 0.54-2.18) and 2.62 (95% CI, 0.56-12.34), suggesting that rituximab plus GemOx was more effective; for the rest of the world (n = 161), it was 0.41 (95% 0.27-0.64).
Further, the FDA modified the groupings to include an Asian region consisting of China, Korea, and Taiwan, and a non-Asia region consisting of North America, Europe, and Australia.
In the Asian region, the median OS was NE (19.2 months-NE) with glofitamab vs 8.2 months (95% CI, 4.5-14.3) with rituximab (HR, 0.39; 95% CI, 0.25-0.63); in the non-Asian region, the median OS was 21.2 months (95% CI, 11.9-NE) with the glofitamab combination and 27.8 months (95% CI, 12.5-NE) with the rituximab regimen (HR, 1.06; 95% CI, 0.61-1.84). The p-value for this OS difference was .0081.
The FDA ran an exploratory, post-hoc analysis using interaction tests to determine the consistency of the treatment effect across various efficacy end points. The PFS hazard ratio for glofitamab vs rituximab was 0.25 (95% CI, 0.15-0.41) in the Asian region and 0.81 (95% CI, 0.48-1.35) in the non-Asian region (P = .0006); the CR risk difference was 44% (95% CI, 27%-60%) in the Asian region vs 22% (95% CI, 4%-41%) in the non-Asian region (P = .0612); and the ORR risk difference was 46% (95% CI, 28%-63%) in the Asian region and 9% (95% CI, –10% to 28%) in the non-Asian region (P = .0036).
“These observed differences and their potential contributing factors raise substantial concerns regarding both the robustness of the trial results and their applicability to the intended US patient population. Consequently, these findings warrant careful consideration in the interpretation and generalizability of the STARGLO trial results,” wrote the FDA ODAC panel, in the briefing.5
Trial Breakdown
A total of 274 patients were randomly assigned, in a 2:1 ratio, to receive glofitamab step-up dosing in cycle 1 then 30 mg on day 1 from cycle 2 onwards, or rituximab. Eligible patients had relapsed or refractory DLBCL not otherwise specified after at least 1 prior line of systemic therapy—those with 1 prior line were required to be transplant ineligible—and an ECOG performance status of 0 or 2.
Regarding patient race, 56.0% and 47.0% of those who received rituximab and glofitamab were Asian, 36.3% and 44.8% were White, 1.1% and 1.1% were Black, and 6.6% and 7.1% were other. Regarding region, 161 patients were from the Asia Pacific region, 88 were from Europe, and 25 were from North America.
“While we are disappointed with this outcome, we remain confident in the data supporting the value of [glofitamab] for U.S. patients who have relapsed following initial treatment, and its key role as monotherapy in the third-line setting,” said Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development, in the press release.1 “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.”
References
- 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/4k5cs25n
- FDA accepts supplemental Biologics License Application for Roche’s Columvi combination for people with relapsed or refractory diffuse large B-cell lymphoma. News release. Roche. December 5, 2024. Accessed July 7, 2025. https://tinyurl.com/5edss86j
- May 20-21, 2025, Meeting of the Oncologic Drugs Advisory Committee (ODAC) – day 1. FDA. Accessed July 7, 2025. https://tinyurl.com/28cema3t
- Abramson JS, Ku M, Hertzberg M, et al. Glofitamab plus gemcitabine and oxaliplatin (Glofit-GemOx) in patients (pts) with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL): 2-year (yr) follow-up of STARGLO. J Clin Oncol. 2025;43(suppl 16):7015. doi:10.1200/JCO.2025.43.16_suppl.7015
- Oncologic Drugs Advisory Committee (ODAC) Meeting May 20, 2025. BLA 761309/Supplement 001. FDA. Accessed May 20, 2025. https://tinyurl.com/3mcx9yvx