Takeda’s Arcotatug Tavatecan Deliver Dual Survival Benefits in G-HOPE-001 Trial

Takeda has reported positive Phase 3 results for arcotatug tavatecan (TAK-921; IBI343), an investigational Claudin 18.2 (CLDN18.2)-targeted antibody-drug conjugate (ADC), in previously treated advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJA). The G-HOPE-001 study met both primary endpoints, demonstrating statistically significant improvements in overall survival (OS) and progression-free survival (PFS) compared with treatment of physician’s choice (TPC).

At the second prespecified interim analysis, median OS was 10.2 months with arcotatug tavatecan versus 6.9 months with TPC, while independently assessed median PFS was 7.1 months versus 3.1 months. The findings, presented at the 2026 European Society for Medical Oncology (ESMO) Congress, support Takeda’s planned regulatory filing in Japan.

Phase 3 G-HOPE-001 Study Design

G-HOPE-001 (NCT06238843) is an ongoing, randomized, open-label Phase 3 trial that enrolled 464 patients in China and Japan. Participants had unresectable locally advanced or metastatic CLDN18.2-positive G/GEJA that had progressed after two to four prior systemic treatment regimens.

Eligible tumors were defined by immunohistochemistry (IHC) staining of at least 2+ intensity in at least 75% of tumor cells using the VENTANA CLDN18 (43-14A) assay. Patients were randomized 1:1 to receive arcotatug tavatecan at 6 mg/kg intravenously every three weeks or investigator-selected TPC: irinotecan, paclitaxel or trifluridine/tipiracil.

The dual primary endpoints were PFS assessed according to RECIST v1.1 and OS. Secondary endpoints included objective response rate (ORR), disease control rate, duration of response, time to response and safety.

Overall and Progression-Free Survival Results

At the second interim analysis (IA2), with a data cutoff of September 3, 2026, arcotatug tavatecan demonstrated a statistically significant OS benefit. Median OS reached 10.2 months compared with 6.9 months with TPC, corresponding to a hazard ratio (HR) of 0.57 (95% confidence interval [CI]: 0.45–0.73; P<0.0001), or a 43% reduction in the hazard of death.

Independent radiological review committee-assessed median PFS was 7.1 months versus 3.1 months (HR 0.45; 95% CI: 0.35–0.58), representing a 55% reduction in the hazard of progression or death.

The earlier interim analysis (IA1), with a data cutoff of February 13, 2026, had already met the prespecified PFS criteria. Median PFS was 5.5 months with arcotatug tavatecan versus 2.9 months with TPC (HR 0.47; 95% CI: 0.34–0.65; P<0.0001).

The confirmed ORR at IA2 was 37.4% with arcotatug tavatecan compared with 7.7% with TPC, providing additional evidence of antitumor activity.

Safety and Tolerability

Grade 3 or higher treatment-related adverse events occurred in 47.4% of patients receiving arcotatug tavatecan versus 55.9% with TPC. However, the safety findings also identified clinically relevant hematologic toxicity.

The most common Grade 3 or higher treatment-emergent adverse events included anemia (20.4% versus 13.1%), decreased neutrophil count (17.4% versus 32.0%) and decreased white blood cell count (11.7% versus 22.5%), respectively.

Severe nausea, vomiting and diarrhea occurred in 0.9%, 2.6% and 1.3% of patients receiving arcotatug tavatecan, compared with 1.8%, 3.2% and 4.1% with TPC. Adverse events leading to treatment interruption occurred in 47.4% and 51.4%, respectively. Treatment-related drug discontinuations were uncommon and comparable between groups, with a rate of 1.7% reported for arcotatug tavatecan. One treatment-related fatal adverse event, described as sudden death of unknown cause, occurred in the investigational treatment arm.

Mechanism and Development Strategy

Arcotatug tavatecan combines an anti-CLDN18.2 antibody with exatecan, a cytotoxic topoisomerase I inhibitor. Its Fc-silenced backbone is designed to reduce Fc-mediated effects. CLDN18.2 is normally associated with gastric tissue but can be expressed on the surface of certain gastrointestinal cancer cells, providing a target for selective drug delivery.

Takeda holds development, manufacturing and commercialization rights outside Greater China under its collaboration with Innovent. The company plans to use the G-HOPE-001 findings to support a regulatory filing in Japan. In China, Innovent’s application has been accepted for Priority Review by the National Medical Products Administration. Takeda also plans to initiate global Phase 3 studies in gastric and pancreatic cancer. The drug has received FDA Fast Track designation for specified previously treated CLDN18.2-positive advanced pancreatic cancer.

Clinical Interpretation

G-HOPE-001 provides evidence that CLDN18.2-directed ADC therapy can improve survival outcomes against established later-line treatment options in the studied population. The 3.3-month difference in median OS, accompanied by a substantial PFS improvement and higher response rate, strengthens the case for further development.

However, the findings should be interpreted alongside the hematologic toxicities and the reported treatment-related fatal event. The study’s enrollment in China and Japan also means that further global studies will be important to assess generalizability. Arcotatug tavatecan remains investigational and has not been approved by the FDA or other regulatory authorities.

Reference

Takeda Announces Arcotatug Tavatecan (TAK-921) Demonstrated Statistically Significant and Clinically Meaningful Improvements in Overall Survival and Progression-Free Survival in Phase 3 Advanced Gastric Cancer Study, Takeda, 23 October 2026

A Multicenter, Phase 3 Study of IBI343 Monotherapy Versus Treatment of Investigator’s Choice in Subjects with Previously Treated, Claudin (CLDN) 18.2-positive, HER2-negative, Gastric or Gastroesophageal Junction Adenocarcinoma (G-HOPE-001) (G-HOPE-001), ClinicalTrials.gov ID NCT06238843