Patients with previously treated Claudin 18.2-positive advanced or metastatic gastroesophageal carcinoma had longer progression-free and overall survival with the investigational antibody-drug conjugate sonesitatug vedotin than with investigator’s choice of therapy.

“Sonesitatug vedotin is a potential new standard of care in the second-line-plus setting for patients with advanced or metastatic Claudin 18.2-positive gastroesophageal carcinoma,” said Rui-Hua Xu, MD, PhD, of Sun Yat-sen University Cancer Center in Guangzhou, China. 

Xu presented the results of the randomized phase 3 CLARITY-Gastric01 trial at the European Society for Medical Oncology (ESMO) Annual Meeting 2026 in Madrid, Spain, on October 25.

Sonesitatug vedotin targets Claudin 18.2, a protein expressed in 40%-80% of gastroesophageal cancers that has become a therapeutic target. Currently, no Claudin 18.2-targeted therapies are approved for the second-line setting.

The open-label study enrolled 594 participants with advanced gastroesophageal carcinoma expressing at least 25% of Claudin 18.2 who had already received first-line treatment. Of these, 62 were assigned to receive 1.8 mg/kg of sonesitatug vedotin every 3 weeks, and this arm was closed after dose selection was determined. The data analysis presented then focused on the remaining 532 participants, with 265 participants receiving the investigator’s choice of therapy and 267 participants receiving 2.2 mg/kg of sonesitatug vedotin every 3 weeks.

Investigator’s choice therapy could include ramucirumab plus paclitaxel, paclitaxel alone, or docetaxel in the second line; and irinotecan, TAS-102 (except in China), or apatinib (in China only) in the third line and later.

The participants were mostly male (58%) and had an average age of 57. About 20% came from Japan or South Korea, 40% from another part of Asia, and 40% from other parts of the world. The primary tumor location was the stomach for 76.5% of participants, and the gastroesophageal junction and/or esophagus was the primary location for the other 23.5% of participants. Most participants (71%) had over 75% expression of Claudin 18.2, and 29% had 25%-75% expression.

About a third of participants (36%) had a prior gastrectomy, and about a third (33%) were receiving second-line therapy, while the remaining 66% were receiving their third-line or later therapy. Very few (3.1%) had received zolbetuximab or another anti-Claudin 18.2 therapy (1.7%). All these characteristics were generally balanced between the two groups. Peritoneal metastasis was present in 61% of the sonesitatug vedotin group and 56% of the investigator’s choice group.

Over a median follow-up of 8.6 months, overall survival was 10 months in patients receiving sonesitatug vedotin and 5 months in patients receiving investigator’s choice (hazard ratio [HR], 0.47; P < .000001). The overall survival benefit held up in third-line and later for nearly all the prespecified subgroups but was not significant in the subgroup with a primary tumor in the esophagus or in the subgroup of patients without peritoneal metastasis. 

The intent-to-treat (ITT) analysis was similar, with 10.6 months overall survival for those receiving sonesitatug vedotin compared with 6.4 months in the investigator’s choice group (HR, 0.58; P < .000004). In the ITT analysis of subgroups by Claudin 18.2 expression, the overall survival benefit was similar for those expressing over 75% as for those expressing 25%-75%.

Progression-free survival was 4.2 months in the sonesitatug vedotin group and 3.8 months in the investigator’s choice group in the ITT analysis but was not significantly different (HR, 0.77; P = .053). The progression-free survival in the third-line and later, however, was significantly greater for the sonesitatug vedotin group (4.1 months) than the investigator’s choice group (2.7 months; HR, 0.56).

The objective response rate was significantly greater in the sonesitatug vedotin group (23.3%) than in the investigator’s choice group (13.8%; risk difference, 10.2), and more participants achieved a complete response with sonesitatug vedotin. 

The disease control rate was also higher for sonesitatug vedotin (70.4%) than for the investigator’s choice (55.6%). The median duration of response was 8.5 months for sonesitatug vedotin and 6.8 months for investigator’s choice.

Rates of adverse events possibly due to treatment were similar for sonesitatug vedotin (85.3%) and investigator’s choice (81.3%), as were serious adverse events (34.9% and 31.3%, respectively). There were fewer adverse events of three or greater, possibly due to treatment with sonesitatug vedotin (36.4%) than with the investigator’s choice (44.8%). There were three deaths from adverse events possibly due to treatment in the sonesitatug vedotin group and two in the investigator’s choice group. 

Overall, more gastrointestinal adverse events occurred with sonesitatug vedotin than with investigator’s choice therapy, but sonesitatug vedotin had lower rates of hematologic toxicity. The most common adverse events of grade 3 or more were neutropenia (25.4% with investigator’s choice vs 10.3% with sonesitatug vedotin), decreased appetite, anemia, nausea, decreased neutrophil count (18.7% with investigator’s choice vs 6.9% with sonesitatug vedotin), vomiting, and fatigue. Pulmonary embolism occurred in 4.2% of patients taking sonesitatug vedotin and 1.6% receiving the investigator’s choice. 

As an invited discussant, Salah-Eddin Al-Batran, MD, director of gastrointestinal oncology at Krankenhaus Nordwest-University Cancer Center in Frankfurt, Germany, noted that previously treated advanced gastroesophageal adenocarcinoma is an area of high unmet medical need.

Referencing the G-HOPE-001 trial in which arcotatug tavatecan, another Claudin-18.2-targeted antibody drug conjugate, similarly demonstrated longer overall survival and progression-free survival in the third-line setting, and later, he said, “This consistent benefit strongly supports the potential of Claudin 18.2-targeting antibody drug conjugates as a new therapeutic strategy in gastroesophageal adenocarcinoma.”

But it’s also important to look at the duration of toxicity and its impact on quality of life, , noting the high rates of nausea — 54.4% with sonesitatug vedotin in this trial and 75.8% in the SPOTLIGHT and GLOW trials evaluating the Claudin 18.2-targeting monoclonal antibody zolbetuximab in gastric cancer.

Effective antiemetic prophylaxis may be necessary to maintain adequate treatment exposure, he noted.

“There is no doubt Sone-Ve [sonesitatug vedotin] represents an important therapeutic advance in gastroesophageal carcinoma,” but the study design’s combining of second- and third-line patients “complicates clinical interpretation,” Al-Batran said.

“In the third-line and beyond setting, we have seen impressive efficacy in a setting of high unmet need. In the second-line population, there is a potential benefit, but more data are needed.”

The research was funded by AstraZeneca. Xu has consulted or advised for Astellas, AstraZeneca, BeiGene, Innovent, Junshi, and MSD. Al-Batran reported grant funding, speaking/advisory/consulting fees, and/or financial interests with AstraZeneca, MSD, Bristol Myers Squibb, Celgene, Immutep, Ipsen, Jazz Pharmaceuticals, Lilly, Roche, Sanofi, and Takeda.

Tara Haelle has been an independent science and health journalist for over 15 years, with work appearing in over two dozen trade and consumer publications. She is the author of Vaccination Investigation: The History and Science of Vaccines and The Informed Parent: A Science-Based Resource for Your Child’s First Four Years. Haelle is the public health beat leader for the Association of Health Care Journalists, where she develops resources to help other journalists report on medical studies and public health. She is based in Dallas.