Esophagus to Small Intestine
Lancet. 2025;405(10494):2049-2060
Claudin-18 isoform 2-specific CAR T-cell therapy (satri-cel) versus treatment of physician’s choice for previously treated advanced gastric or gastro-oesophageal junction cancer (CT041-ST-01): A randomised, open-label, phase 2 trial
Background: Claudin-18 isoform 2 (CLDN18.2) has emerged as a promising therapeutic target in gastric or gastro-oesophageal junction cancer. Satricabtagene autoleucel (satri-cel; also known as CT041), an autologous CLDN18.2-specific chimeric antigen receptor (CAR) T-cell therapy, showed encouraging activity in previously treated patients with advanced gastric or gastro-oesophageal junction cancer in phase 1 clinical trials. In this article, the authors report the primary results from the phase 2 pivotal trial (CT041-ST-01) investigating the efficacy and safety of satri-cel for gastric or gastro-oesophageal junction cancer.
Methods: In this open-label, multicentre, randomised controlled trial conducted in China, patients with CLDN18.2-positive (immunohistochemistry expression intensity ≥ 2+ and positive tumour cells ≥ 40%) advanced gastric or gastro-oesophageal junction cancer, who were refractory to at least two previous lines of treatment, were randomly allocated (2:1) to receive satri-cel or treatment of physician’s choice (TPC). In the satri-cel group, satri-cel was infused up to three times at a dose of 250 × 106 cells. For the TPC group, one of the standard-of-care drugs (nivolumab, paclitaxel, docetaxel, irinotecan, or rivoceranib [apatinib]) was given, per the physician’s decision. Those who had disease progression or drug intolerance in the TPC group could receive subsequent satri-cel, if eligible. The primary endpoint was progression-free survival, assessed by an independent review committee, in the intention-to-treat population.
Findings: Between March 22, 2022, and July 29, 2024, 266 patients were screened, of whom 156 were randomly allocated to the satri-cel group (n = 104) or TPC group (n = 52). 88 (85%) patients in the satri-cel group and 48 (92%) patients in the TPC group received study drug. In the satri-cel group, 28 (27%) patients had previously received three or more lines of treatment and 72 (69%) patients had peritoneal metastasis. In the TPC group, 10 (19%) patients had previously received three or more lines of treatment and 31 (60%) patients had peritoneal metastasis. The median follow-up time for progression-free survival was 9.07 months (95% confidence interval [CI]: 6.21–13.01) in the satri-cel group and 3.45 months (2.89–not estimable) in the TPC group, based on the reverse Kaplan-Meier method. In the intention-to-treat population, median progression-free survival was 3.25 months (95% CI: 2.86–4.53) in the satri-cel group and 1.77 months (1.61–2.04) in the TPC group (hazard ratio = 0.37 [95% CI: 0.24–0.56]; one-sided log-rank p < 0.0001). In the safety analysis set (all patients who received at least one dose of study drug), grade 3 or higher treatment-emergent adverse events occurred in 87 (99%) of 88 patients in the satri-cel group and 30 (63%) of 48 patients in the TPC group. The most common grade 3 or worse treatment-emergent adverse events related to treatment were decreased lymphocyte count (86 [98%] of 88 patients), decreased white blood cell count (68 [77%] patients), and decreased neutrophil count (58 [66%] patients) in the satri-cel group. Cytokine release syndrome occurred in 84 (95%) of 88 patients in the satri-cel group.
Interpretation: This is the first randomised controlled trial of CAR T-cell therapy in solid tumours globally. Satri-cel treatment resulted in a significant improvement in progression-free survival, with a manageable safety profile. These results support satri-cel as a new third-line treatment for advanced gastric or gastro-oesophageal junction cancer patients.
DOI: 10.1016/s0140-6736(25)00860-8
Prof. Dr. Michael Quante
Head of Gastrointestinal Oncology, University Medical Center Freiburg, Department of Internal Medicine II, Hugstetter Str. 55, 79106 Freiburg, Germany
CLDN18.2 CAR-T cell therapy for gastric and gastroesophageal junction cancer: A promising new approach with challenges
In a randomized, open-label phase 2 study published in The Lancet in 2025, Qi et al. investigated the CLDN18.2-specific CAR-T cell therapy satri-cel in 156 patients with advanced gastric or gastroesophageal junction (GEJ) cancer refractory to at least two prior lines of therapy. Patients were randomly assigned in a 2:1 ratio to receive either satri-cel or treatment of physician’s choice (TPC). The primary endpoint, progression-free survival (PFS), was significantly prolonged with satri-cel: median 3.25 months versus 1.77 months in the TPC arm (hazard ratio [HR] = 0.37; p < 0.0001). The objective response rate (ORR) was 22% (95% CI: 15–31) in the satri-cel arm compared with 4% (95% CI: 0–13) under TPC. In the intention-to-treat (ITT) population, overall survival (OS) showed a favorable trend (7.92 vs 5.49 months; HR = 0.69), which became more pronounced after adjustment for crossover of 20 patients to satri-cel (7.92 vs. 4.37 months; HR = 0.47; 95% CI: 0.30–0.72). Notably, patients who received satri-cel only after crossover achieved an ORR of 20%, further underscoring the biological activity of the therapy.
These results are noteworthy, as they represent the first randomized study in solid tumors to demonstrate a clear signal of superiority for a CAR-T cell therapy. While CAR-T cells are well established in hematologic malignancies, their success in solid tumors has thus far been limited.
However, interpretation of these findings requires a nuanced perspective: The cutoff for CLDN18.2 expression in this study was set at ≥ 40% of tumor cells with 2+/3+ expression, lower than the ≥ 75% cutoff used in previous zolbetuximab studies. This broadened the potential target population but might have led to greater heterogeneous treatment responses. Moreover, the study population was limited to Chinese patients, and the TPC arm included therapies such as apatinib, which are not standard in Western countries. This limits the generalizability of the results to European and North American populations.
The practical implementation of this therapy is also complex, requiring apheresis, lymphodepletion, and CAR-T cell infusion in specialized centers. Sixteen patients in the CAR-T arm did not receive the infusion due to disease progression during manufacturing, underscoring the logistical challenges inherent to personalized cell therapies.
The safety profile was consistent with that observed for other CAR-T cell products: hematologic toxicities grade ≥ 3 occurred in nearly all patients, and cytokine release syndrome (CRS) was reported in 95%, predominantly of mild to moderate severity. Immune effector cell-associated neurotoxicity syndrome (ICANS) was not observed.
In summary, the CT041-ST-01 study provides compelling evidence that CLDN18.2-targeted CAR-T cell therapy represents a promising treatment approach for carefully selected patients with refractory gastric or GEJ cancer. The results support the initiation of phase 3 studies in earlier lines of therapy but underscore the need for precise biomarker definitions, careful patient selection, and administration in experienced CAR-T referral centers.