Japan’s MHLW Approves Zolbetuximab in CLDN18.2-Positive Gastric Cancer

Kohei Shitara, MD

Japan’s Ministry of Health, Labour and Welfare (MHLW) has granted approval to the anti-claudin 18.2 (CLDN18.2) monoclonal antibody zolbetuximab (Vyloy) for the treatment of patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer. The regulatory decision makes zolbetuximab the first and only CLDN18.2-targeted agented approved by a regulatory agency.¹

The approval was supported by findings from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials, which compared zolbetuximab plus mFOLFOX6 (5-fluorouracil, leucovoin, and oxaliplatin) vs placebo plus mFOLFOX6 and zolbetuximab plus CAPOX vs placebo plus capecitabine and oxaliplatin (CAPOX), respectively, in patients with treatment-naive CLDN18.2-positiveunresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma. Both studies met their primary end points of progression-free survival (PFS); the median PFS in the investigational vs control arms of SPOTLIGHT was 10.61 months (95% CI, 8.90-12.48) vs 8.67 months (95% CI, 8.21-10.28), respectively (HR, 0.75; 95% CI, 0.60-0.94; P = .0066), and the median PFS in the investigational vs control arms of GLOW was 8.21 months vs 6.80 months, respectively (HR, 0.687; 95% CI, 0.544-0.866; P = .0007).^2,3

“Developing new targeted therapies is critical for diseases like advanced gastric adenocarcinoma, which has had very limited treatment options and is often discovered at an advanced stage,” Kohei Shitara, MD, head of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Kashiwa, Japan, said in a press release. “As the primary investigator for the Phase 3 SPOTLIGHT clinical trial, I witnessed firsthand the significant improvement in PFS and overall survival [OS] for patients treated with [zolbetuximab] in combination with chemotherapy compared with those treated with placebo plus chemotherapy. These results support [zolbetuximab] as a new treatment option for the CLDN18.2-positive population in Japan, where there were nearly 44,000 deaths caused by gastric cancer in 2022 alone.”¹

SPOTLIGHT was a global, placebo-controlled, double-blind trial that enrolled adult patients with CLDN18.2-positive (defined as ≥ 75% of tumor cells showing moderate-to-strong membranous CLDN18 staining), HER2-negative, treatment-naive, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Patients were randomly assigned 1:1 to receive zolbetuximab at an 800 mg/m² loading dose followed by a dose of 600 mg/m² every 3 weeks in combination with mFOLFOX6 every 2 weeks (n = 279) or placebo plus mFOLFOX6 (n = 278). Key secondary end points included OS and time to confirmed deterioration.²

GLOW was a global, double-blind trial that enrolled patients with CLDN18.2-positive (defined as ≥ 75% of tumor cells with moderate-to-strong membranous CLDN18 staining), HER2-negative, previously untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Patients were randomly assigned 1:1 to receive intravenous zolbetuximab at 800 mg/m² on day 1 of cycle 1 followed by 600 mg/m² on day 1 of subsequent cycles plus CAPOX (n = 254) or placebo plus CAPOX (n = 253). OS was a key secondary end point, with other secondary end points including objective response rate and duration of response.³

Additional findings from SPOTLIGHT showed that the median OS in the investigational and control arms was 18.23 months (95% CI, 16.43-22.90) and 15.54 months (95% CI,13.47-16.53), respectively (HR, 0.75; 95% CI, 0.60-0.94; P = .0053). In GLOW, the median OS in the investigational and control arms was 14.39 months vs 12.16 months, respectively (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).^2,3

In terms of safety, in SPOTLIGHT, the most common any-grade treatment-emergent adverse effects (TEAEs) in the zolbetuximab arm included nausea (82%), vomiting (67%), and decreased appetite (47%); the most common any-grade TEAEs in the control arm included nausea (61%), diarrhea (44%), and peripheral sensory neuropathy (42%). In GLOW, the most common any-grade TEAEs in the investigational arm included nausea (68.5%), vomiting (66.1%), and decreased appetite (41.3%); the most common any-grade TEAEs in the control arm included nausea (50.2%), anemia (36.5%), and diarrhea (34.5%).^2,3

Additionally, Astellas Pharma Inc., the manufacturer of zolbetuximab, collaborated with Roche Diagnostics to create the Ventana CLDN18 (43-14A) RxDx Assay, which is an immunohistochemistry companion diagnostic test that aims to identify patients who could be eligible for zolbetuximab. The company has also submitted applications for zolbetuximab to regulatory agencies worldwide, and review of the applications is ongoing.¹

“The approval of zolbetuximab by the MHLW marks a new era in the treatment of [patients with] gastric cancer, offering the first and only targeted therapy option for CLDN18.2-positive patients living with this devastating disease,” Moitreyee Chatterjee-Kishore, PhD, MBA, senior vice president and head of Immuno-Oncology Development at Astellas, said in the press release. “Astellas is proud to help address the urgent therapeutic need for this hard-to-treat cancer in Japan, where incidence rates are among the highest globally. Importantly, this approval holds the potential to provide eligible patients with more precious time with their loved ones, delivering on our commitment to improve patient outcomes.”¹

References

1. Astellas’ VYLOY™ (zolbetuximab) Approved in Japan for treatment of gastric cancer. News release. Astellas Pharma Inc. March 26, 2024. Accessed March 26, 2024. https://www.astellas.com/en/news/29026
2. 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
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