CLARITY-Gastric01 Shows OS Benefit With Sonesitatug Vedotin in Pretreated CLDN18.2+ Gastroesophageal Carcinoma

Sonesitatug vedotin improved overall survival (OS) vs investigator’s choice of therapy in patients with previously treated Claudin 18.2 (CLDN18.2)–positive advanced or metastatic gastroesophageal carcinoma (GEC), meeting one of the dual primary end points in the third- or later-line population of the phase 3 CLARITY-Gastric01 trial (NCT06346392).¹ The other dual primary end point, progression-free survival (PFS), did not reach statistical significance.

Data shared during the second Presidential Symposium at the 2026 ESMO Congress revealed that in the third- or later-line population, the median OS was 10.0 months (95% CI, 7.2-11.4) with sonesitatug vedotin given at a dose of 2.2 mg/kg (n = 178) vs 5.0 months (95% CI, 4.2-6.4) with investigator’s choice of therapy (n = 177), translating to a 53% reduction in the risk of death (HR, 0.47; 95% CI, 0.36-0.62; P < .000001). The 12-month OS rates were 38.1% and 18.1%, respectively.

In the intent-to-treat (ITT) population, which comprised all randomly assigned patients in the second- or later-line setting, median OS, a key secondary end point, was 10.6 months (95% CI, 9.1-12.0) with sonesitatug vedotin (n = 267) vs 6.4 months (95% CI, 5.8-7.6) with investigator’s choice (n = 265; HR, 0.58; 95% CI, 0.47-0.73; P = .000004); 12-month OS rates were 42.6% and 27.8%, respectively. The median PFS by blinded independent central review (BICR) in the ITT population was 4.2 months (95% CI, 3.5-5.3) vs 3.8 months (95% CI, 3.0-4.2), respectively (HR, 0.77; 95% CI, 0.62-0.96; P = .053193).

“[Sonesitatug vedotin] is a potential new standard of care in the second- or later-line setting for patients with advanced or metastatic Claudin 18.2–positive gastroesophageal carcinoma,” said Rui-Hua Xu, MD, PhD, a professor in the Department of Medical Oncology at Sun Yat-sen University Cancer Center in Guangzhou, China, and principal investigator of the trial, in his presentation of the data.

How was the phase 3 CLARITY-Gastric01 trial of sonesitatug vedotin in CLDN18.2-positive GEC designed?

Sonesitatug vedotin (AZD0901) is a CLDN18.2-directed antibody-drug conjugate (ADC) with a monomethyl auristatin E payload. The open-label, sponsor-blinded trial enrolled patients with advanced GEC that had progressed after at least 1 prior line of therapy and expressed CLDN18.2 in at least 25% of tumor cells at any staining intensity. After a dose-selection stage, in which a 1.8-mg/kg arm (n = 62) was closed, patients were randomly assigned 1:1 to sonesitatug vedotin at 2.2 mg/kg every 3 weeks or investigator’s choice of therapy. Comparators were ramucirumab (Cyramza) plus paclitaxel, paclitaxel, or docetaxel in the second line; and irinotecan, trifluridine/tipiracil (Lonsurf), or apatinib (China only) in later lines.

The median age was 57 years (range, 24-82) in each arm, and 61.0% and 55.8% of patients in the sonesitatug vedotin and investigator’s choice arms had peritoneal metastases, a feature Xu noted is associated with poor prognosis. Few patients had received prior zolbetuximab-clzb (Vyloy; 3.7% and 2.6%, respectively), limiting analysis of that subgroup.

Was the OS benefit with sonesitatug vedotin consistent across CLDN18.2 expression levels in GEC?

In an exploratory ITT analysis, the OS HR was 0.59 (95% CI, 0.45-0.78) among patients with CLDN18.2 expression in at least 75% of tumor cells (sonesitatug vedotin, n = 183; investigator’s choice, n = 194) and 0.63 (95% CI, 0.42-0.94) among those with expression in 25% to less than 75% (n = 83 and n = 71, respectively), which Xu said supports the lower expression threshold.

OS HR point estimates favored sonesitatug vedotin across all prespecified subgroups in the third- or later-line population. In the ITT population, the HR was 0.88 (95% CI, 0.60-1.30) among patients treated in the second line (n = 89 and n = 88, respectively) and 1.08 (95% CI, 0.68-1.71) among those with gastroesophageal junction or esophageal adenocarcinoma (n = 54 and n = 71, respectively); subgroup CIs were not adjusted for multiplicity.

What did PFS and response analyses show with sonesitatug vedotin in CLDN18.2-positive GEC?

In the third- or later-line population, median PFS by BICR, which was not formally tested, was 4.1 months (95% CI, 3.0-5.3) with sonesitatug vedotin (n = 178) vs 2.7 months (95% CI, 2.4-3.0) with investigator’s choice (n = 177; HR, 0.56; 95% CI, 0.43-0.74). Investigator-assessed PFS in the ITT population, an exploratory end point, was 4.4 months (95% CI, 3.8-5.7) vs 3.0 months (95% CI, 2.7-4.1), respectively (HR, 0.59; 95% CI, 0.48-0.73).

Among patients with measurable disease at baseline (n = 189 per arm), the confirmed objective response rate was 23.3% vs 13.8% (risk difference estimate, 10.2; 95% CI, 2.68-17.83), with complete responses in 3.7% vs 0.5% of patients. The median duration of response was 8.5 months (95% CI, 5.8-not calculable [NC]) vs 6.8 months (95% CI, 2.9-NC).

What was the safety profile of sonesitatug vedotin in CLARITY-Gastric01?

The median duration of exposure to sonesitatug vedotin (n = 261) was 3.9 months (range, 0.2-24.7) vs 2.1 months (range, 0.2-22.0) with investigator’s choice of therapy (n = 252). Adverse effects (AEs) were experienced by 97.3% of those in the sonesitatug vedotin arm vs 94.0% of those in the investigator’s choice arm; 85.8% and 81.3% of these events were possibly related to treatment in the respective arms. Serious AEs were experienced by 34.9% and 31.3% of patients, respectively.

Moreover, in the sonesitatug vedotin arm, AEs led to dose delay or reduction of 36.4% and 21.1% of patients, respectively; in the investigator’s choice arm, these respective rates were 40.5% and 23.0%. In the sonesitatug vedotin and investigator’s choice arms, AEs resulted in treatment discontinuation for 5.0% and 4.4% of patients, respectively; 3.1% and 4.4% of these AEs were potentially related to treatment.

The most common AEs reported with sonesitatug vedotin vs invesigator’s choice of therapy were nausea (54.4% vs 26.6%), decreased appetite (43.3% vs 24.2%), and vomiting (41.0% vs 24.6%), which Xu said were generally manageable with per-protocol antiemetic prophylaxis and supportive care.

Grade 3 or higher neutropenia occurred in 10.3% vs 25.4% of patients. Additional common grade 3 or higher AEs experienced in the sonesitatug vedotin and investigator’s choice arms were decreased appetite (9.6%; 1.6%), anemia (8.4%; 11.1%), and nausea (6.9%; 2.8%).

Xu noted that higher rates of GI-related toxicities were reported with sonesitatug vedotin vs investigator’s choice of chemotherapy, and lower rates of hematologic toxicity were observed with the ADC vs investigator’s choice.

What comes next for sonesitatug vedotin?

Sonesitatug vedotin is also being evaluated with capecitabine, with or without rilvegostomig, as first-line therapy in the phase 3 CLARITY-Gastric02 trial (NCT07431281), according to AstraZeneca.² The company first announced topline OS results from CLARITY-Gastric01 in July 2026.³ At the same meeting, another CLDN18.2-directed ADC, arcotatug tavatecan (IBI343/TAK-921), improved PFS and OS in the phase 3 G-HOPE-001 trial (NCT06238843) in previously treated CLDN18.2-positive, HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma.⁴

Disclosures: Xu reported serving in a consulting or advisory role for Astellas, AstraZeneca, BeiGene, Innovent, Junshi, and MSD.

References

1. 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 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA7.
2. AstraZeneca. Sonesitatug vedotin reduced the risk of death by 42% in 2nd- and later-line CLDN18.2-positive advanced gastric/GEJ cancers in CLARITY-Gastric01. News release. October 25, 2026. Accessed October 25, 2026. https://www.astrazeneca.com/media-centre/press-releases/2026/sonesitatug-vedotin-reduced-the-risk-of-death-by-42-pct-in-2nd-and-later-line-cldn182-positive-advanced-gastricgej-cancers-in-clarity-gastric01.html
3. Sonesitatug vedotin improves overall survival in second- and later-line CLDN18.2-positive gastric/GEJ cancer. OncLive. Published July 27, 2026. Accessed October 25, 2026. https://www.onclive.com/view/sonesitatug-vedotin-improves-overall-survival-in-second--and-later-line-cldn18-2-positive-gastric-gej-cancer
4. Arcotatug tavatecan improves survival in CLDN18.2+ advanced gastric or GEJ adenocarcinoma. OncLive. Published October 23, 2026. Accessed October 25, 2026. https://www.onclive.com/view/arcotatug-tavatecan-improves-survival-in-cldn18-2-advanced-gastric-or-gej-adenocarcinoma