Multicenter phase Ib trial in the U.S. of salvage CT041 CLDN18.2-specific chimeric antigen receptor T-cell therapy for patients with advanced gastric and pancreatic adenocarcinoma.

2538 Background: Claudin 18.2 (CLDN18.2) is a highly selective cell lineage marker with limited expression in normal gastric tissues and significantly higher expression in primary gastric, pancreatic tumors and their metastases. Anti-CLDN18.2-targeted CAR T cells, termed CT041, were developed to evaluate tumor response and patient-reported outcomes in the gastric and pancreatic cancer. Preliminary results of the trial (NCT03874897) showed an objective response rate (ORR) of about 60% in gastric cancer from a non-Western population. Here we report the results of CT041 for metastatic gastric cancer after ≥ 2 prior lines of systemic therapy or pancreatic cancer ≥ 1 prior line from six centers in the United States. Methods: This single-arm, open-label, phase Ib study (NCT04404595) investigated autologous CT041 CAR T cells in patients with CLDN18.2 positive advanced gastric (including diffuse, signet-ring) or pancreatic adenocarcinoma. All patients completed a conditioning regimen consisting of fludarabine, cyclophosphamide, and nab-paclitaxel prior to CT041 CAR T cells. The primary objective was to assess the safety, efficacy and cytokinetic profile of CT041. Adverse Events (AEs) were graded according to CTCAE 5.0, and tumor response was assessed per RECIST 1.1. Results: As of February 15, 2022, 11 patients (5 gastric and 6 pancreatic) with a median of 2 prior lines of therapy (range 1- 4) were treated with CT041 at a dose between 2.5 and 4 x 10 8 cells. There were no dose limiting toxicities, treatment-related deaths, severe cytokine release syndrome (CRS), immune effector cell-associated neurologic syndrome (ICANS), or severe gastrointestinal (GI) related AEs. All CRS were grade 1 or 2. Only one patient received tocilizumab. No grade 4 AEs were observed except for hematologic toxicities related to conditioning. The first eight patients were evaluable for response by the date of data cut-off: 1 patient achieved a complete response after two CT041 doses (gastric), 2 had partial response (gastric), 2 had stable disease with tumor shrinkage (pancreatic) and 3 (pancreatic) had progression of disease after an initial biochemical response. ORR was 37.5% (3/8) in all patients including 100% (3/3) in the gastric subgroup (all ≥ 3 prior lines). The last three patients had not reached the time for response assessment. CAR T cell expansion correlated with ctDNA reduction. The median duration of response and the progression-free survival had not been reached. Conclusions: These preliminary results indicate that CT041 therapy was safe and had therapeutic efficacy in patients with advanced GI cancers. In heavily pre-treated gastric cancer, CT041 may have significantly improved anti-tumor activity compared to historical treatment regimens. Clinical trial information: NCT04404595.