GLOW Trial: Zolbetuximab Plus CAPOX Extends Survival in Gastric Cancer Subtype

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First-line treatment with zolbetuximab in combination with capecitabine and oxaliplatin (CAPOX) extended overall survival in patients with claudin-18.2 (CLDN18.2)-positive/HER2-negative locally advanced or metastatic gastric adenocarcinoma, according to results of the GLOW trial reported by Xu et al during the ASCO Plenary Series: March 2023 Session (Abstract 405736).

Median progression-free survival was 8.2 months in the zolbetuximab group compared to 6.8 months in the placebo group (hazard ratio [HR] = 0.687, P = .0007) and median overall survival was 14.4 vs 12.2 months (HR = 0.771, P = .0118), respectively, according to the study’s senior investigator, Manish Shah, MD, who presented the findings in a virtual session. Dr. Shah is Director of the Gastrointestinal Oncology Program at Weill Cornell Medicine, New York and Chief of the Solid Tumor Oncology Service and Co-Director of the Center for Advanced Digestive Care at New York Presbyterian Hospital. GLOW’s first author was Rui-Hua Xu, MD, PhD, of the Sun Yat-Sen University Cancer Center in Guangzhou, China.

GLOW confirmed that zolbetuximab plus chemotherapy is a new standard-of-care treatment for patients with CLDN18.2-positive, HER2-negative, locally advanced disease.
— Manish Shah, MD

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“The progression-free and overall survival benefits were sustained at 24 months, and the survival benefits were observed across most subgroups,” Dr. Shah reported. “Zolbetuximab successfully targets CLDN18.2 and meets a highly unmet medical need in the treatment of metastatic gastric/gastroesophageal adenocarcinoma. GLOW confirmed that zolbetuximab plus chemotherapy is a new standard-of-care treatment for patients with CLDN18.2-positive, HER2-negative, locally advanced disease.”

GLOW Validates Previous SPOTLIGHT Trial

The results validate findings from the global phase III SPOTLIGHT trial, recently presented at the 2023 ASCO Gastrointestinal Cancers Symposium (Abstract LBA292). Patients treated with the combination of zolbetuximab and leucovorin, fluorouracil, and oxaliplatin (mFOLFOX6) had a 25% reduction in the risk of disease progression or death (P = .0066), as well as a 25% reduction in mortality (P = .0053).

Rui-Hua Xu, MD, PhD

Rui-Hua Xu, MD, PhD

Pamela L. Kunz, MD

Pamela L. Kunz, MD

ASCO expert in gastrointestinal cancers Pamela L. Kunz, MD, Director of the Center for Gastrointestinal Cancers and Chief of GI Medical Oncology at Smilow Cancer Hospital and Yale Cancer Center, commented on the findings: “Together, the results of the GLOW and SPOTLIGHT trials are poised to change the treatment landscape for patients with CLDN18.2-positive, HER2-negative advanced gastric/gastroesophageal junction cancer.” Noting that the current standard of care for the first-line treatment of this malignancy is platinum/fluoropyrimidine plus nivolumab, Dr. Kunz added, “The biggest question this trial [GLOW] raises is how zolbetuximab will compare to or combine with checkpoint inhibitors.”

About the Biomarker and the Agent

CLDN18.2 is a protein found on cells in the stomach and in the gastroesophageal junction. Zolbetuximab binds to CLDN18.2 on cancer cells, causing cancer cell death. CLDN18.2 status is not routinely evaluated in patients with locally advanced, resectable, or metastatic gastric/gastroesophageal junction adenocarcinoma, and there is currently no approved therapy for these patients. Zolbetuximab is a first-in-class chimeric IgG1 monoclonal antibody that targets and binds to CLDN18.2; it induces both antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity.

GLOW Details

The global phase III GLOW trial enrolled 507 previously untreated patients with locally advanced unresectable or metastatic gastric (86%) or gastroesophageal junction (14%) adenocarcinoma. All patients were HER2-negative and CLDN18.2-positive, as defined by ≥ 75% of tumor cells with moderate-to-strong membranous staining.

Patients were randomly assigned 1:1 to receive zolbetuximab at 800/600 mg/m2 every 3 weeks plus CAPOX, or placebo plus CAPOX. After eight cycles, patients continued on zolbetuximab at 600 mg/m2 every 3 weeks or placebo plus capecitabine until progressive disease or a discontinuation criterium was met. The primary endpoint was progression-free survival by independent review.

Other Outcomes

At a median follow-up of 12.6 months, the combination of zolbetuximab and CAPOX significantly improved progression-free survival and overall survival, with the curves remaining separate over time, but did not increase objective response rates.

For the zolbetuximab and placebo arms, respectively, progression-free survival rates were 35% vs 19% at 12 months and 14% vs 7% at 24 months (HR = 0.687, P = .0007). Similarly, overall survival rates were 58% vs 61% at 12 months and 29% vs 17% at 24 months (HR = 0.771, P = .0118). Objective response rates were 53.8% in the zolbetuximab arm vs 48.8% in the placebo arm.

Almost all patient subgroups benefited from zolbetuximab, though benefit was notably lacking in patients with gastroesophageal junction adenocarcinoma; the hazard ratios for this subset were 1.351 for progression-free survival and 1.013 for overall survival. Questioned on the poor performance of zolbetuximab in this group, Dr. Shah noted this subset comprised just 16% of the study population, although the small size of this group is an “unsatisfactory” explanation for this difference, he maintained. It is possible the biology and microenvironments of these tumors may be different, but the question of the drug’s relative efficacy remains unanswered, he said.

Regimen Generally Well Tolerated

The most common treatment-emergent adverse events with zolbetuximab plus CAPOX vs CAPOX alone were nausea (68.5% vs 50.2%), vomiting (66.1% vs 30.9%), and decreased appetite (41.3% vs 33.7%). Serious treatment-emergent adverse events (47.2% vs 49.8%), grade ≥ 3 events (72.8% vs 69.9%), and drug-related events leading to death (2.4% vs 2.8%) were similar between the arms.

“Nausea and vomiting were the most frequent treatment-emergent adverse events, and their initial onset was mostly [during] the first and second zolbetuximab cycles,” Dr. Shah said.

Interest is now focused on identifying which patients might benefit from this novel therapy, should it become approved. It is generally accepted that zoletuximab’s utility will be in patients with CLDN18.2-expressing tumors—though this is currently difficult to accomplish without a companion diagnostic or readily available assay.  

Yelena Y. Janjigian, MD

Yelena Y. Janjigian, MD

The study’s invited discussant Yelena Y. Janjigian, MD, Chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, concluded that while GLOW is “practice-changing” in that it validates CLDN18.2 expression as an important biomarker, “we need to wait for the U.S. Food and Drug Administration–approved immunohistochemistry test before we start testing in the clinic.”

Disclosure: For full disclosures of the study authors, visit


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