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.