Editor’s Note: Two pivotal studies in targeted therapy for gastric cancer drew significant attention at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. The world’s first randomized controlled trial (RCT) of CAR-T therapy in solid tumors (Abstract #4003) produced positive results, demonstrating the superior efficacy and manageable safety profile of Claudin 18.2-targeted CAR-T compared to standard therapies. Meanwhile, the DESTINY-Gastric04 phase III trial (Abstract #LBA4002) comparing trastuzumab deruxtecan (T-DXd) to the current second-line standard of ramucirumab (RAM) plus paclitaxel (PTX) in HER2-positive unresectable/metastatic gastric cancer also reported encouraging efficacy and safety data. On-site, we invited the lead investigators—Dr. Changsong Qi from Beijing Cancer Hospital and Dr. Kohei Shitara from the National Cancer Center Hospital in Japan—for an in-depth conversation on the background, results, and clinical significance of these two studies.

Oncology Frontier: What is the current progress of CAR-T cell therapy (e.g., CT041) in gastric cancer? What was the rationale behind the study design?

Dr. Changsong Qi: I’m pleased to have the opportunity to speak with Oncology Frontier Digestive Oncology to discuss our study. CAR-T cell therapy for solid tumors is still in the early exploratory stages. The study we presented at ASCO this year represents the first randomized controlled clinical trial of CAR-T in solid tumors globally. It demonstrated that Claudin 18.2-targeted CAR-T therapy provides superior efficacy and controllable safety compared to standard treatments. We believe this may soon become the first CAR-T treatment with true clinical applicability in gastric cancer, not just in China but potentially worldwide.

Oncology Frontier: What unmet needs exist in second-line treatment for HER2-positive gastric cancer? Why did your study compare T-DXd to RAM+PTX?

Dr. Kohei Shitara: For HER2-positive gastric cancer globally, paclitaxel combined with ramucirumab (PacRAM) remains the standard second-line treatment because T-DXd has not yet been approved or reimbursed in many countries. In the earlier DESTINY-Gastric01 trial conducted in Asia, T-DXd demonstrated superior survival compared to physician’s choice chemotherapy; however, that was a third-line trial. We needed to determine whether T-DXd could be a better option than PacRAM in the second-line setting, hence the design of DESTINY-Gastric04.

Oncology Frontier: What are the efficacy and safety results of CT041, the Claudin 18.2-targeted CAR-T, in gastric cancer?

Dr. Changsong Qi: At ASCO this year, we presented efficacy and safety data for Claudin 18.2 CAR-T therapy in Claudin 18.2-positive, HER2-negative gastric cancer patients who had failed standard treatments. The primary endpoint was median progression-free survival (PFS). The trial met this endpoint: the median PFS was 3.25 months in the experimental arm versus 1.77 months in the control arm (HR = 0.3). This represents a significant improvement in disease control. The overall survival (OS), a secondary endpoint, did not reach statistical significance, primarily because nearly half of the patients in the control group crossed over to receive CAR-T therapy after disease progression. However, after adjusting for this crossover using statistical models, the OS benefit of Claudin 18.2 CAR-T remains evident.

Oncology Frontier: Can you share the key PFS and objective response rate (ORR) data? How do they compare to previous studies like DESTINY-Gastric01?

Dr. Kohei Shitara: In DESTINY-Gastric04, we compared T-DXd to PacRAM in patients who had previously received trastuzumab. The primary endpoint was OS. The T-DXd group achieved a median OS of 14.7 months, compared to 11.4 months in the PacRAM group—a 3.3-month improvement (HR = 0.70). PFS and ORR were also significantly better: T-DXd showed a confirmed ORR of 44% versus 29% in the PacRAM arm. These results are consistent with prior studies—DESTINY-Gastric02 (a non-Asian, phase II, single-arm study) reported an ORR of around 42%, while the DESTINY-Gastric01 study in Asia showed an ORR of 43%. Across trials, T-DXd demonstrates consistently strong efficacy in terms of ORR and PFS.

Oncology Frontier: Could T-DXd (an ADC) and CAR-T therapy (e.g., CT041) be used sequentially or in combination? What is the theoretical rationale?

Dr. Changsong Qi: Currently, the populations eligible for T-DXd and CT041 are largely distinct, with minimal overlap. T-DXd targets HER2-positive patients, while our CAR-T trial enrolled Claudin 18.2-positive, HER2-negative patients. There are reports of 1–2% of patients being double-positive for HER2 and Claudin 18.2. Although we haven’t confirmed the feasibility of combining both therapies in this subgroup, I believe it’s worth exploring from an investigational perspective.

Oncology Frontier: Does T-DXd’s toxicity profile limit its use as a second-line therapy, and how should these adverse events be managed?

Dr. Kohei Shitara: Common toxicities with T-DXd include bone marrow suppression, fatigue, gastrointestinal symptoms, and interstitial lung disease (ILD)/pneumonitis. GI side effects should be managed with prophylactic antiemetics, such as NK1 and 5-HT3 receptor antagonists, and corticosteroids. A recent Japanese study showed that olanzapine can also effectively prevent nausea and anorexia. Hematologic toxicity is usually managed with supportive care, such as G-CSF or treatment delays. In our study, 14% of patients developed ILD, but most were grade 1 or 2. Only one patient experienced grade 3 ILD. Early CT monitoring and timely corticosteroid treatment are key strategies already established in previous trials.

Oncology Frontier: How can biomarkers like HER2 and Claudin 18.2 guide treatment decisions in gastric cancer?

Dr. Changsong Qi: HER2 and Claudin 18.2 serve as biomarkers to guide personalized treatment strategies. For HER2-positive or high-expressing patients, anti-HER2 therapies are recommended; for Claudin 18.2-positive patients, anti-Claudin therapies are appropriate. We are still refining the cut-off thresholds for positivity. Initially, HER2 status was categorized as positive or negative, but now we consider high, medium, low, or no expression. For Claudin 18.2, positivity definitions differ based on the drug. In the zolbetuximab trials, the cut-off identifies 35–38% of patients, while the CT041 CAR-T trial includes up to 58–60%—nearly double—suggesting broader applicability for the CAR-T approach.

Dr. Kohei Shitara: In first-line settings, at least four biomarkers should be assessed: MSI/dMMR, HER2, Claudin 18.2, and PD-L1 CPS. Stratification based on these helps guide optimal therapy. HER2 status is especially important, as HER2-positive patients were excluded from Claudin trials. For HER2-positive cases, chemotherapy plus trastuzumab remains the standard. In high PD-L1 CPS cases, pembrolizumab can be added, as shown in KEYNOTE-811. For Claudin-positive cases, zolbetuximab plus chemotherapy is approved and effective, including in China. For high PD-L1 CPS but Claudin-negative patients, chemo plus checkpoint inhibitors is best. In patients with both high CPS and Claudin positivity, the ideal approach is unclear, though trials are underway to evaluate combination strategies.

Oncology Frontier: What are the clinical implications of your study, and what’s next?

Dr. Changsong Qi: This was a pivotal phase II registration trial, and it met its primary endpoint. We plan to work with collaborators to pursue approval for CT041 in third-line treatment for Claudin 18.2-positive gastric cancer in China. If approved, it could fundamentally shift treatment paradigms for this patient population. But that’s not our endpoint—we’re also exploring CT041 in second-line and potentially first-line settings, as well as in perioperative scenarios. For instance, we aim to study its use before or after surgery to reduce recurrence risk and increase the chance of cure in high-risk patients.

Dr. Kohei Shitara: While gastric cancer outcomes are improving, the gains are still modest compared to cancers like breast or EGFR/ALK-positive lung cancer. We need better treatments, and a critical step is identifying predictive and resistance biomarkers. For example, understanding resistance mechanisms to T-DXd or Claudin-targeted therapies could lead to more effective combinations. At ASCO this year, we presented data from the LEAP-015 study—a trial of pembrolizumab plus lenvatinib targeting immunosuppressive cells like T-cells and macrophages. Unfortunately, the trial was negative due to toxicity and insufficient efficacy. Nevertheless, translational and preclinical research into resistance mechanisms remains a key area for future breakthroughs.

Oncology Frontier: What are your key takeaways from ASCO 2025?

Dr. Changsong Qi:Several points stood out for me at ASCO this year. First, liquid biopsy is showing increasingly strong evidence as a guide for precision medicine—not just in GI cancers, but also breast and lung cancers. It’s having a real clinical impact.

Second, AI is making its way into every aspect of oncology—from medical education and clinical trials to drug design, follow-up, and intervention. With the maturation of AI models and accumulation of data, we believe AI will soon play a transformative role in clinical decision-making and patient care.