FDA Approves Zolbetuximab in Advanced CLDN18.2+ Gastric/GEJ Adenocarcinoma

Supporting data for the approval came from the phase 3 SPOTLIGHT trial (NCT03504397) and the phase 3 GLOW trial (NCT03653507).

The FDA has approved zolbetuximab-clzb (Vyloy) plus fluoropyrimidine- and platinum-based chemotherapy as frontline therapy for patients 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 drug’s developer, Astellas Pharmaceuticals.¹

Supporting Data

The zolbetuximab approval was supported by data from the phase 3 SPOTLIGHT trial (NCT03504397) and the phase 3 GLOW trial (NCT03653507), in which investigators assessed zolbetuximab plus chemotherapy among patients with locally advanced or unresectable CDN18.2-positive gastric or GEJ adenocarcinoma.^2,3

SPOTLIGHT Trial

Data from the phase 3 SPOTLIGHT trial published in The Lancet showed a median progression-free survival (PFS) benefit with zolbetuximab plus modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) vs FOLFOX6 alone; 10.61 months (95% CI, 8.90-12.48) and 8.67 months (95% CI, 8.21-10.28), respectively (HR, 0.75; 95% CI, 0.60-0.94; P = .0066).²

In each respective arm, the 12-month PFS rates were 49% (95% CI, 42%-55%) vs 35% (95% CI, 28%-42%). Additionally, the 24-month PFS rates were 24% (95% CI, 17%-32%) vs 15% (95% CI, 9%-22%). Furthermore, most patient subgroups exhibited comparable PFS outcomes.

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

Results from the phase 3 GLOW trial published in Nature Medicine showed a median PFS benefit with zolbetuximab plus capecitabine (Xeloda) and oxaliplatin (CAPOX) vs CAPOX alone; 8.21 months and 6.80 months, respectively (HR, 0.687; 95% CI, 0.544-0.866; P = .0007).³

In each respective arm, the 12-month PFS rates were 35% vs 19% and the 24-month PFS rates were 14% vs 7%. Furthermore, most patient subgroups in the zolbetuximab arm exhibited comparable PFS outcomes.

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.

Expert Perspective

“In [gastrointestinal] cancers, we have been longing for new therapies. Finally, we are getting one. CLDN18.2 has been out there a while, and drug development targeting this has been going on for a while. Two big, randomized studies now support benefit in this patient population, and so now we are going to get the drug….We are all looking forward to incorporating this into our treatment paradigm,” John L. Marshall, MD, said in an interview with CancerNetwork^® on the approval.

Marshall is the physician executive director of the MedStar Washington DC Integrated Hematology-Oncology Division and the Otto J Ruesch Center for the Cure of GI Cancers, and chief medical officer of the Lombardi Comprehensive Cancer Center at Georgetown University.

Phase 3 SPOTLIGHT Study Design

The global, randomized, phase 3 SPOTLIGHT study enrolled 2735 patients assessable for CLDN18.2 status, of which 38% were positive. The 565 patients included in the final analysis were randomly assigned 1:1 to receive either zolbetuximab (n = 283) or placebo (n = 282). At least 1 dose of treatment was received by 99% of patients, with 218 in the experimental arm and 232 in the control arm discontinuing treatment most frequently due to disease progression (48% vs 64%).

Eligible patients were 18 years or older with CLDN18.2-positive disease, HER2-negative disease, and previously untreated disease. The median patient age was 61 years, and most patients were male (62%). Most patients presented with gastric adenocarcinoma (76%) and GEJ adenocarcinoma (24%).

Patients in the investigational arm received intravenous zolbetuximab at 800 mg/m² on day 1 of cycle 1 and 600 mg/m² on day 22 of cycle 1. Additionally, on days 1, 15, and 29, 400 mg/m2 of folinic acid, 200 mg/m² of levofolinate, 400 mg/m² of fluorouracil bolus with a subsequent 2400 mg/m² infusion, and 85 mg/m² of oxaliplatin was received. Patients in the placebo arm received the same FOLFOX6 backbone and placebo dosage comparable to the investigational agent.

Phase 3 GLOW Trial Study Design

The global, randomized phase 3 GLOW trial randomly assigned patients to receive zolbetuximab plus CAPOX (n = 254) or placebo plus CAPOX (n = 253). In the experimental arm, patients received 800 mg/m² of intravenous zolbetuximab on day 1 of cycle 1 followed by 600 mg/m² on day 1 of subsequent cycles once every 3 weeks plus CAPOX. Patients then received 600 mg/m² of zolbetuximab intravenously once every 3 weeks plus capecitabine for cycle 9 and onwards. Patients received matched placebo plus the same CAPOX regimen in the comparator arm.

Patients were eligible if they had previously untreated locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. The median patient ages was 61.0 years (range, 22-82) in the zolbetuximab arm and 59.0 years (range, 21-83) in the placebo arm, with most patients being male (62.6% vs 61.7%) in each. In respective arms, most patients were from Asia (61.8% vs 62.5%), had 0 to 2 organs with metastases (74.4% vs 74.3%), and had not received prior gastrectomy (70.5% vs 70.4%).

Adverse Effects

In the investigational and chemotherapy alone arms of the phase 3 SPOTLIGHT trial, respectively, the most common any-grade treatment-related adverse effects (TEAEs) were nausea (82% vs 61%), vomiting (67% vs 36%), and decrease appetite (47% vs 33%). Additionally, TEAEs leading to discontinuation occurred in 43% and 38% of the respective arms, and TEAEs leading to death were reported in 8% and 9% of patients.

Furthermore, in the phase 3 GLOW trial, common grade 3 or higher TEAEs in the zolbetuximab and chemotherapy only arms included vomiting (12.2% vs 3.6%), anemia (10.6% vs 11.2%), and decreased neutrophil counts (10.2% vs 9.6%), respectively. Additionally, grade 3 or higher TEAEs affected 72.8% of patients in the zolbetuximab arm vs 69.9% of those in the chemotherapy alone arm.

The FDA previously acknowledged a BLA resubmission for zolbetuximab in CLDN18.2-positive gastric cancer in May 2024.⁴

Additionally, zolbetuximab earned European approval in advanced CLDN18.2-positive gastric cancer in September 2024.⁵

References

1. Astellas' VYLOY™ (zolbetuximab-clzb) approved by U.S. FDA for treatment of advanced gastric and GEJ cancer. News release. Astellas Pharmaceuticals. October 18, 2024. Accessed October 18, 2024. https://tinyurl.com/5745k9a8
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. 2023;401(10389):1655-1668. doi:10.1016/S0140-6736(23)00620-7
3. 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. Nat Med. 2023;29:2133-2141. doi:10.1038/s41591-023-02465-7
4. 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 October 18, 2024. https://tinyurl.com/4nhkr7u7
5. Astellas receives approval from the European Commission for VYLOY‚Ñ¢ (zolbetuximab) in combination with chemotherapy for advanced gastric and gastroesophageal junction cancer. News release. Astellas Pharma Inc. September 20, 2024. Accessed October 18, 2024. https://tinyurl.com/4vbdesyb