A New Treatment Path Emerges for Later-Line Gastric Cancer: CLDN18.2 Antibody-Drug Conjugate Extends Survival

After first-line treatment fails in advanced gastric cancer, options capable of extending life remain limited. AstraZeneca announced preliminary results from the Phase III CLARITY-Gastric01 trial: sonesitatug vedotin, an antibody-drug conjugate targeting CLDN18.2, delivered a statistically significant improvement in overall survival that the company described as clinically meaningful in previously treated patients with advanced gastric or gastroesophageal junction cancer.

This randomized, open-label, global trial enrolled 594 participants across 175 centers in 19 countries and compared sonesitatug vedotin with the investigator’s choice of treatment. Participants had locally advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma, with CLDN18.2 expression in at least 25% of tumor cells; following dose selection, the study drug entered the primary evaluation phase at 2.2 mg/kg every three weeks.

The results showed that the trial met its primary overall survival endpoint in the third-line and later-line population, as well as the key secondary overall survival endpoint covering all participants treated in the second-line setting or later. Another primary endpoint—progression-free survival as assessed by blinded independent central review—showed a trend toward improvement but did not cross the threshold for statistical significance. The current evidence therefore does not show consistent success across all prespecified efficacy endpoints.

Sonesitatug vedotin consists of an antibody that recognizes CLDN18.2, a protease-cleavable linker, and the cytotoxic molecule MMAE. The design is intended to use the antibody to deliver the drug payload to tumor cells expressing CLDN18.2, reducing widespread exposure in non-target tissues. CLDN18.2 is normally located primarily on gastric mucosal cells, but after malignant transformation it can become a more accessible therapeutic marker, and has therefore gradually emerged as an important target for precision treatment of gastrointestinal tumors.

The company said the overall safety profile was consistent with existing data and that no new safety signals were identified; however, the announcement did not provide hazard ratios, median survival times, adverse-event rates for each group, or treatment-discontinuation data. The trial used an open-label design, while the number of prior treatment lines, control therapies, and tumor types may also affect interpretation of the results. Full data and the prespecified subgroup analyses are still needed.

AstraZeneca plans to present the detailed results at a medical meeting and discuss them with regulators in different regions. If subsequent data support the current conclusions, this could not only add a later-line treatment option for advanced gastric cancer, but could also expand the eligibility threshold for CLDN18.2-directed treatment to patients whose tumors show expression in at least 25% of cells; however, before regulatory review and approval, these topline results cannot be considered equivalent to the treatment being available for clinical use.