Zolbetuximab/Chemo Gets Positive EU CHMP Opinion in Advanced Gastric Cancer

The recommendation is based on findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT036535073) trials, which evaluated frontline zolbetuximab in adult patients with locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive, gastric or GEJ adenocarcinoma.

The European Medicines Agency’s Committee for Medicinal Products for Human Use has granted a positive opinion for the approval of zolbetuximab (Vyloy) plus chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) cancer, according to a news release by the drug developer, Astellas.¹

Zolbetuximab, a first-in-class claudin 18.2 (CLDN18.2)–targeted monoclonal antibody, is being combined with a regimen of fluoropyrimidine- and platinum-containing chemotherapy. If approved, this will be the first and only CLDN18.2-targeted treatment indicated for patients in the European Union. Additionally, upon approval, the VENTANA CLDN18 (43-14A) RxDx Assay is expected to be indicated for use to identify patients eligible for zolbetuximab therapy.

The recommendation is based on findings from the phase 3 SPOTLIGHT (NCT03504397)² and GLOW (NCT03653507)³ trials, which evaluated frontline zolbetuximab in adult patients with locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive, gastric or GEJ adenocarcinoma.

“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 the Immuno-Oncology Development at Astellas, stated in the 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.”

In May 2024, the FDA acknowledged a resubmitted biologics license application for frontline zolbetuximab as a treatment for this patient population.⁴ The BLA was resubmitted after the agency issued a complete response letter due to insufficiencies linked with a pre-license inspection at a third-party manufacturing site for zolbetuximab; no issues were related to the drug’s efficacy and safety data, and no further studies were requested.⁵ The new action date for the FDA under the Prescription Drug User Fee Act is November 9, 2024.

In the international, placebo-controlled, double-blind, phase 3 SPOTLIGHT trial, patients with CDLDN18.2-positive, HER2-negative, previously untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma were randomly assigned to receive zolbetuximab at an 800 mg/m² loading dose followed by 600 mg/m² every 3 weeks plus modified folinic acid, fluorouracil, and oxaliplatin (mFOLFOX6) every 2 weeks (n = 283), or placebo plus mFOLFOX6 (n = 282).

The median follow-up for progression-free survival (PFS) was the 12.94 and 12.65 months in the zolbetuximab and placebo arms, respectively. The median PFS with zolbetuximab was 10.61 months (95% CI, 8.90-12.48) compared with 8.67 months (95% CI, 8.21-10.28) with placebo, leading to a 25% reduction in the risk of disease progression or death (HR, 0.75; 95% CI, 0.60-0.94; P = .0066). Overall survival (OS) was also improved with zolbetuximab (HR, 0.75; 95% CI, 0.60-0.94; P = .0053).

In the international, double-blind, phase 3 GLOW trial, investigators compared first-line zolbetuximab plus capecitabine (Xeloda) and oxaliplatin (CAPOX; n = 254) or placebo plus CAPOX (n = 253) in patients with CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Zolbetuximab was given intravenously at 800 mg/m² on cycle 1, day 1 followed by 600 mg/m² on day 1 of subsequent cycles; oral capecitabine was given at 1000 mg/m² twice daily on days 1 to 14 of each cycle, intravenous oxaliplatin was given at 130 mg/m² on day 1 of each cycle for eight 21-day cycles. Treatment was given beyond 8 cycles with either zolbetuximab or placebo until disease progression, unacceptable toxicity, start of another therapy for cancer, or other discontinuation criteria were met.

At a median follow-up for PFS of 12.62 months and 12.09 months for zolbetuximab and placebo, respectively, findings showed that the median PFS with zolbetuximab was 8.21 months vs 6.80 months with placebo (HR, 0.687; 95% CI, 0.544-0.866; P = .0007).

At an interim analysis for OS, of which the median follow-up was 17.71 and 18.43 months for zolbetuximab and placebo, respectively, the median OS was 14.39 months and 12.16 months for zolbetuximab and placebo, respectively (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).

Zolbetuximab was approved in March 2024 in Japan as a treatment for patients with CLDN18.2 positive, unresectable, advanced or recurrent gastric cancer.⁶

References

1. Astellas receives positive CHMP Opinion for zolbetuximab in combination with chemotherapy for treatment of advanced gastric and gastroesophageal junction cancer. Astellas. News release. Published July 29, 2024. Accessed July 31, 2024.
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. Nature Med. 2023;29:2133-2141. doi:10.1038/s41591-023-02465-7
4. 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 August 1, 2024. https://tinyurl.com/4nhkr7u7
5. Astellas provides update on zolbetuximab biologics license application in U.S. News release. Astellas Pharma Inc. January 9, 2024. Accessed August 1, 2024. https://rb.gy/bl225f
6. Astellas’ VYLOY (zolbetuximab) approved in Japan for treatment of gastric cancer. Astellas. News release. Published March 26, 2024. Accessed July 31, 2024. https://www.astellas.com/en/news/29026