As the fifth most common malignancy worldwide and a top priority in the prevention and treatment of gastrointestinal cancers in China, gastric cancer is characterized by its insidious onset, poor prognosis in advanced stages, and limited efficacy of conventional therapies. Approximately 80% of patients lose the opportunity for radical surgery at the time of diagnosis.

In recent years, precision therapy centered on antibody-drug conjugates (ADCs) has achieved a dual breakthrough: a surge in scientific research outputs and the rapid launch of novel drugs. ADCs targeting the two core biomarkers, HER2 and CLDN18.2, have not only completed multiple pivotal clinical trials and obtained new indications, but also yielded significant progress in basic research on their resistance mechanisms and combination strategies. These advances bring new survival hope to gastric cancer patients with different molecular subtypes and disease stages.

I. In-depth Basic Research Unlocks the Core Secrets of ADC Drug Development and Resistance

Clinical breakthroughs of ADC drugs rely on solid basic research. In recent years, studies on the mechanisms of HER2 and CLDN18.2 targets, as well as the action and resistance pathways of ADCs in gastric cancer, have laid a foundation for their development and combination therapy, driving precision therapy from “target selection” to “mechanism optimization”. Meanwhile, the role of gastric microbiota in gastric cancer metastasis has been gradually revealed, providing new directions for targeted therapy of metastatic disease.

In target research, it has been confirmed that HER2 is highly expressed in 10%–20% of gastric cancer patients, and its heterogeneity affects therapeutic efficacy. CLDN18.2 is specifically and highly expressed in 40%–60% of relevant patients, representing the most promising target for ADC development, with its expression level correlated with tumor malignancy. Furthermore, the “immunogenic cell death” mechanism of ADCs provides a theoretical basis for their combination with PD-1/PD-L1 inhibitors.

In February 2026, a research team led by Teng Lisong from Zhejiang University published a study in GUT, revealing that Acinetobacter baumannii can act as a pro-metastatic factor in gastric cancer. It promotes metastasis by interfering with NAD metabolism, activating HIF-1, and enhancing glycolysis, providing a novel mechanism for targeted anti-metastatic therapy.

Source: Mechanism schematic from GUT

II. New Drugs Launched Successively, ADCs Cover Multiple Targets and Treatment Stages

2025–2026 mark a critical breakthrough period for the clinical translation of ADCs in gastric cancer. Multiple novel ADCs targeting HER2 and CLDN18.2 have completed pivotal clinical trials and obtained new indications. Among them, domestically innovated ADCs have stood out, achieving a leap from “catching up” to “leading globally”.

From filling the second-line treatment gap for HER2-positive gastric cancer, to completing the world’s first registrational clinical trial for CLDN18.2-targeted ADCs, and delivering impressive data from combination regimens, ADCs now achieve full coverage across multiple targets, multiple treatment lines, and both monotherapy and combination strategies, establishing themselves as a core pillar of precision gastric cancer therapy.

(I) HER2 ADCs: Trastuzumab Deruxtecan Approved for Second-Line Indication, Reshaping Later-Line Therapy

HER2-positive gastric cancer long suffered from the dilemma of “no effective targeted therapy after first-line trastuzumab failure”. In January 2026, trastuzumab deruxtecan (T-DXd) was approved by the NMPA as monotherapy for the second-line treatment of HER2-positive gastric cancer.

It became the first and only ADC approved for this indication in China, filling a major clinical gap. The approval took only 6 months from NDA submission to approval, highlighting the urgent clinical value of this innovative drug.

The approval was based on pivotal data from the international multicenter phase III DESTINY-Gastric04 trial, published in The New England Journal of Medicine.

Compared with the conventional regimen of ramucirumab plus paclitaxel, trastuzumab deruxtecan improved median overall survival (OS) from 11.4 months to 14.7 months, reducing the risk of death by 30%. The 24-month OS rate doubled: 29% vs. 13.9%. Median progression-free survival (PFS) increased from 5.6 months to6.7 months, and the objective response rate (ORR) reached 44.3%.

(II) CLDN18.2 ADCs: Domestic Innovations Lead Globally, Multiple Agents Demonstrate Superior Efficacy

CLDN18.2 is a core focus of gastric cancer ADC development. During 2025–2026, domestic innovative drugs in this field have taken a global lead. Multiple agents have completed pivotal clinical trials and released impressive data, breaking the limitation of traditional targeted drugs that only benefit patients with high target expression. They now cover patients with low CLDN18.2 expression and low PD-L1 expression, greatly expanding the scope of benefit.

(1) LM-302 (Lianxin Medicine / Lanova Pharmaceuticals):In February 2026, LM-302 completed enrollment of all subjects in the world’s first Phase III registrational clinical trial of a CLDN18.2-targeted ADC for thirdline and beyond gastric cancer treatment, marking a milestone in this field.As a national Class 1 innovative drug, it specifically binds to CLDN18.2positive tumor cells and achieves precise killing by releasing cytotoxic payload through endocytosis.To date, multiple indications of LM-302 have been granted Breakthrough Therapy Designation by the CDE and Orphan Drug Designation by the U.S. FDA. A Phase III trial of LM-302 combined with immunotherapy as firstline treatment is also under planning.

Source: Announcement of Sino Biopharmaceutical Limited

(2) ATG-022 (Deqiao Medicine / Antengene Corporation):Data from the Phase I/II CLINCH study presented at ASCO GI 2025 showed that this agent achieved promising efficacy and manageable safety in patients with advanced gastric cancer across various CLDN18.2 expression levels.

In patients with CLDN18.2 IHC 2+ ≥ 20%, the ORR was 42.9% and DCR was 95.2%.Even in low-expression patients with IHC 2+ < 20%, the ORR still reached 30%. Notably, 1 patient with CLDN18.2 IHC 2+ < 5% achieved complete remission (CR), with response duration exceeding 14 months.

The 1.8 mg/kg dose cohort demonstrated excellent safety profiles, laying a solid foundation for subsequent first-line combination therapy studies.

Source: Announcement of Antengene Corporation Limited

(3) JS107 (Junshi Biosciences): The Phase I data of first-line triple combination therapy released at ESMO GI 2025 was remarkable in the field. The combination regimen of JS107, toripalimab and XELOX chemotherapy showed a positive correlation between therapeutic effect and CLDN18.2 expression level, with significant anti-tumor efficacy, high response rates, potential survival improvement and manageable safety. This regimen achieves synergistic anti-cancer effects through the triple mechanisms of ADC precise targeting, immune activation and chemotherapeutic suppression, providing a novel first-line treatment strategy for CLDN18.2-positive gastric cancer.

Source: ESMO, compiled by the Medical Department

(4) SHR-A1904 (Hengrui Medicine): On December 16, 2025, SHR-A1904, a CLDN18.2-targeted ADC developed by Hengrui Medicine, was granted Breakthrough Therapy Designation by the CDE for the proposed indication of CLDN18.2-positive locally advanced or metastatic gastric/gastroesophageal junction adenocarcinoma after at least one line of systemic therapy. This drug uses a topoisomerase inhibitor as its payload and exerts antitumor effects by specifically binding to tumor cells and releasing cytotoxic agents via endocytosis. Phase I study results showed that among 95 previously treated patients, the confirmed ORR was 24.2% and 25.0% in the 6.0 mg/kg and 8.0 mg/kg dose groups, with median PFS of 5.6 months and 5.8 months, respectively. It demonstrated promising antitumor activity and manageable safety, providing a new option for pretreated patients.

III Combination Therapy: ADC + Immunotherapy/Chemotherapy Becomes Mainstream, Scientific Data Confirms Synergistic Effect

Based on basic research findings of “immunogenic cell death,” combination therapy of ADCs with PD-1/PD-L1 inhibitors and chemotherapy has become a core development direction in gastric cancer treatment. Multiple clinical studies in 2025 confirmed the synergistic advantages of combination regimens, with significantly improved efficacy compared with monotherapy, providing new approaches to expand the beneficiary population and overcome drug resistance.

In addition to combination data from LM-302 and JS107, studies of trastuzumab deruxtecan combined with PD-1 inhibitors for HER2-positive gastric cancer are also underway. Preliminary data show that this combination can effectively reverse HER2 expression heterogeneity resistance in some patients. Furthermore, explorations of CLDN18.2 bispecific antibodies combined with ADCs and immunotherapy have also made progress. Phase Ib data of Xinqiao Bio’s givastomig combined with nivolumab and chemotherapy showed an ORR of 77% and median PFS of 16.9 months, providing new insights for multi-target combination therapy. These studies confirm that the combination of ADCs and immunotherapy can achieve a “1+1>2” anticancer effect and will become a mainstream trend in future gastric cancer treatment.