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

Abstract

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, we 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. This study is registered with ClinicalTrials.gov (NCT04581473), and is closed to new patients.

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, ten (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% 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.

Funding: CARsgen Therapeutics.