FDA Grants Priority Review to BLA for Zolbetuximab in Advanced, HER2-, CLDN18.2+ Gastric/GEJ Cancer


The FDA plans to conduct a speedy review of an approval application for zolbetuximab in first-line locally advanced, unresectable, or metastatic HER2-negative, claudin18.2-positive gastric or gastroesophageal junction adenocarcinoma.

  • Positive results from 2 phase 3 clincial trials led to the filing of a biologic license application (BLA) for zolbetuximab to treat first-line, advanced, HER2-negative,claudin (CLDN)18.2-positive gastric or gastoesophageal junction (GEJ) adenocarcinoma by Astellas Pharma, Inc.

  • The FDA has set a Prescription Drug User Fee Act target action date of January 12, 2024 for the BLA.

  • Zolbetuximab is a first-in-class investigational Claudin 18.2 (CLDN18.2)-targeted monoclonal antibody.

The FDA has granted priority review to the BLA for zolbetuximab for the upfront treatment of patients with locally advanced, unresectable, or metastatic HER2-negative, CLDN18.2-positive gastric or GEJ adenocarcinoma.1

Supporting the BLA are results from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies. In both studies, the addition of zolbetuximab to a chemotherapy regimen provided a significant overall survival (OS) and progression-free survival (PFS) benefit in patients with advanced, HER2-negative, CLDN18.2-positive gastric/GEJ cancer.2,3 The FDA’s swift review of the data in these studies is expected to conclude on the Prescription Drug User Fee Act target action date of January 12, 2024.1

"Astellas is committed to bringing innovative therapies to patients with hard-to-treat cancers, including gastric cancer. While rare in the United States, gastric cancer can be deadly when diagnosed in the late stages," said Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development, Astellas, in a press release. "The FDA's acceptance of the biologics license application filing and priority review designation for zolbetuximab confirms the urgent therapeutic need and brings us one step closer to delivering on this commitment to patients, families, and caregivers."

Results from the GLOW trial were announced during the 2023 March ASCO Plenary Series by Manish Shah, MD, PhD. Overall, 507 patients were included in the study and treated with either zolbetuximab plus oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6; n = 254) or placebo plus mFOLFOX6 (n = 253).

At a median follow-up of 12.62 months in the experimental arm vs 12.09 months in the comparator arm, the median PFS was 8.21 months (95% CI, 7.46-8.84 months) compared with 6.80 months (95% CI, 6.14-8.08 months), respectively (HR, 0.687; 95% CI, 0.544-0.866; P =.0007). The 12-month PFS rate with zolbetuximab/CAPOX was 35% vs 19% with placebo/CAPOX, and the 24-month PFS rate was 14% vs 7%, respectively.2

Image Credit: © LASZLO - www.stock.adobe.com| Early stage gastric cancer tumor on the stomach wall angle view 3d illustration

Image Credit: © LASZLO - www.stock.adobe.com

Treatment with zolbetuximab plus CAPOX also showed a median OS of 14.39 months (95% CI, 12.29-16.49 months) vs 12.16 months (95% CI, 10.28-13.67 months) with the comparator (HR, 0.771; 95% CI, 0.615-0.965; P = .0118). At 12 months, the OS rate was 58% with zolbetuximab/CAPOX compared with 51% in the placebo/CAPOX arm. The 24-month OS was 29% in the experimental arm vs 17% in the comparator arm.

Notably, the survival benefit shown with the addition of zolbetuximab to chemotherapy was consistent in the subgroups assessed during the study.

Further, efficacy results showed that the objective response rate (ORR) in the zolbetuximab/CAPOX arm was 53.5% (95%, 46.58%-60.99%) vs 48.4% (95% CI, 41.76%-55.84%) in the comparator arm. The median duration of response (DOR) was similar in both arms at 6.28 (95% CI, 5.39-8.28 months) with zolbetuximab and CAPOX compared with 6.18 (95% CI, 4.53-6.41 months) with the combination of placebo and CAPOX.

Safety findings from GLOW showed the addition of zolbetuximab to CAPOX to be tolerable with manageable adverse events (AEs).

Treatment-emergent adverse events (TEAEs) occurred in 98.8% of the experimental arm vs 98.0% of the comparator arm, and TEAEs were grade 3 or higher in 72.8% vs 69.6% of patients, respectively. Serious TEAEs occurred in 47.2% of the zolbetuximab/CAPOX arm vs 49.8% of those treated with placebo and CAPOX. Percentages of patients needing to discontinue any study drug due to treatment-related AEs (TRAES) were similar in both arms. TRAEs leading to discontinuation of zolbetuximab or CAPOX alone occurred in 7.1% of the experimental arm vs 4.4% of the comparator arm.

The most common TEAEs in experimental vs comparator the study were nausea (8.7% v 2.4%) and vomiting (12.2% v 3.6%). During the presentation, Shah noted that these were predominantly grade 1 events that were resolved after the first or second treatment cycle.

Prior to GLOW, results from SPOTLIGHT were reported, which came from 565 patients with advanced, HER2-negative, CLDN18.2-positie gastric/GEJ cancers. A 25% reduction in the risk of disease progression or death was achieved with zolbetuximab plus mFOLFOX6 compared with placebo plus mFOLFOX6 (HR, 0.751; 95% CI, 0.589-0.942; P = .0066). The median PFS shown was 10.61 (95% CI, 8.90-12.48) in the zolbetuximab/mFOLFOX6 arm vs 8.67 months (95% CI, 8.21-10.28) with placebo plus mFOLFOX6.

At months 12 and 24, the PFS rates were 49% and 24%, respectively, in the zolbetuximab arm and 35% and 15%, respectively, in the placebo arm. The PFS benefit with zolbetuximab/mFOLFOX6 was consistent in the prespecified subgroups, excluding patients for whom the primary site of disease was GEJ (HR, 1.015; 95% CI, 0.649-1.586) as well as those with mixed/other classification (HR, 0.929; 95% CI, 0.601-1.434).

The combination of zolbetuximab and mFOLFOX6 led to a median OS 18.23 months (95% CI, 16.43-22.90) compared with 15.54 months (95% CI, 13.47-16.53) in the placebo/mFOLFOX6 arm (HR, 0.750; 95% CI, 0.601-0.936; P = .0053).

The OS rates were assessed at months 12, 24, and 36. The 12-24-, and 26-month OS rates in experimental arm vs the control arm were 68% vs 28%, 60% vs 21%, and 39% vs 9%, respectively.

In terms of responses to treatment, the ORR observed with zolbetuximab was 60.7% (95% CI, 53.72%-67.30%) vs 62.1% (95% CI, 55.17%-68.66%). The median DOR was 8.51 months (95% CI, 6.80-10.25) on the zolbetuximab arm and 8.11 months (95% CI, 6.47-11.37) on the placebo arm.

Safety findings from SPOTLIGHT showed that a 99.6% incidence of TEAEs in both arms. Grade 3 or higher TEAEs were reported in 86.7% and 77.7% of those on the zolbetuximab and placebo arms, respectively. Serious TEAEs occurred in 44.8% and 43.5%. TRAEs that led to treatment discontinuation of zolbetuximab or placebo occurred in 13.6% and 2.2% of patients, respectively. TRAEs led to death in 1.8% and 1.4% of patients, respectively.

The most common TEAEs associated with zolbetuximab/mFOLFOX6 were nausea (all-grade, 81.0%; grade ≥3, 16.1%), vomiting (all-grade, 64.5%; grade ≥3, 16.1%), and decreased appetite (all-grade, 47.0%; grade ≥3, 5.7%).

“We are committed to the ongoing clinical development of zolbetuximab and to bringing new therapeutic options for patients with locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma,” said Ahsan Arozullah, MD, MPH, senior vice president and head of Development Therapeutic Areas, Astellas, in a press release.4 “These 2 statistically significant phase 3 trials, GLOW and SPOTLIGHT, will serve as the basis for global regulatory submissions, marking remarkable progress in our gastric cancer development program.”


1. Astellas announces U.S. FDA grants priority review for zolbetuximab biologics license application. News release. Astellas. July 6, 2023. Accessed July 6, 2023. https://tinyurl.com/yd7d3p5s

2. Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. Published April 12, 2023. doi:10.1016/S0140-6736(23)00620-7

3. Xu RH, Shitara K, Ajani JA, et al. Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary phase 3 results from GLOW. Presented at: 2023 March ASCO Plenary Series. Abstract 405736.

4. Astellas announces positive findings from phase 3 glow trial of zolbetuximab during March ASCO Plenary Series. News release. Astellas Pharma, Inc. March 21, 2023. Accessed July 6, 2023. https://www.astellas.com/en/news/27481

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