Arcotatug Tavatecan Improves Survival in CLDN18.2+ Advanced Gastric or GEJ Adenocarcinoma

Treatment with arcotatug tavatecan (IBI343/TAK-921) led to improvements in both progression-free survival (PFS) and overall survival (OS) vs treatment of physician's choice (TPC) in patients with previously treated, claudin 18.2 (CLDN18.2)–positive, HER2-negative advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma, meeting both primary end points of the phase 3 G-HOPE-001 trial (NCT06238843), according to findings presented at the 2026 ESMO Congress.¹

At the time of the first interim analysis (IA1), which had a data cutoff date February 2026 and included the final PFS analysis in the first 408 randomly assigned patients, median PFS by independent radiological review committee (IRRC) assessment was 5.5 months (95% CI, 4.3-8.2) with arcotatug tavatecan (n = 203) vs 2.9 months (95% CI, 2.6-3.4) with TPC (n = 205; HR, 0.47; 95% CI, 0.34-0.65; P < .0001). At the second interim analysis (IA2), which had a data cutoff dat of September 3, 2026, the median OS in the intent-to-treat (ITT) population was 10.2 months (95% CI, 9.1-12.3) with arcotatug tavatecan (n = 230) vs 6.9 months (95% CI, 5.7-7.8) with TPC (n = 230; HR, 0.57; 95% CI, 0.45-0.73; P < .0001).

"These results support arcotatug tavatecan, a novel Fc-silenced CLDN18.2-targeted ADC, as an effective treatment option in the third-line setting for patients with CLDN18.2–positive, HER2-negative gastric/GEJ adenocarcinoma," said Kohei Shitara, MD, of the Department of Gastrointestinal Oncology at National Cancer Center Hospital East in Kashiwa, Japan.

How was the G-HOPE-001 trial designed?

The open-label trial, conducted in China and Japan, enrolled adults with locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma that had progressed on 2 to 4 prior therapies, including a fluoropyrimidine, a platinum, and a taxane or irinotecan. CLDN18.2 positivity was defined as membrane staining intensity of 2+ or higher in at least 75% of tumor cells by central or local immunohistochemistry. Patients who previously received zolbetuximab-clzb (Vyloy) or another CLDN18.2-targeted therapy were eligible if positivity was confirmed on a biopsy obtained after progression; prior topoisomerase inhibitor–based ADCs were not permitted.

Patients were randomly assigned 1:1 to arcotatug tavatecan at 6 mg/kg every 3 weeks or TPC consisting of irinotecan, paclitaxel, or trifluridine/tipiracil (Lonsurf). Of 2550 prescreened patients with evaluable samples, 1215 (47.6%) were CLDN18.2 positive, and 460 were randomly assigned. In the TPC arm, 92.2% of patients received irinotecan. The final OS analysis is planned at 371 events. Shitara noted that IA2 results became available shortly before the presentation.

Baseline characteristics were balanced. The median age was 59 years (range, 22-86) with arcotatug tavatecan and 58 years (range, 21-82) with TPC, 83.0% and 81.7% of patients were enrolled in China, 51.3% and 47.8% had peritoneal metastases, and 88.7% in each arm had received prior immunotherapy. Prior anti-CLDN18.2 therapy was reported in 9.6% and 5.2% of patients, respectively.

What were the additional efficacy findings?

At IA1, the 6-month PFS rates were 48.5% with arcotatug tavatecan and 24.0% with TPC, and investigator-assessed PFS was consistent (HR, 0.39; 95% CI, 0.30-0.53). The descriptive PFS update at IA2 showed a median of 7.1 months (95% CI, 5.3-9.7) vs 3.1 months (95% CI, 2.8-3.8), respectively (HR, 0.45; 95% CI, 0.35-0.58). The 12-month OS rates in the respective arms were 43.2% and 24.7%, respectively.

PFS and OS benefits were generally consistent across prespecified subgroups. Among patients without prior immunotherapy, the OS HR was 1.17 (95% CI, 0.58-2.35; n = 26 per arm); Shitara noted this subgroup was small. Among patients with prior CLDN18.2-targeted therapy, the OS HR was 0.39 (95% CI, 0.17-0.92; arcotatug tavatecan, n = 22; TPC, n = 12).

Among patients with measurable disease, the confirmed objective response rate by IRRC was 37.4% (95% CI, 30.3%-44.4%) with arcotatug tavatecan vs 7.7% (95% CI, 3.8%-11.6%) with TPC, including complete responses in 1.6% and 0.5% of patients, respectively. The median duration of response with arcotatug tavatecan was 9.9 months (95% CI, 8.1-12.1); the disease control rate was 83.5% (95% CI, 78.1%-88.9%) with arcotatug tavatecan vs 54.4% (95% CI, 47.2%-61.6%) with TPC.

What did the safety analysis show?

The median treatment duration was 5.0 months (range, 0.7-18.8) with arcotatug tavatecan (n = 230) vs 2.0 months (range, 0.5-14.3) with TPC (n = 222). Grade 3 or higher treatment-emergent adverse effects (TEAEs) occurred in 58.3% vs 62.6% of patients, and treatment-related grade 3 or higher TEAEs occurred in 47.4% vs 55.9%, respectively. TEAEs led to dose reduction in 17.8% vs 35.1% of patients, dose interruption in 47.4% vs 51.4% of patients, and discontinuation in 3.5% vs 2.3% of patients. One treatment-related death (0.4%), a sudden death of unknown cause, occurred in the arcotatug tavatecan arm.

The most common any-grade TEAEs experienced with arcotatug tavatecan were anemia (any grade, 66.1%; grade ≥3, 20.4%), decreased white blood cell count (58.3%; 11.7%), and decreased neutrophil count (55.2%; 17.4%). Gastrointestinal toxicities were comparable or less frequent with arcotatug tavatecan vs TPC, and included nausea (43.9% vs 43.7%), vomiting (25.2% vs 32.9%), and diarrhea (15.2% vs 40.5%).

What are the next steps for arcotatug tavatecan?

According to Takeda, which holds rights to the agent outside of greater China, the G-HOPE-001 data will support a planned regulatory filing in Japan, and Innovent's new drug application for arcotatug tavatecan has been accepted with priority review by China's National Medical Products Administration.²

Previously, another CLDN18.2-directed ADC, sonesitatug vedotin, improved OS in the third- and later-line setting of the phase 3 CLARITY-Gastric01 trial (NCT06346392), according to a news release from AstraZeneca.³

Disclosures: Shitara reported receiving consulting fees from Bristol Myers Squibb, Takeda, Ono Pharmaceutical, Novartis, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Merck Pharmaceutical, Astellas, Guardant Health Japan, AstraZeneca, Zymeworks Biopharmaceuticals, ALX Oncology, Bayer, HEALIOS K.K., Arcus Biosciences, AbbVie, CMIC Co., Ltd., Elevation Oncology, Oncolys BioPharma, Sanofi, Suzhou Lingyhui Network Technology, Gilead Sciences, eChinaHealth, Leap Therapeutics, Phanes Therapeutics, Scandion Oncology, and Revolution Medicines; honoraria from Astellas; and research funding (all to institution) from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck Pharmaceutical, Amgen, Eisai, PRA Health Sciences, Syneos Health, AstraZeneca, PPD-SNBL K.K., TORAY, Incyte Biosciences G.K., Medpace Japan K.K., AbbVie GK, and ICON Clinical Research GK. G-HOPE-001 was funded by Innovent Biologics and Takeda Pharmaceuticals.

References

1. Shitara K, Peng Z, Li C, et al. Arcotatug tavatecan (IBI343/TAK-921) versus treatment of physician's choice (TPC) in previously treated, advanced gastric or gastroesophageal junction adenocarcinoma (G/GEJA): first interim analysis of the randomized, open-label, phase 3, G-HOPE-001 study. Presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract LBA77.
2. 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. News release. Takeda. October 23, 2026. Accessed October 23, 2026. https://www.takedaoncology.com/newsroom/news-releases/2026/arcotatug-tavatecan-phase-3-study/
3. Ryan C. Sonesitatug vedotin improves overall survival in second- and later-line CLDN18.2-positive gastric/GEJ cancer. OncLive. Published July 27, 2026. Accessed October 23, 2026. https://www.onclive.com/view/sonesitatug-vedotin-improves-overall-survival-in-second--and-later-line-cldn18-2-positive-gastric-gej-cancer