Zolbetuximab Plus Chemo Approaches EU Approval for Advanced Gastric/GEJ Cancer

The European Medicines Agency’s Committee for Medicinal Products for Human Use has recommended the approval of zolbetuximab plus fluoropyrimidine- and platinum-containing chemotherapy as a frontline treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors have CLDN18.2 positivity.¹

The positive opinion was supported by findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials.

Data from SPOTLIGHT indicated that the addition of zolbetuximab to mFOLFOX6 (modified folinic acid, fluorouracil, and oxaliplatin; n = 283) led to a significant improvement in progression-free survival (PFS) vs mFOLFOX6 alone (n = 282), at a median of 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 Zolbetuximab plus chemotherapy also led to a significant 25% reduction in the risk of death vs chemotherapy alone, with a median overall survival (OS) of 18.23 months (95% CI, 16.43-22.90) vs 15.54 months (95% CI, 13.47-16.53), respectively (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).

GLOW findings revealed that zolbetuximab plus CAPOX (capecitabine plus oxaliplatin; n = 254) significantly reduced the risk of disease progression or death vs CAPOX alone (n = 253), with a median PFS of 8.21 months vs 6.80 months (HR, 0.687; 95% CI, 0.544-0.866; P = .0007).³ Again, the zolbetuximab regimen improved OS over chemotherapy, with a median OS of 14.39 months and 12.16 months, respectively (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).

“More than 135,000 new cases of gastric cancer were diagnosed in Europe in 2022, requiring new treatment options that can improve patient outcomes and address the considerable unmet needs associated with this life-limiting cancer,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, stated in a news release.¹ “Zolbetuximab has the potential to become the first approved CLDN18.2 targeted treatment for patients with HER2 negative advanced gastric or GEJ cancers in the European Union, underscoring Astellas' ongoing dedication to delivering therapeutic advancements that drive value for patients.”

A Snapshot of SPOTLIGHT: Trial Design, Treatment, and More

The global, randomized, placebo-controlled, double-blind phase 3 trial enrolled patients with treatment-naive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma who had radiologically evaluable disease and CLDN18.2 positivity.² Patients were required to be at least 18 years of age, have an ECOG performance status of 0 or 1, and acceptable organ function.

They were randomly assigned 1:1 to receive an 800-mg/m2 loading dose of zolbetuximab followed by 600 mg/m2 given every 3 weeks paired with mFOLFOX6, which was administered every 2 weeks. Those who experienced progressive disease (PD) continued beyond 4 cycles of zolbetuximab or placebo plus folinic acid and fluorouracil per investigator discretion. Treatment continued until PD, intolerable toxicity, another anticancer treatment was initiated, or other discontinuation criteria were met

PFS by RECIST 1.1 criteria served as the trial’s primary end point, and key secondary end points were OS, objective response rate (ORR), duration of response (DOR), safety, tolerability, pharmacokinetics and immunogenicity of zolbetuximab, and patient-reported outcomes (PROs).

Additional efficacy data showed that the zolbetuximab combination elicited an ORR of 48% (95% CI, 42%-54%) vs 48% (95% CI, 42%-54%) with chemotherapy alone. The median DORs in the respective arms were 9.00 months (95% CI, 6.87-10.25) and 8.05 months (95% CI, 6.47-10.81).

Regarding safety, 87% of patients in the zolbetuximab arm experienced grade 3 or higher treatment-emergent adverse effects (AEs) vs 78% of those in the placebo arm. The most common AEs were nausea, vomiting, and reduced appetite. Treatment-related AEs (TRAEs) led to zolbetuximab discontinuation for 14% of patients; 2% of patients in the placebo arm discontinued treatment. Grade 5 TRAEs occurred in 2% and 1% of patients, respectively.

Getting to Know GLOW: Eligibility Criteria, Treatment, End Points, and More

Patients with CLDN18.2-positive, HER2-negative, treatment-naive, locally advanced unresectable or metastatic gastric or GEJ cancers were enrolled to the global, randomized, double-blind, phase 3 GLOW study.³ To participate, they needed to have radiologically evaluable disease by RECIST 1.1 criteria, an ECOG performance status of 0 or 1, a life expectancy of at least 12 weeks, and acceptable organ function.

Study participants were randomized 1:1 to receive 800 mg/m2 of zolbetuximab on day 1 of cycle 1 followed by 600 mg/m2 on day 1 of subsequent cycles plus CAPOX vs placebo plus CAPOX. Again, patients were able to continue past 8 cycles with zolbetuximab or placebo and capecitabine at the investigator’s discretion, until PD, unacceptable toxicity, another anticancer therapy was started, or other discontinuation criteria were met.

PFS by independent review committee assessment and RECIST 1.1 criteria served as the trial’s primary end point, and important secondary end points included OS, ORR, DOR, safety, tolerability, pharmacokinetics and immunogenicity of zolbetuximab, and PROs.

The zolbetuximab regimen elicited an ORR of 42.5% (95% CI, 36.36%-48.85%) vs 40.3% (95% CI, 34.22%-46.64%) with chemotherapy alone. The respective median DORs were 6.14 months (95% CI, 5.03-8.08) and 6.08 months (95% CI, 4.44-6.34).

Grade 3 or higher TEAEs occurred in 72.8% of those in the zolbetuximab arm vs 69.9% of those in the placebo arm. The most common grade 3 or higher TEAEs were vomiting, anemia, decreased neutrophil count, and nausea.

References

1. 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. July 26, 2024. Accessed July 26, 2024. https://newsroom.astellas.us/2024-07-26-Astellas-Receives-Positive-CHMP-Opinion-for-Zolbetuximab-in-Combination-with-Chemotherapy-for-Treatment-of-Advanced-Gastric-and-Gastroesophageal-Junction-Cancer
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(8):2133-2141. doi:10.1038/s41591-023-02465-7