Sonesitatug Vedotin Improves OS in Pretreated CLDN18.2+ Gastroesophageal Cancer

At the 2026 European Society for Medical Oncology (ESMO) Congress, Rui-Hua Xu, MD, PhD, presented results from the global phase 3 CLARITY-Gastric01 trial (NCT06346392), which showed that sonesitatug vedotin (Sone-Ve; AZD0901) significantly improved overall survival (OS) vs investigator’s choice of therapy in patients with previously treated advanced or metastatic claudin 18.2 (CLDN18.2)–positive gastroesophageal carcinoma (GEC).¹

In the third-line or later (3L+) population, which was 1 of 2 primary end points, the median OS was 10.0 months (95% CI, 7.2-11.4) with Sone-Ve vs 5.0 months (95% CI, 4.2-6.4) with investigator’s choice of therapy (HR, 0.47; 95% CI, 0.36-0.62; P <.000001). The 12-month OS rates were 38.1% vs 18.1%, respectively. In the intention-to-treat (ITT) population, the key secondary end point, the median OS was 10.6 months (95% CI, 9.1-12.0) vs 6.4 months (95% CI, 5.8-7.6; HR, 0.58; 95% CI, 0.47-0.73; P = .000004), with 12-month OS rates of 42.6% vs 27.8%.

According to Xu, of the Department of Medical Oncology at Sun Yat-sen University Cancer Center in Guangzhou, China, CLDN18.2 is a tight junction protein expressed in 40% to 80% of GEC cases depending on the positivity threshold, and no CLDN18.2-targeted therapies are approved globally for patients in the second-line or later (2L+) setting. Median OS is under 10 months with ramucirumab (Cyramza) plus paclitaxel in the second line, and single-agent chemotherapy in the 3L+ setting is associated with an OS benefit of under 6 months. Sone-Ve is a first-in-class CLDN18.2-targeted antibody-drug conjugate (ADC) consisting of a CLDN18.2-directed antibody conjugated to the microtubule-disrupting payload monomethyl auristatin E via a protease-cleavable linker.

The randomized, open-label, sponsor-blinded trial enrolled 594 patients with 2L+ GEC whose tumors had at least 25% of tumor cells with membranous CLDN18.2 staining at any intensity. Patients were initially randomly assigned 1:1:1 to receive Sone-Ve at 2.2 mg/kg or 1.8 mg/kg every 3 weeks or investigator’s choice of therapy. After the 2.2-mg/kg dose was selected as optimal in January 2025, the 1.8-mg/kg arm (n = 62) was closed and randomization continued 1:1, with 267 patients ultimately assigned to Sone-Ve 2.2 mg/kg and 265 to investigator’s choice. Investigator’s choice options included ramucirumab plus paclitaxel, paclitaxel, or docetaxel in the second line, and irinotecan, trifluridine/tipiracil (TAS-102; excluding China), or apatinib (China only) in the 3L+ setting. Randomization was stratified by region, prior gastrectomy, and line of therapy.

The dual primary end points were OS in the 3L+ population and progression-free survival (PFS) by blinded independent central review (BICR) in the ITT population. Baseline characteristics were generally balanced. The median age was 57 years (range, 24-82) in both arms, 61.0% of patients in the Sone-Ve arm and 55.8% in the control arm had peritoneal metastases, and approximately two-thirds of patients in each arm were receiving treatment in the 3L+ setting. A small proportion had received prior zolbetuximab (3.7% vs 2.6%).

The OS benefit was consistent across CLDN18.2 expression levels. Among patients with expression of 75% or greater, the median OS was 10.6 months vs 6.4 months (HR, 0.59; 95% CI, 0.45-0.78); among those with expression of at least 25% to less than 75%, it was 10.5 months vs 6.2 months (HR, 0.63; 95% CI, 0.42-0.94). OS hazard ratio point estimates favored Sone-Ve across all clinically relevant prespecified subgroups in the 3L+ population and across most subgroups in the ITT population. In the ITT analysis, the HR was 0.88 (95% CI, 0.60-1.30) among patients treated in the second line and 1.08 (95% CI, 0.68-1.71) among those with gastroesophageal junction or esophageal adenocarcinoma; subgroup CIs were not adjusted for multiplicity.

PFS by BICR in the ITT population did not meet the threshold for statistical significance, with a median PFS of 4.2 months (95% CI, 3.5-5.3) vs 3.8 months (95% CI, 3.0-4.2; HR, 0.77; 95% CI, 0.62-0.96; P = .053193). In the 3L+ population, the median PFS by BICR was 4.1 months vs 2.7 months (HR, 0.56; 95% CI, 0.43-0.74), though this was not formally tested. Investigator-assessed PFS in the ITT population showed a more pronounced treatment effect, at 4.4 months vs 3.0 months (HR, 0.59; 95% CI, 0.48-0.73).

Among 189 patients per arm with measurable disease at baseline, the confirmed objective response rate was 23.3% with Sone-Ve vs 13.8% with investigator’s choice (risk difference, 10.2; 95% CI, 2.68-17.83), including complete response rates of 3.7% vs 0.5%. The disease control rates were 70.4% vs 55.6%, respectively, and the median duration of response was 8.5 months (95% CI, 5.8-not calculated) vs 6.8 months (95% CI, 2.9-not calculated).

Regarding safety, grade 3 or higher adverse effects (AEs) occurred in 52.9% of patients in the Sone-Ve arm (n = 261) vs 61.1% in the control arm (n = 252), despite a longer median duration of exposure (3.9 months vs 2.1 months). Serious AEs occurred in 34.9% vs 31.3% of patients, respectively, and AEs led to treatment discontinuation in 5.0% vs 4.4% and dose reductions in 21.1% vs 23.0%. Treatment-related deaths occurred in 1.1% vs 0.8% of patients.

Gastrointestinal AEs were more frequent with Sone-Ve, including any-grade nausea (54.4% vs 26.6%), decreased appetite (43.3% vs 24.2%), vomiting (41.0% vs 24.6%), and weight decrease (28.0% vs 11.9%). Hematologic toxicity was lower with Sone-Ve, including any-grade anemia (29.9% vs 40.9%), any-grade neutropenia (23.8% vs 39.7%), and grade 3 or higher neutropenia (10.3% vs 25.4%). Any-grade peripheral neuropathy occurred in 21.5% vs 14.3% of patients, with grade 3 or higher events in 0.8% vs 0.4%.

Xu concluded that CLARITY-Gastric01 is the first global phase 3 trial to demonstrate a statistically significant OS benefit with a manageable safety profile for a CLDN18.2-targeted ADC in this population, and that Sone-Ve represents a potential new standard of care in the 2L+ setting for patients with advanced or metastatic CLDN18.2-positive GEC.

Reference

Xu RH, Janjigian Y, Chen MH, et al. CLARITY-Gastric01: a phase 3 study of sonesitatug vedotin (Sone-Ve, AZD0901) in second or later-line advanced or metastatic Claudin 18.2-positive gastroesophageal carcinoma. Presented at: 2026 European Society for Medical Oncology Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA7.