Zolbetuximab Plus Chemo Wins Approval in China for CLDN18.2+ Advanced Gastric/GEJ Adenocarcinoma

China's National Medical Products Administration (NMPA) has approved zolbetuximab (Vyloy) in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are Claudin18.2 (CLDN18.2) positive.1

The regulatory decision was supported by data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials.

“Approximately 35% of Chinese patients with advanced and metastatic gastric and GEJ cancers have tumors that positively express CLDN18.2. By specifically targeting this biomarker with zolbetuximab, we are able to stimulate selective cell death, reducing the overall number of CLDN18.2-positive cells in a tumor,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, stated in a news release. “The NMPA approval of zolbetuximab offers a new precision medicine for first-line use in China, supporting our ongoing ambition to drive progress and innovation in cancer care.”

In October 2024, the FDA approved zolbetuximab-clzb in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test.2

SPOTLIGHT Data

Findings from the global, randomized, placebo-controlled, double-blind SPOTLIGHT study showed that zolbetuximab plus chemotherapy produced a statistically significant reduction in the risk of progression or death compared with placebo plus chemotherapy (HR, 0.75, 95% CI 0.60-0.94; P = .0066).3 Patients treated with zolbetuximab plus chemotherapy (n = 283) experienced a median progression-free survival (PFS) of 10.61 months (95% CI, 8.90-12.48) compared with 8.67 months (95% CI, 8.21-10.28) for those given placebo plus chemotherapy (n = 282). The estimated 12- and 24-month PFS rates in the zolbetuximab group were 49% (95% CI, 42%-55%) and 24% (95% CI, 17%-32%), respectively. In the placebo group, these respective rates were 35% (95% CI, 28%-42%) and 15% (95% CI, 9%-22%).

The study included patients at least 18 years of age with CLDN18.2-positive, HER2-negative, previously untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. CLDN18.2 positivity was defined as at least 75% of tumor cells showing moderate-to-strong membranous CLDN18 staining, determined by central immunohistochemistry. Other key inclusion criteria consisted of radiologically evaluable disease per RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function.

Patients were randomly assigned 1:1 to receive zolbetuximab plus mFOLFOX6 or placebo plus mFOLFOX6. In the experimental arm, zolbetuximab was given at 800 mg/m2 on day 1 of cycle 1, followed by 600 mg/m2 on day 22 of cycle 1 and days 1 and 22 of subsequent cycles, in combination with folinic acid at 400 mg/m2, fluorouracil at 400 mg/m2 bolus followed by 2400 mg/m2 in a 46- to 48-hour infusion, and oxaliplatin at 85 mg/m2 on days 1, 15, and 29 for the first 4 42-day cycles. In cycle 5 and beyond, those without disease progression continued to receive zolbetuximab; folinic acid and fluorouracil were allowed to be continued at the investigators' discretion. In the control arm, patients received placebo in place of zolbetuximab along with the same mFOLFOX6 regimen.

PFS per RECIST 1.1 criteria served as the trial’s primary end point. Key secondary end points included overall survival (OS) and time to confirmed deterioration.

GLOW Overview

In the global, randomized, double-blind, placebo-controlled GLOW trial, patients treated with zolbetuximab plus CAPOX (n = 254) experienced a median PFS of 8.21 months (95% CI, 7.46-8.84) compared with 6.80 months (95% CI, 6.14-8.08) for those given placebo plus CAPOX (n = 253; HR, 0.687; 95% CI, 0.544-0.866; P = .0007).4 In the experimental arm, the 12- and 24-month PFS rates were 35% and 14%, respectively. These respective rates were 19% and 7% in the placebo arm.

Investigators enrolled patients with previously untreated, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma that was CLDN18.2 positive and HER2 negative. The definition for CLDN18.2 positivity mirrored the SPOTLIGHT trial criteria. Patients also needed to have an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive zolbetuximab plus CAPOX or placebo plus CAPOX. In the experimental arm, zolbetuximab was given at 800 mg/m2 on day 1 of the first 21-day cycle, then 600 mg/m2 on day 1 of subsequent cycles, plus CAPOX consisting of 1000 mg/m2 of capecitabine twice per day on days 1 to 14 of each cycle and 130 mg/m2 of oxaliplatin on day 1 of each cycle for up to 8 cycles. Zolbetuximab plus capecitabine was continued in cycle 9 and beyond. Patients in the control arm received placebo in lieu of zolbetuximab, plus the same chemotherapy regimen.

PFS was the trial’s primary end point. Secondary end points included OS, time to confirmed deterioration, overall response rate, duration of response, safety, and patient-reported outcomes.

Safety Data for Zolbetuximab

Findings from SPOTLIGHT and GLOW showed that the incidence of serious treatment-emergent adverse effects (TEAEs) was similar between the zolbetuximab and placebo groups.1 The most common any-grade TEAEs that occurred in patients treated with zolbetuximab included nausea, vomiting, and decreased appetite.

“Approximately 30% of patients enrolled in the global phase 3 GLOW trial were from mainland China. The results of this study demonstrated that the combination of zolbetuximab and chemotherapy provided significant survival benefits to patients with CLDN18.2-positive, HER2-negative advanced gastric and GEJ cancers,” Xu Ruihua, MD, PhD, lead primary investigator of GLOW, director of the Cancer Prevention and Treatment Center of Sun Yat-sen University, and president of the Chinese Society of Clinical Oncology, stated in a news release.1 “The analysis of the China subgroup data showed that Chinese [patients with] gastric cancer benefited substantially in terms of both survival and quality of life. We are excited that the NMPA has approved zolbetuximab, which will provide a valuable and effective first-line treatment option for patients with advanced gastric cancer in China.”

References

1. China's National Medical Products Administration (NMPA) approves Vyloy (zolbetuximab) for first-line treatment of advanced gastric or gastroesophageal junction adenocarcinoma. News release. Astellas. January 5, 2025. Accessed January 6, 2025. https://newsroom.astellas.us/2025-01-05-Chinas-National-Medical-Products-Administration-NMPA-Approves-VYLOY-TM-zolbetuximab-for-First-Line-Treatment-of-Advanced-Gastric-or-Gastroesophageal-Junction-Adenocarcinoma
2. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed January 6, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma
3. Shitara K, Lordick F, Bang YJ, 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. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7
4. Xu R-H, 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. J Clin Oncol. 2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736