Zolbetuximab Earns European Approval in Advanced CLDN18.2+ Gastric Cancer

Supporting data for the European approval came from the phase 3 SPOTLIGHT trial (NCT03504397) and the phase 3 GLOW trial (NCT03653507), in which investigators assessed treatment with zolbetuximab plus chemotherapy among patients with locally advanced or unresectable CDN18.2-positive gastric or GEJ adenocarcinoma.

The European Commission has approved zolbetuximab (Vyloy) plus fluoropyrimidine- and platinum-based chemotherapy as a frontline treatment for adults with locally advanced, unresectable, or metastatic HER2-negative, Claudin 18.2 (CLDN18.2)–positive gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to a press release from the developers, Astellas Pharma Inc.¹

Approval from the European Commission follows a positive opinion from the European Medicine Agency’s Committee for Medicinal Products for Human Use issued in support of zolbetuximab in July 2024.² With this regulatory decision, zolbetuximab is now the only approved monoclonal antibody intended to target CLDN18.2 expressed in gastric tumor cells in the European Union.

“Sadly, due to similar symptoms to more common stomach conditions, gastric and [GEJ] cancers are often diagnosed at the advanced or metastatic stage when treatment options have traditionally been relatively limited,” Zorana Maravic, chief executive officer at Digestive Cancers Europe, said in the press release.¹ “Ensuring timely diagnosis, followed by personalized treatment and care, will be essential to better survival and quality of life for patients.”

Supporting data for the European approval came from the phase 3 SPOTLIGHT trial (NCT03504397) and the phase 3 GLOW trial (NCT03653507), in which investigators assessed treatment with zolbetuximab plus chemotherapy among patients with locally advanced or unresectable CDN18.2-positive gastric or GEJ adenocarcinoma.

SPOTLIGHT Trial

According to findings from the SPOTLIGHT trial published in The Lancet, the median progression-free survival (PFS) was 10.61 months (95% CI, 8.90-12.48) in patients who received zolbetuximab plus modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) vs 8.67 months (95% CI, 8.21-10.28) in those who received mFOLFOX6 alone (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).³ The 12-month PFS rates in each respective arm were 49% (95% CI, 42%-55%) vs 35% (95% CI, 28%-42%), and the 24-month rates were 24% (95% CI, 17%-32%) vs 15% (95% CI, 9%-22%). PFS outcomes were comparable across most patient subgroups.

In the zolbetuximab and chemotherapy alone arms, respectively, the most common any-grade treatment-emergent adverse effects (TEAEs) included nausea (82% vs 61%), vomiting (67% vs 36%), and decreased appetite (47% vs 33%). Additionally, 43% and 38% of patients from each arm had TEAEs leading to treatment discontinuation of any study drug. TEAES leading to death were reported in 8% and 9% of patients, respectively.

The trial’s primary end point was PFS per RECIST v1.1 criteria based on an independent review committee (IRC) assessment. Key secondary end points included overall survival (OS) and time to confirmed deterioration.

GLOW Trial

Data published in Nature Medicine showed that the median PFS was 8.21 months (95% CI, 7.46-8.84) with zolbetuximab plus capecitabine (Xeloda) and oxaliplatin (CAPOX) vs 6.80 months (95% CI, 6.14-8.08) with CAPOX alone (HR, 0.687; 95% CI, 0.544-0.866; P = .0007).⁴ At 12 months, the estimated PFS rates in each arm were 35% vs 19%, and at 24 months, the estimated rates were 14% vs 7%. Additionally, the PFS improvement in the zolbetuximab arm extended to most prespecified subgroups.

Grade 3 or higher TEAEs affected 72.8% of patients in the zolbetuximab arm compared with 69.9% of those in the chemotherapy alone arm. Common grade 3 or higher TEAEs in each respective arm included vomiting (12.2% vs 3.6%), anemia (10.6% vs 11.2%), and decreased neutrophil counts (10.2% vs 9.6%).

The trial’s primary end point was PFS based on IRC evaluation using RECIST v1.1 criteria. Secondary end points included OS and objective response rate.

The FDA acknowledged a resubmitted biologics license application (BLA) for zolbetuximab as a therapy for patients with CLDN18.2-positive gastric or GEJ adenocarcinoma in May 2024.⁵ Developers resubmitted the BLA after the FDA sent a complete response letter in January 2024; at the time, the agency highlighted issues associated with a pre-license inspection at a third-party manufacturing site for zolbetuximab.⁶ The FDA raised no problems related to the efficacy and safety data related to zolbetuximab in this population.

References

1. Astellas receives approval from the European Commission for VYLOY™ (zolbetuximab) in combination with chemotherapy for advanced gastric and gastroesophageal junction cancer. News release. Astellas Pharma Inc. September 20, 2024. Accessed September 23, 2024. https://tinyurl.com/4vbdesyb
2. Astellas receives positive CHMP Opinion for zolbetuximab in combination with chemotherapy for treatment of advanced gastric and gastroesophageal junction cancer. News release. Astellas Pharma Inc. Published July 29, 2024. Accessed September 23, 2024. https://tinyurl.com/yn8zaywb
3. 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. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7
4. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nature Med. 2023;29:2133-2141. doi:10.1038/s41591-023-02465-7
5. U.S FDA acknowledges Astellas’ resubmission of biologics license application for zolbetuximab and sets new action date. News release. Astellas Pharma Inc. May 30, 2024. Accessed September 23, 2024. https://tinyurl.com/4nhkr7u7
6. Astellas provides update on zolbetuximab biologics license application in U.S. News release. Astellas Pharma Inc. January 9, 2024. Accessed September 23, 2024. https://rb.gy/bl225f