Clinical Summary: 

• Design/Population: The phase 3 CLARITY-Gastric 01 trial evaluated sonesevotug vedotin, a CLDN18.2-directed antibody-drug conjugate, versus investigator’s choice in patients with unresectable locally advanced or metastatic CLDN18.2-positive gastroesophageal cancer who had received at least 1 prior line of treatment.
• Key Outcomes: Sonesevotug vedotin significantly improved overall survival in both the third-line or later population and the overall second-line or later population, reducing the risk of death by 53% and 42%, respectively. Progression-free survival was numerically longer but did not meet the threshold for statistical significance.
• Clinical Relevance: These findings support sonesevotug vedotin as a potential treatment option for previously treated CLDN18.2-positive advanced gastroesophageal cancer, with survival benefits observed across different CLDN18.2 expression levels. The results suggest that a broader biomarker-defined population may benefit from CLDN18.2-directed therapy.

Results from the phase 3 CLARITY-Gastric 01 trial demonstrated that sonesevotug vedotin, a CLDN18.2-directed antibody-drug conjugate, significantly improved overall survival (OS) compared with investigator’s choice in patients with previously treated CLDN18.2-positive advanced gastroesophageal cancer, supporting the agent as a potential second-line or later treatment option.

These findings were presented by Rui-Hua Xu, MD, PhD, Sun Yat-sen University Cancer Center, Guangzhou, China, during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress.

In this open-label trial, 594 patients with unresectable locally advanced or metastatic gastroesophageal cancer expressing CLDN18.2 in at least 25% of tumor cells who had received at least 1 prior line of therapy were enrolled. Patients were initially randomized 1:1:1 to receive 1.8 mg/kg of sonesevotug vedotin, 2.2 mg/kg of sonesevotug vedotin, or investigator-selected therapy.

Following dose selection, patients were randomized 1:1 to receive 2.2 mg/kg of sonesevotug vedotin or investigator-selected therapy. At the data cutoff, the analysis included 532 patients assigned to the selected dose (n = 267) or investigator-selected therapy (n = 265).

In the second-line setting, investigator-selected treatments included ramucirumab plus paclitaxel, paclitaxel, or docetaxel. Third-line or later options included irinotecan, trifluridine/tipiracil, or apatinib in China. Randomization was stratified by geographic region, prior gastrectomy, and line of therapy.

The dual primary end points were overall survival (OS) in the third-line or later population and progression-free survival (PFS), assessed by blinded independent central review, in the overall second-line or later intent-to-treat population. A key secondary end point was OS in the overall population.

At a median follow-up of 8.6 months, median OS in the third-line or later population was 10 months in the sonesevotug vedotin arm and 5 months in the  investigator’s choice arm, reducing the risk of death by 53% (hazard ratio [HR], 0.47; 95% confidence interval [CI], 0.36 to 0.62; P < .001).

In the overall second-line or later population, median OS was 10.6 months in the sonesevotug vedotin arm and 6.4 months in the investigator’s choice arm, reducing the risk of death by 42% (HR, 0.58; 95% CI, 0.47 to 0.73; P < .001).

The OS benefit was generally consistent across CLDN18.2 expression subgroups. Among patients with CLDN18.2 expression in at least 75% of tumor cells, the HR for OS was 0.59, compared with 0.63 among patients with expression in at least 25% but less than 75% of tumor cells.

Median PFS in the overall population was 4.2 months and 3.8 months, respectively (HR, 0.77; 95% CI, 0.62 to 0.96; P = .05). Although PFS numerically favored sonesevotug vedotin, the difference did not meet the prespecified threshold for statistical significance.

Treatment-related adverse events occurred in 85.8% of patients receiving sonesevotug vedotin and 81.3% receiving investigator-selected therapy. Grade ≥3 treatment-related adverse events were reported in 36.4% and 44.8% of patients, respectively.

Grade ≥3 gastrointestinal toxicity occurred in 11.1% of patients receiving sonesevotug vedotin compared with 6.3% receiving investigator-selected therapy, while grade ≥3 hematologic toxicity occurred in 7.7% and 15.9%, respectively.

Treatment-related adverse events led to treatment discontinuation in 3.1% of patients receiving sonesevotug vedotin and 4.4% receiving investigator-selected therapy. Treatment-related deaths occurred in 1.1% and 0.8% of patients, respectively.

As Dr Xu concluded, “these findings support sonesitatug vedotin as a potential 2L+ treatment for a broad patient population with advanced CLDN18.2-positive gastroesophageal carcinoma.” 

Source: 

Xu RH, et al. CLARITY-Gastric 01 (CG-01): A phase 3 study of sonesitatug vedotin (Sone-Ve) in second or later-line (2L+) advanced or metastatic Claudin 18.2 (CLDN18.2)-positive gastroesophageal carcinoma (GEC). Presented at ESMO Congress. October 23-27, 2026; Madrid, Spain. LBA7.