Results from the phase 3 CLARITY-Gastric 01 (CG-01) trial showed that sonesitatug vedotin (Sone-Ve), a CLDN18.2-targeting antibody-drug conjugate, significantly improved overall survival (OS) compared with investigator’s choice of chemotherapy in patients with previously treated, advanced or metastatic CLDN18.2-positive gastroesophageal carcinoma (GEC). The findings were presented by Rui-Hua Xu, MD, at the European Society of Medical Oncology Congress 2026 in Madrid, Spain.
In the intent-to-treat population (2L+), Sone-Ve 2.2 mg/kg reduced hazard by 42% compared with standard therapy (median OS 10.6 vs 6.4 months; HR 0.58 [95% CI 0.47–0.73]; p<0.001). The co-primary endpoint of progression-free survival (PFS) by blinded independent central review (BICR) in the ITT population did not meet the prespecified threshold for statistical significance.
Key finding
In the phase 3 CLARITY-Gastric01 (CG-01) trial, sonesitatug vedotin reduced the hazard of death by 53% versus investigator’s choice of therapy in patients with CLDN18.2-positive gastroesophageal carcinoma receiving third-line or later treatment (HR, 0.47; 95% CI, 0.36–0.62; P < 0.000001), doubling median overall survival (10.0 vs 5.0 months). However, the co-primary progression-free survival endpoint in the overall second-line-or-later population did not reach statistical significance.
Study Design
| Trial | CLARITY-Gastric 01 (CG-01); randomised, open-label, global phase 3 (NCT06346392) |
|---|---|
| Population | Adults with unresectable, locally advanced or metastatic CLDN18.2-positive GEC (≥25% of tumour cells with membranous staining at any intensity) who had received ≥1 prior line of therapy |
| Treatment | Sonesitatug vedotin 2.2 mg/kg vs investigator’s choice of therapy (2L: ramucirumab + paclitaxel, paclitaxel, or docetaxel; 3L+: irinotecan, trifluridine/tipiracil, or apatinib [China only]); randomised 1:1, stratified by region, prior gastrectomy, and line of therapy |
| Primary endpoints | OS in the 3L+ subgroup; PFS by BICR in the ITT (2L+) population (dual primary) |
| Key secondary endpoints | OS in the ITT (2L+) population |
The trial initially randomised patients 1:1:1 across two Sone-Ve dose levels (1.8 mg/kg and 2.2 mg/kg) and investigator’s choice; following a dose-selection phase, subsequent randomisation was 1:1 to Sone-Ve 2.2 mg/kg or investigator’s choice. The analysis reported here includes 532 of 594 total enrolled patients randomised to the 2.2 mg/kg or investigator’s choice arms, with a median follow-up of 8.6 months at the May 31, 2026 data cutoff.
Results and Safety
Both dual primary endpoints were evaluated at the prespecified analysis. In the 3L+ subgroup (Sone-Ve n=178; investigator’s choice n=177), Sone-Ve 2.2 mg/kg demonstrated a statistically significant and clinically meaningful OS benefit, with a median of 10.0 months versus 5.0 months for investigator’s choice (HR 0.47 [95% CI 0.36–0.62]; p<0.001). In the broader ITT population (2L+), median OS was 10.6 months versus 6.4 months (HR 0.58 [95% CI 0.47–0.73]; p<0.001), meeting the key secondary endpoint. The OS benefit was consistent across CLDN18.2 expression subgroups, including those with ≥75% expression (HR 0.59 [95% CI 0.45–0.78]) and those with ≥25% to <75% expression (HR 0.63 [95% CI 0.42–0.94]).
The co-primary PFS endpoint in the ITT population did not meet the prespecified threshold for statistical significance. Median PFS by BICR was 4.2 months with Sone-Ve versus 3.8 months with investigator’s choice (HR 0.77 [95% CI 0.62–0.96]; p=0.05). Objective response rates and duration of response were not reported in the source material.
In the safety analysis set, treatment-related adverse events (TRAEs) of any grade occurred in 85.8% of Sone-Ve-treated patients versus 81.3% in the comparator arm. Grade ≥3 TRAEs were reported in 36.4% versus 44.8%, respectively. Gastrointestinal toxicity of grade ≥3 was more frequent with Sone-Ve (11.1% vs 6.3%), while grade ≥3 haematological toxicity was more frequent in the investigator’s choice arm (7.7% vs 15.9%). TRAEs leading to death occurred in 1.1% of Sone-Ve patients and 0.8% of comparator patients; discontinuation due to TRAEs was 3.1% versus 4.4%, respectively.
Clinical Context
CLDN18.2 has emerged as a validated therapeutic target in gastroesophageal carcinoma, and CG-01 represents one of the first phase 3 trials to demonstrate a significant OS benefit with a CLDN18.2-directed ADC in the second-line or later setting. The magnitude of the OS benefit in the 3L+ subgroup, a near-doubling of median survival with a hazard ratio of 0.47, is notable given the historically poor outcomes in this population. The broad eligibility threshold (CLDN18.2 expression in ≥25% of tumor cells) and consistency of benefit across expression subgroups suggest potential applicability across a wide patient population.
Several questions remain open. The failure of the PFS endpoint to reach statistical significance, despite a meaningful OS benefit, warrants further investigation. Longer-term follow-up data, quality-of-life outcomes, and head-to-head comparisons with other CLDN18.2-directed agents, including approved therapies such as zolbetuximab, have not yet been reported.
Sources
- Xu R-H, 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 the European Society of Medical Oncology Congress 2026. Abstract LBA7. View source.