Later-Line Treatment for Advanced Gastric Cancer Crosses the Survival Threshold: CLDN18.2 Antibody-Drug Conjugate Succeeds in Phase III

Once advanced gastric cancer progresses after first-line treatment, subsequent therapies often provide only limited additional time. AstraZeneca announced topline results from the Phase III CLARITY-Gastric01 trial: sonesitatug vedotin, an antibody-drug conjugate targeting CLDN18.2-positive tumors, improved overall survival in previously treated patients, marking the first time a drug of this type has met a Phase III survival endpoint at this stage of treatment.

This global, randomized, open-label study with blinded assessment by the trial sponsor enrolled 594 adults with locally advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma across 175 centers in 19 countries. Patients’ tumors were required to have CLDN18.2 expression in at least 25% of cells, regardless of immunohistochemistry staining intensity. Depending on line of therapy and region, the control group received an established treatment selected by the investigator.

The hierarchy of the trial results requires careful interpretation. Overall survival in patients receiving third-line or later treatment met the co-primary endpoint; overall survival across all patients receiving second-line or later treatment also met a key secondary endpoint. By contrast, progression-free survival assessed by blinded independent central review showed a trend toward improvement but did not reach statistical significance, meaning that not all prespecified endpoints were consistently positive.

CLDN18.2 is a gastric mucosa-associated protein and has become an important target for precision treatment of gastric cancer in recent years. Sonesitatug vedotin uses a monoclonal antibody to recognize cancer cells expressing CLDN18.2, then delivers the cytotoxic molecule MMAE through a protease-cleavable linker. The first stage of the trial compared two doses, and the second stage selected a regimen of 2.2 mg/kg once every three weeks.

The company said the safety profile was consistent with previous experience and that no new safety signals were identified. However, the hazard ratio for overall survival, median survival, objective response rate, rates of individual adverse events, and treatment discontinuation rates have not yet been disclosed. For now, “clinically meaningful” remains the company’s characterization of the topline results; the full magnitude of benefit and the toxicity patients must bear cannot be independently assessed until the data are presented at a medical meeting.

The findings may also broaden the potential scope of CLDN18.2-directed treatment because the trial used a threshold of expression in at least 25% of tumor cells rather than focusing only on patients with high expression. However, the failure of progression-free survival to reach statistical significance, whether the testing method can reliably identify patients, and whether benefits are consistent across different lines of therapy will all be key questions before regulatory review and clinical adoption. AstraZeneca said it will present the full data at a future medical meeting and submit them to regulatory authorities in different regions.