Editorial Note: In recent years, as research has deepened, the exploration of gastric cancer's molecular mechanisms has gradually shifted from histological classification to molecular classification. Different biomarkers have profoundly influenced the treatment landscape of advanced gastric cancer in first-line and subsequent therapies. At the close of this year, Oncology Frontier  is honored to invite Dr. Ai Li Suo from The First Affiliated Hospital of Xi’an Jiaotong University to review and summarize the latest advancements and hot topics in targeted therapy for advanced gastric cancer in 2024. Reflecting on the past and looking toward the future, Professor Suo provides insights and recommendations for the development of advanced gastric cancer treatment.

First-Line Treatment for Advanced Gastric Cancer

With the progress of research, the exploration of gastric cancer’s molecular mechanisms has transitioned from histological classifications (Lauren classification and WHO classification) to molecular classifications (TCGA and ACRG classifications). The Cancer Genome Atlas (TCGA) categorized gastric cancer into four molecular subtypes based on genetic differences: Epstein-Barr virus-positive (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). The CIN subtype is characterized by molecular features such as TP53 mutations, RTK mutations (EGFR, ERBB2, ERBB3, FGFR, JAK2, MET), KRAS/NRAS mutations, and VEGFA alterations. These molecular characteristics provide potential therapeutic targets for targeted therapies in gastric cancer. While HER2 has been established as a standard treatment target, new drugs are being explored, with targeted therapies for CLDN18.2 and FGFR making strides into HER2-negative settings.

HER2: The First Biomarker to Guide Clinical Decision-Making in Advanced Gastric/GEJ Cancer

The HER2 overexpression or amplification rate in gastric cancer varies across studies, ranging from 13% to 22%. Two large multicenter studies previously indicated an HER2 positivity rate of 12%-13% among Chinese gastric cancer patients. The ToGA study marked the beginning of HER2-targeted therapy in advanced gastric cancer with the combination of trastuzumab and chemotherapy as first-line treatment.

Subsequently, the journey of HER2-targeted therapy encountered multiple challenges, including the failed phase III TRIO-013/LOGIC trial of lapatinib plus chemotherapy and the JACOB trial of pertuzumab, trastuzumab, and chemotherapy. With the advent of immunotherapy, the KEYNOTE-811 trial reshaped the first-line treatment for HER2-positive advanced gastric cancer by combining pembrolizumab, trastuzumab, and chemotherapy. Final analysis of KEYNOTE-811 demonstrated significant benefits in both the intent-to-treat population (overall survival: 20 vs. 16.8 months) and patients with PD-L1 CPS ≥1 (overall survival: 20.1 vs. 15.7 months), supporting this combination as the standard first-line treatment for unresectable/metastatic HER2+ gastric/GEJ cancer with PD-L1 CPS ≥1.

Zanidatamab (ZW25), a humanized bispecific antibody, is being developed for HER2-expressing cancers, including HER2-positive gastric/GEJ cancer. Preliminary results from a phase Ib/II study of ZW25 combined with tislelizumab and CAPOX as first-line therapy showed good efficacy and safety. As of November 22, 2022, after a median follow-up of 18.2 months (range: 2.1–30.9), 13 patients (39.4%) were still undergoing treatment, with a duration of response of 22.8 months and median progression-free survival of 16.7 months.

DESTINY-Gastric03 (DG-03) is a phase Ib/II trial exploring the safety, tolerability, pharmacokinetics, immunogenicity, and preliminary anti-tumor activity of T-DXd alone or in combination with chemotherapy/immunotherapy for HER2-positive advanced/metastatic esophageal, gastric, or GEJ adenocarcinomas. Part 2 of the DG-03 study (dose expansion) evaluated T-DXd monotherapy or its combination with fluoropyrimidine and/or pembrolizumab as first-line treatment for HER2+ (IHC 3+ or IHC 2+/ISH+) gastric/GEJ adenocarcinomas. Results demonstrated promising efficacy for T-DXd combined with fluoropyrimidine and/or pembrolizumab as first-line treatment.

CLDN18.2: An Emerging Confirmed Target for Gastric Cancer

Claudins are a family of 27 different proteins and serve as key structural components of tight junctions, present in various tissues throughout the body. Claudin18.2 (CLDN18.2), a subtype of Claudin18, is widely expressed in several cancers, including gastric, esophageal, pancreatic, lung, and ovarian cancers. Preliminary results of various CLDN18.2-targeted therapies were announced at the 2023-2024 ASCO GI/ASCO/ESMO conferences. In 2024, regulatory agencies in Japan, the UK, the EU, South Korea, and the US FDA approved VYLOY (zolbetuximab) combined with chemotherapy as first-line treatment for HER2-negative, CLDN18.2-positive locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma.

In 2018, Astellas initiated two phase III trials—SPOTLIGHT and GLOW—on zolbetuximab. Of 4,507 patients with valid CLDN18.2 IHC results, 1,730 (38.4%) showed high CLDN18.2 expression. Among 3,705 HER2-negative patients with valid CLDN18.2 IHC results, 1,568 (42.3%) exhibited high CLDN18.2 expression. The studies demonstrated that zolbetuximab combined with chemotherapy significantly reduced the risk of disease progression and death. Nausea and vomiting were the most common treatment-emergent adverse events (TEAEs), primarily occurring during the first cycle and decreasing in subsequent cycles. Based on these results, zolbetuximab became the first and currently the only approved CLDN18.2-targeted therapy worldwide. The latest ESMO online guidelines for gastric cancer also include CLDN18.2 as a stratification factor for first-line treatment in HER2-negative patients, recommending zolbetuximab combined with chemotherapy. Additionally, a phase II trial of zolbetuximab combined with mFOLFOX6 and nivolumab is underway for CLDN18.2-positive, HER2-negative advanced gastric/GEJ cancer patients. Exploration of other CLDN18.2-targeted therapies in advanced gastric/GEJ cancer is primarily focused on monoclonal antibodies.

FGFR2b: An Emerging Biomarker for Identifying Subgroups in mG/GEJ Patients

FGFR2 is a member of the fibroblast growth factor receptor (FGFR) family, a group of transmembrane tyrosine kinase receptors that regulate cell survival, differentiation, and proliferation. Genomic aberrations of FGFR2, including amplification, point mutations, and oncogenic fusions, have been identified in various cancers, including gastric cancer. A large cohort study of 493 gastric cancer (GC) patients reported FGFR2 overexpression rates of 21.9%–32.1%.

Bemarituzumab is a humanized IgG1 monoclonal antibody that selectively binds to FGFR2b, inhibiting the FGFR2b signaling pathway and mediating antibody-dependent cellular cytotoxicity (ADCC). The global, randomized, double-blind, placebo-controlled phase II FIGHT trial evaluated bemarituzumab combined with mFOLFOX6 as a first-line treatment for FGFR2b-positive gastric/GEJ adenocarcinoma. In the intent-to-treat (ITT) population, bemarituzumab extended median overall survival (mOS) by 5.7 months (19.2 months vs. 13.5 months; HR 0.77). Patients with FGFR2b+ (IHC 2+/3+, ≥10%) tumors demonstrated improved survival benefits, with a median progression-free survival (mPFS) HR of 0.43 and mOS HR of 0.52. In patients with ≥10% FGFR2b expression, the objective response rate (ORR) reached 56.5%, with manageable safety. Corneal treatment-emergent adverse events (TEAEs) were the primary reason for treatment discontinuation in the bemarituzumab-mFOLFOX6 group. The median onset time for grade ≥2 corneal events was longer than for any-grade corneal events (23.7 weeks vs. 16.9 weeks), suggesting potential opportunities for early detection and active management in future studies.

Led by Professor Ruihua Xu of the Sun Yat-sen University Cancer Center, the randomized, multicenter, double-blind, placebo-controlled phase III FORTITUDE-101 trial is underway to evaluate bemarituzumab combined with chemotherapy in patients with advanced gastric/GEJ adenocarcinoma expressing FGFR2b in ≥10% of tumor cells and no prior treatment for unresectable or metastatic disease. The results are eagerly awaited to provide a new therapeutic option for first-line treatment of advanced gastric cancer.

DKK1: A Potential Therapeutic Target in the Wnt/β-Catenin Pathway

DKK1 is highly expressed in various tumors and promotes angiogenesis by activating the Akt signaling pathway and upregulating VEGFR2 expression, thereby supporting tumor survival and proliferation. Additionally, DKK1 modulates the Wnt signaling pathway, enhancing the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). In gastric cancer (GC) and gastroesophageal junction cancer (GEJ), DKK1 expression correlates with poor prognosis, an immunosuppressive tumor microenvironment, and chemotherapy resistance.

The phase II DisTinGuish study evaluated the efficacy and safety of DKN-01 combined with tislelizumab (TIS) and CAPOX as a first-line treatment for HER2-negative advanced G/GEJ cancer. Results showed good tolerability, with most DKN-01-related adverse events being low-grade (76%). Over a two-year follow-up, DKN-01 + TIS + CAPOX demonstrated improved median PFS and mOS compared to historical controls (CheckMate-649), both in the overall population and in the PD-L1 low-expression subgroup. The treatment achieved an ORR of 73% in the modified intent-to-treat (mlTT) population and 86% in the PD-L1 low-expression subgroup. A phase II randomized controlled trial of TIS combined with CAPOX/mFOLFOX6 for first-line GEA treatment (Part C) is ongoing (NCT04363801).

Second-Line Treatment

HER2

The DESTINY-Gastric01 trial, conducted in Japan and South Korea, was a randomized, phase II, multicenter, open-label study (NCT03329690) evaluating trastuzumab deruxtecan (T-DXd; DS-8201) versus chemotherapy in HER2-positive advanced gastric cancer patients who had progressed after at least two prior therapies. T-DXd demonstrated significantly better efficacy than chemotherapy in third-line treatment of HER2-positive gastric cancer (OS: 12.5 vs. 8.9 months; HR 0.60). In January 2021, the FDA approved trastuzumab deruxtecan for HER2-positive locally advanced or metastatic gastric/GEJ adenocarcinoma previously treated with trastuzumab.

Based on the Chinese bridging DESTINY-Gastric06 trial, trastuzumab deruxtecan was approved in China for third-line and beyond treatment of gastric cancer. The phase II DESTINY-Gastric02 study, conducted in Western countries (Belgium, the UK, Italy, Spain, and the USA), confirmed the efficacy of T-DXd in second-line treatment of HER2-positive gastric cancer, with a median OS of 12.1 months and durable clinical responses.

ARX788, in a phase I multicenter dose-expansion study, demonstrated an ORR of 37.9% as monotherapy for HER2-positive advanced gastric cancer. The phase II/III ACE-Gastric-02 trial is ongoing to compare ARX788 monotherapy versus irinotecan/docetaxel in second-line treatment. HER2 ADCs are reshaping the treatment paradigm for HER2-positive advanced gastric cancer, progressing toward earlier treatment lines and exploring combinations with other novel agents.

CLDN18.2

CMG901, an ADC targeting CLDN18.2, demonstrated promising clinical efficacy in a phase I trial for pretreated advanced G/GEJ cancer patients. The confirmed ORR was 48% in the 2.2 mg/kg cohort, with a median PFS of 4.8 months and median OS of 11.8 months. CMG901 showed good tolerability and manageable safety.

IBI389, a bispecific antibody targeting CLDN18.2/CD3, induces immune synapse formation by linking CD3 molecules on T cells with CLDN18.2 antigens on tumor cells. A phase I dose-escalation and expansion study showed manageable safety and promising efficacy in CLDN18.2-positive advanced G/GEJ cancer. Among 26 patients with CLDN18.2 2+/3+ and ≥10% expression, ORR was 30.8%, DCR was 73.1%, and median PFS was 3.5 months.

Satri-cel (CT041), an autologous CAR-T therapy targeting CLDN18.2, showed impressive results in the CT041-CG4006 trial (NCT03874897) for CLDN18.2-positive advanced gastrointestinal tumors. Among 59 patients, the ORR was 54.9%, DCR was 96.1%, and median OS was 9.0 months. Long-term follow-up suggests promising efficacy and safety, positioning satri-cel as a potential game-changer in treatment.

VEGFR TKI

The FRUTIGA trial is the first randomized phase III study to evaluate the efficacy and safety of fruquintinib, a VEGFR TKI, combined with chemotherapy as second-line treatment for G/GEJ adenocarcinoma. At the 2024 ASCO Plenary Series, results showed significant improvements in mPFS (5.6 months vs. 2.7 months; HR 0.57; P<0.0001), ORR (42.5% vs. 22.4%; P<0.0001), and DCR (77.2% vs. 56.3%; P<0.0001) for the fruquintinib-chemotherapy group compared to placebo. Median OS showed a trend toward benefit (9.6 months vs. 8.4 months; HR 0.96; P=0.6064). Fruquintinib demonstrated good tolerability and consistent safety, with exploratory analysis highlighting superior efficacy in non-diffuse G/GEJ adenocarcinoma with lymph node metastasis.

Summary

Key biomarkers such as HER2, dMMR, PD-L1, and CLDN18.2 guide patient selection for targeted therapies, heralding a new era of precision treatment for advanced gastric cancer.

DKK1 has emerged as a potential target, showing initial efficacy and representing a promising candidate for future therapies.

CLDN18.2, a newly validated target, holds significant promise, with over one-third of gastric cancer patients potentially benefiting from zolbetuximab. Chinese researchers have become pioneers in developing CLDN18.2-targeted therapies.

Emerging therapies targeting established markers and clinical trials of drugs such as bemarituzumab and FGFR2b inhibitors are actively underway. Optimizing targeted therapy choices to maximize efficacy remains a key research focus for the future.

Dr. Ai Li Suo

• Deputy Director, Department of Oncology, First Affiliated Hospital of Xi’an Jiaotong University
• Chief Physician, Professor, and Doctoral Supervisor
• Visiting Scholar at Emory University, USA
• Standing Member, Committee of Esophageal Cancer Integrated Rehabilitation, Chinese Anti-Cancer Association
• Standing Member, Committee of Oncogastroenterology, Chinese Anti-Cancer Association
• Member, Committee of Integrated Oncology and Nephrology, Chinese Anti-Cancer Association
• Youth Committee Chair, Chemotherapy Committee, Shaanxi Anti-Cancer Association
• Deputy Chair, Geriatric Surgical Oncology Committee, Shaanxi Anti-Cancer Association
• Deputy Chair, Palliative Care Committee, Shaanxi Anti-Cancer Association

Professor Suo has led two National Natural Science Foundation of China projects and authored over 20 SCI-indexed papers, including more than 10 with impact factors exceeding 10. She also holds three authorized national invention patents.