Editor’s note: China, Japan, and other Asian countries have some of the highest rates of gastric cancer worldwide. In China, the majority of patients are still diagnosed at an advanced stage, having already lost the opportunity for curative surgery. Effective systemic therapy is therefore essential for improving survival. In recent years, innovative drugs represented by antibody–drug conjugates (ADCs)—such as the HER2-targeted ADC trastuzumab deruxtecan (T-DXd)—have achieved major breakthroughs in pivotal clinical studies including DESTINY-Gastric04. These advances are expected to gradually transform the treatment landscape starting from later lines of therapy. Asian clinical researchers have played an important role in these studies, contributing insights that are redefining clinical practice.During the 13th Annual Meeting of the Federation of Asian Clinical Oncology (FACO) held in Shanghai, Oncology Frontier invited FACO President Prof. Jin Li (Shanghai Gaobo Oncology Hospital, China Pharmaceutical University), Prof. Xiaotian Zhang (Peking University Cancer Hospital), and Prof. Koji Kono (Vice President of the Japanese Society of Clinical Oncology; Fukushima Medical University) to participate in a China–Japan expert roundtable. The discussion focused on the latest advances in precision treatment for HER2-positive advanced gastric cancer—represented by DESTINY-Gastric04—evaluating the current clinical value of HER2-targeted ADCs and exploring future directions in clinical research.
Part 1. Characteristics and Current Management of HER2-Positive Gastric Cancer in China and Japan
Prof. Jin Li:
HER2 is an important therapeutic target in precision treatment for gastric cancer, and clinically around 12–16% of patients show high HER2 expression. Based on your experience, could you share the epidemiological characteristics and current diagnostic and therapeutic practices for HER2-positive gastric cancer in China and Japan?
Prof. Koji Kono:
Japan once had the highest incidence of gastric cancer in the world. However, with widespread Helicobacter pylori eradication, dietary improvements, and the establishment of a nationwide screening program over several decades, both incidence and mortality have declined significantly.
- In 2020, Japan recorded 109,700 new cases and 40,000 deaths,
- The five-year overall survival rate was approximately 70%,
- HER2-positive disease accounted for 15.6–17% of cases.
A 2021 analysis based on Japan’s national health insurance database examined treatment patterns in advanced gastric cancer. It showed that approximately 14% of patients received trastuzumab-containing regimens as first-line therapy—essentially achieving a “treat when indicated” standard. Second-line therapy was dominated by paclitaxel plus ramucirumab (68%), in line with Japanese guidelines.
Another real-world study from 2021 showed that for HER2-positive gastric cancer in Japan, the most commonly used third-line and later therapies were nivolumab monotherapy, followed by irinotecan and trifluridine/tipiracil. The median overall survival was 6.2 months, indicating that both patient outcomes and the integration of HER2-targeted ADCs still have considerable room for improvement.
Prof. Xiaotian Zhang:
China is also a high-incidence country for gastric cancer, with 358,000 new cases and 260,000 deaths every year—ranking fourth and third among all malignancies in China—and these numbers together account for roughly half of the global burden.
A recent nationwide survey on gastric and gastroesophageal junction adenocarcinoma led by Prof. Lin Shen found that:
- Median age at diagnosis: 63 years
- Approximately 70% were male
- 60% of tumors were located in the gastric body or antrum
- The most common pathology was moderately differentiated adenocarcinoma
With the growing use of screening and other early-detection methods, the proportion of early-stage disease has risen markedly:
- 35% of patients were diagnosed at stage I–II with a five-year survival rate of ~85%
- However, ~25% were still diagnosed at stage IV, whose five-year survival is only 13%
- Overall national five-year survival remains low at 33%
Approximately 13% of Chinese gastric cancer patients have high HER2 expression, with positivity increasing with disease stage, and more common in older patients, males, and those with liver metastasis.
However, real-world treatment of HER2-positive gastric cancer in China remains suboptimal. The EVIDENCE study, led by our institution, analyzed treatment patterns and outcomes in China and found that:
- Patients receiving first-line trastuzumab had a median PFS of 8.2 months and a median OS of nearly 20 months
- Those not receiving trastuzumab had significantly worse outcomes
But a 2025 survey revealed that trastuzumab still fails to cover all eligible patients:
- Only ~5% of all gastric cancer patients received HER2-targeted therapy in the first line
- Only ~6% received such therapy in the second line
This underscores the urgent need to educate gastrointestinal oncologists, surgeons, and other specialists on the importance of HER2-targeted therapy. Given the heavy national disease burden, we must also strengthen public education to raise awareness of gastric cancer screening and proper treatment. Early and appropriate therapy—not simply rapid initiation of any treatment—is crucial for improving outcomes.
Prof. Jin Li:
Only 5–6% of HER2-high patients receive HER2-targeted monoclonal antibody therapy. Why is the rate so low? Could this be due, at least in part, to patients in poorer regions being unable to afford the treatment?
Prof. Xiaotian Zhang:
In some cases, patients are not identified as HER2-high at initial diagnosis; HER2 positivity is only discovered after surgery or later in the treatment course. This highlights the need to educate gastroenterologists who perform endoscopic biopsies to ensure HER2 testing is performed even on small biopsy specimens.
Prof. Jin Li:
Thank you both for your insights and for sharing the China–Japan data. The differences in HER2 testing coverage, diagnosis, and treatment between the two countries are clear. In China, a relatively small proportion of patients receive biopsy-based HER2 testing, which prevents many HER2-high patients from receiving targeted therapy. Much work remains to expand testing and ensure more patients benefit from HER2-directed treatments.
Part 2. Interpreting Past HER2-Targeted Therapy and the Clinical Value of ADCs
Prof. Jin Li:
HER2-targeted therapy is one of the principal treatment modalities for HER2-high gastric cancer. How do you view HER2-directed therapy across the whole course of patient management, and which targeted regimens do you particularly recommend?
Prof. Xiaotian Zhang:
HER2 is a key driver of tumor growth, so the concept of HER2-directed therapy should be promoted across all tumor-related specialties—medical oncology, surgical oncology, pathology, and radiology—and must follow the principle of “precision therapy, testing first.” The Chinese Expert Consensus on HER2 Testing of Endoscopic Biopsy Specimens in Gastric Cancer (2023 edition) emphasizes that accurate assessment of HER2 protein expression and gene amplification is critical for clinical decision-making. Every patient with suspected gastric cancer should have HER2 status confirmed before selecting a treatment strategy.
For HER2-high advanced gastric cancer, the CSCO guidelines recommend:
- PD-L1 CPS ≥ 1: first-line trastuzumab combined with chemotherapy plus pembrolizumab;
- PD-L1 CPS < 1: first-line trastuzumab plus chemotherapy. These recommendations are supported by evidence from KEYNOTE-811. However, I believe that even PD-L1–negative patients should be considered for innovative agents—such as the bispecific antibody zanidatamab (ZW25) or novel immune checkpoint inhibitors—and be offered participation in relevant clinical trials.
This year’s CSCO guideline updates on HER2-targeted therapy were driven mainly by the phase II DESTINY-Gastric06 study and the approval of T-DXd for third-line use. As a China-bridging registration trial, DESTINY-Gastric06 established T-DXd as the new standard for third-line therapy in China. In addition, the domestically developed HER2 ADC disitamab vedotin (RC48) has been approved for HER2-intermediate disease (IHC2+) in third line. At the ASCO 2025 meeting, DESTINY-Gastric04 data were presented: in patients who progressed after first-line trastuzumab, second-line T-DXd demonstrated a significant overall survival benefit versus paclitaxel plus ramucirumab. I expect these results will be incorporated into the 2026 CSCO guidelines.
Therefore, targeted options now cover HER2-high advanced gastric cancer across first, second, and third lines. Our goal is to extend benefit to more patients by moving targeted therapies earlier—into the perioperative, neoadjuvant, and adjuvant settings for locally advanced disease. Last year our group published a randomized phase II trial comparing trastuzumab + XELOX versus trastuzumab + atezolizumab + XELOX in the neoadjuvant setting; pathologic complete response (pCR) rates were 14% and 38.1%, respectively. For newly diagnosed HER2-high gastric cancer, neoadjuvant combinations of targeted therapy + immunotherapy + chemotherapy merit consideration. Looking ahead, I hope next-generation HER2-targeted agents will broaden coverage to include all HER2-high patients—and potentially those with HER2 mutations or other HER2 genomic alterations.
Prof. Jin Li:
Raising pCR rates in the neoadjuvant setting is especially important because patients who achieve pCR after surgery may effectively enter a “cured” category. How is HER2-targeted therapy practiced in Japan?
Prof. Koji Kono:
Japanese oncologists strictly follow guideline recommendations and routinely test HER2 at treatment initiation; consequently, a higher proportion of HER2-high patients in Japan receive targeted therapy. Because HER2 expression in gastric cancer displays spatial and temporal heterogeneity, ideal management would include dynamic HER2 monitoring throughout treatment. However, Japan’s national insurance currently covers only a single HER2 test—an issue that should be reconsidered.
A study presented at ASCO 2025 evaluated changes in HER2 expression and their impact on survival. It found an overall HER2 conversion rate of ~42.7%: 38.5% of patients initially HER2-high lost high expression after treatment, while 7.6% converted from HER2 0/1+ to 2+/3+. Yet fewer than one-quarter of patients whose HER2 status increased received targeted therapy. These findings underscore the need for dynamic monitoring of HER2 expression across the treatment course to enable timely, appropriate targeted therapy decisions.
Additionally, the 2025 edition of the Japanese Gastric Cancer Treatment Guidelines was updated in March this year. The recommendations for HER2-targeted therapy were only slightly modified:
- First-line therapy: trastuzumab combined with a platinum agent and a fluoropyrimidine; trastuzumab plus immunotherapy was not yet recommended.
- In the September update, however, the guidelines added trastuzumab + chemotherapy + pembrolizumab as a recommended first-line regimen for HER2-positive gastric cancer with PD-L1 CPS ≥ 1.
- Second-line therapy: The guidelines do not recommend HER2-targeted therapy; the standard regimen remains paclitaxel plus ramucirumab.
- Third-line therapy: Only T-DXd is recommended.
- Fourth-line therapy: Consideration of other previously unused agents or regimens.
Japan adopted T-DXd relatively early. In the DESTINY-Gastric01 study evaluating T-DXd as third-line therapy for HER2-positive gastric cancer, Japanese and Korean patients previously treated with trastuzumab achieved significantly better outcomes with T-DXd vs. chemotherapy:
- Median PFS: 5.6 vs. 3.5 months (HR 0.47, 95% CI 0.31–0.71)
- Median OS: 12.5 vs. 8.4 months (HR 0.59, 95% CI 0.39–0.88; P = 0.01)
These results led to approval of T-DXd for third-line treatment in Japan and its inclusion in the national guidelines.
Subsequently, Western researchers explored T-DXd as second-line therapy. The phase II DESTINY-Gastric02 study showed that in Western patients with HER2-positive advanced gastric cancer who had progressed after trastuzumab:
- Median PFS: 5.6 months
- Median OS: 12.1 months
Based on these findings, the 2023 ASCO guidelines, the NCCN guidelines, and the ESMO e-guidelines all updated their recommendations to establish T-DXd as the standard second-line therapy for HER2-positive advanced gastric cancer.
Building on this, we evaluated second-line feasibility of T-DXd in Asian patients. At ASCO 2025, the results of the phase III DESTINY-Gastric04 trial were presented. Patients whose disease progressed after first-line trastuzumab were randomized 1:1 to receive T-DXd or the current standard second-line regimen—paclitaxel plus ramucirumab. The study showed that T-DXd monotherapy significantly prolonged OS:
- Median OS: 14.7 vs. 11.4 months (HR 0.70, 95% CI 0.55–0.90, P = 0.0044)
Subgroup analyses demonstrated consistent benefit across all subgroups.
- Confirmed ORR: 44.3% vs. 29.1% (P = 0.0006)
- Safety profile remained consistent with previous studies.
Based on these findings, Japan is expected to approve T-DXd for second-line treatment in gastric cancer in the near future, and these results are likely to drive clinical practice in Japan and across Asia toward alignment with Western standards.
Prof. Jin Li:
T-DXd achieves an ORR roughly 15% higher than the previous standard second-line therapy, indicating stronger antitumor activity. In full-course management of HER2-positive disease, if a patient becomes resistant to trastuzumab, do you perform a rebiopsy to confirm persistent HER2 positivity before initiating T-DXd?
Prof. Koji Kono:
That would be ideal in theory. However, in real-world practice, Japanese physicians typically rely on the HER2 status determined at initial diagnosis. If the patient is HER2-positive, targeted therapy is administered throughout treatment; if HER2-negative, the patient is managed according to HER2-negative guidelines. This is a limitation that needs to be addressed—we should ideally reassess HER2 status before each new line of systemic therapy.
Prof. Jin Li:
Loss of HER2 expression during treatment may result from trastuzumab killing most HER2-expressing tumor cells. Such patients may derive limited additional benefit from HER2-targeted ADCs. Therefore, in China, repeat biopsy is recommended to reconfirm HER2 positivity. Currently, T-DXd is approved only for third-line therapy in China, similar to Japan, whereas Western countries have already approved it for second-line use. Previously, we followed Western developments, but going forward, China, Japan, and Korea should lead major clinical studies—allowing Western regions to follow Asia’s innovations.
To keep pace with rapidly evolving drug development and clinical evidence, the CSCO guidelines are updated annually. Current recommendations for HER2-positive advanced gastric cancer largely align with international standards. Based on DESTINY-Gastric04 results, both HER2 IHC 3+ and IHC 2+/FISH-positive patients will likely be recommended for HER2-targeted ADC therapy in the second line next year. Importantly, about 20% of the enrolled patients in DESTINY-Gastric04 were from mainland China, making the findings highly relevant to Chinese clinical practice. We look forward to early approval of the second-line indication for T-DXd to benefit more patients.
Part 3. Outlook: The Future of ADCs in HER2-Positive Gastric Cancer
Prof. Jin Li:
Supported by strong clinical evidence, HER2-targeted ADCs—represented by T-DXd—have achieved breakthrough progress and reshaped the treatment landscape for HER2-high gastric cancer. Ongoing studies are exploring combinations of HER2 ADCs with PD-1/L1 inhibitors in the first-line setting. How do you think HER2 ADCs will influence future diagnosis and treatment? What are your expectations for T-DXd’s future clinical application?
Prof. Koji Kono:
T-DXd is the first ADC developed in Japan and applied to HER2-positive gastric cancer. It opened the ADC era in this field, providing a new therapeutic strategy and inspiring subsequent drug development. Across DESTINY-Gastric01 through DESTINY-Gastric04, T-DXd has mainly been evaluated as monotherapy, but future directions will likely include combination approaches—such as with PD-1/L1 inhibitors, monoclonal antibodies, or multitarget small molecules—to achieve higher ORR or longer OS. Also, in both third- and second-line settings, identifying reliable biomarkers to predict prognosis and select the optimal treatment population will be critical and warrants continued investigation.
Prof. Xiaotian Zhang:
Under the leadership of CSCO, JSCO, and FACO, young oncologists like myself have gained opportunities to participate in collaborative clinical research. For HER2-positive gastric cancer, the emergence of T-DXd and other ADCs presents an opportunity to transform diagnostic pathways. As Prof. Kono mentioned, we must monitor HER2 expression dynamically—before, during, and after treatment—to understand how HER2 evolves under therapeutic pressure.
Current ADC trials now span first through third lines of therapy for HER2-high advanced disease, mirroring T-DXd’s trajectory in breast cancer, where it recently achieved positive results in neoadjuvant and adjuvant studies. Gastric cancer may follow a similar path, with T-DXd already being explored in first-line advanced disease. With rapid advances in ADCs, monoclonal and bispecific antibodies, and immunotherapy, there is increasing room to optimize treatment strategies. At the same time, designing efficient clinical trials will be challenging—we should employ AI-driven trial design and multimodal modeling to accelerate discovery and ensure more patients benefit from targeted therapy. I am optimistic about this future.
Prof. Jin Li:
Thank you to Oncology Frontier for enabling this discussion on HER2-positive gastric cancer management in Asia. And thank you both for sharing insights into the epidemiology, disease characteristics, and treatment experience in Japan and China. With the strong efficacy of T-DXd in advanced HER2-positive gastric cancer, we hope it will move into first-line therapy soon and be further explored in combination with other targeted or immunotherapeutic agents. Ultimately, our goal is to optimize precision therapy, design individualized treatment strategies, and bring more effective HER2-directed options to the patients who need them.
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