ESMO26: AZ's claudin ADC doubles survival in GI cancers

AstraZeneca has fleshed out the data from its CLARITY-Gastric01 trial of sonesitatug vedotin (sone-ve) in CLDN18.2-positive gastrointestinal cancers, revealing a 53% reduction in the risk of death with the antibody-drug conjugate (ADC).

First teased earlier this year, the phase 3 CLARITY-Gastric01 study included previously treated patients with locally advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or oesophageal adenocarcinoma that expresses CLDN18.2, who received the ADC or investigator's choice of therapy.

The trial included patients in whom tumour cell CLDN18.2 expression was 25% or more, a lower threshold for CLDN18.2 positivity than was used in trials of Astellas' Vyloy (zolbetuximab), the first and so far only CLDN18.2-directed drug to reach the market.

Despite what might be a tougher challenge, sone-ve reduced the risk of death by 42% in the overall trial population of second-line or later patients, with median overall survival of 10.6 months compared to 6.4 months in the control group.

Drilling further down into the patient population, sone-ve improved OS by 53% among subjects in the third-line or later setting (10 versus 5 months).

"These are remarkable survival results for sone-ve in 2nd- and later-line metastatic gastric cancer, a disease where patients face a poor prognosis once initial therapy fails," said principal investigator Rui-Hua Xu, of Sun Yat-Sen University Cancer Centre in China.

However, the ADC failed to achieve a significant improvement in progression-free survival (PFS) compared to control, which ESMO commentator Prof Salah-Eddin Al-Batran, of the Frankfurt Institute of Clinical Cancer Research, said makes its role in the second-line setting "less certain."

He added: "Despite the rather complicated nature of dual primary endpoints in different settings in the trial, sone-ve could become an important new treatment option in the third- and later-line settings."

The result seems pretty much in line with the phase 3 G-HOPE-001 trial of Takeda and Innovent's anti-CLDN18.2 drug arcotatug tavatecan (TAK-921), reported earlier at ESMO, which included a patient population from China and Japan and used a threshold of 75% tumour cell expression as its enrolment criteria.

AZ said that consistent data across CLDN18.2 expression levels supports the potential for expanded use in up to 60% of patients in this setting and could replace traditional chemo-based regimens.

Sone-ve (formerly CMG901) was originally developed by KYM Biosciences and licensed by AZ in March 2023 in deal worth as much as $1.1 billion.