At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, two studies in the field of targeted therapy for gastric cancer drew significant attention. The world’s first randomized controlled trial (RCT) of CAR-T cell therapy for solid tumors (Abstract 4003) reported positive results, demonstrating both superior efficacy and manageable safety for Claudin 18.2-targeted CAR-T therapy compared to standard treatment regimens. Meanwhile, the Phase III randomized DESTINY-Gastric04 trial (Abstract LBA 4002) compared trastuzumab deruxtecan (T-DXd) with the current standard second-line regimen of ramucirumab plus paclitaxel (RAM+PTX) for patients with HER2-positive unresectable/metastatic gastric cancer, showing promising efficacy and safety outcomes.On site, Oncology Frontier invited Prof. Kohei Shitara (National Cancer Center Hospital, Japan), the lead authors of these studies, for an in-depth discussion on the studies’ background, results, and clinical significance.
Oncology Frontier: What unmet clinical needs remain in second-line HER2-positive gastric cancer? Why did your study choose to compare T-DXd with RAM+PTX?
Prof. Kohei Shitara: Globally, paclitaxel combined with ramucirumab (PacRAM) is the current standard second-line regimen for HER2-positive gastric cancer because T-DXd has not yet been approved or reimbursed in many countries. In the earlier Asian DESTINY-Gastric01 trial, T-DXd showed survival benefits over physician’s choice chemotherapy, but that was a third-line study. We were unsure whether T-DXd would outperform PacRAM as second-line therapy, so we initiated this study.
Oncology Frontier: Could you share key data on PFS and ORR? How do these results compare to previous studies like DESTINY-Gastric01?
Prof. Kohei Shitara: In DESTINY-Gastric04, we compared T-DXd to PacRAM in patients who had previously received trastuzumab. The primary endpoint was OS: 14.7 months for T-DXd versus 11.4 months for PacRAM, representing a 3.3-month improvement with a hazard ratio of 0.70. PFS and ORR also improved significantly. The investigator-assessed objective response rate (ORR) was 44% in the T-DXd group versus 29% in the PacRAM group. These results are consistent with previous studies like DESTINY-Gastric02 and DESTINY-Gastric01. In DESTINY-Gastric02, a Phase II single-arm study in non-Asian populations, ORR was around 42%, while DESTINY-Gastric01, conducted in Asian patients as third-line therapy, showed an ORR of 43%. Thus, across studies, T-DXd has demonstrated consistent efficacy in terms of ORR and PFS.
Oncology Frontier: Does T-DXd toxicity affect its use as a second-line treatment? How should these toxicities be managed clinically? Prof. Kohei Shitara: Common toxicities of T-DXd include bone marrow suppression, fatigue, gastrointestinal toxicity, and interstitial lung disease (ILD)/pneumonitis. For GI toxicities, prophylactic antiemetics should be used, such as NK1 receptor antagonists, 5-HT3 receptor antagonists, and corticosteroids. A recent Japanese study also showed that olanzapine can be effective in preventing nausea and appetite loss. Hematologic toxicities are generally managed with supportive care (such as G-CSF) or treatment interruptions. ILD occurred in 14% of patients, mostly grades 1 and 2, with only one case of grade 3. Early detection via CT scans and prompt corticosteroid administration are key management strategies, as established in prior studies.
Oncology Frontier: How can biomarkers like HER2 and Claudin 18.2 guide treatment selection in gastric cancer?
Prof. Kohei Shitara: At minimum, four biomarkers should be tested in first-line treatment: MSI/dMMR, HER2, Claudin 18.2, and PD-L1 CPS, so patients can be appropriately stratified. HER2 remains a key factor because many studies exclude HER2-positive patients from Claudin-targeting trials. For HER2-positive patients, chemotherapy combined with trastuzumab is standard. In PD-L1 CPS-high patients, pembrolizumab may be added per KEYNOTE-811 data. Claudin-positive patients can receive chemotherapy plus zolbetuximab, which is now approved in China. For patients with high PD-L1 CPS but Claudin-negative status, chemo plus checkpoint inhibitors is preferred. For Claudin-positive, CPS-high patients, chemotherapy or chemotherapy plus nivolumab are options; combination trials are ongoing and may shift future practice.
Oncology Frontier: What impact do you believe your research will have on clinical practice in advanced gastric cancer? What are the next research directions?
Prof. Kohei Shitara: Outcomes in gastric cancer are gradually improving, though not as markedly as in other cancers like breast cancer or EGFR/ALK-driven lung cancer. Thus, we urgently need better treatments. One key area is identifying predictive and resistance biomarkers. Understanding mechanisms of resistance to T-DXd and Claudin-targeted therapies may allow us to develop combination strategies to overcome resistance. At this year’s ASCO, we also presented LEAP-015 data, which evaluated pembrolizumab plus lenvatinib based on mechanisms targeting immunosuppressive cells like T cells and macrophages. Unfortunately, the trial was negative due to toxicity and limited efficacy. Nevertheless, such studies are essential for translational and preclinical research to overcome resistance. While T-DXd is highly effective, we still do not fully understand why resistance eventually develops. Serial biopsies and elucidating resistance mechanisms in advanced gastric cancer will be a key direction to guide future treatment strategies.
