A systematic review of CAR T-cell therapy in lung cancer: Move forward or move on?

Abstract

e20561 Background: Chimeric antigen receptor (CAR) technology has advanced cancer treatment, but predominantly hematopoietic malignancies. CAR T progress in solid tumors is more challenging due to target availability, antigen heterogeneity, and the tumor microenvironment. Checkpoint inhibitor-based immune therapy or antibody-drug conjugates play a critical role in lung cancer, yet the prognosis is still dismal in advanced, relapsed, or refractory disease. The significant unmet need in lung cancer has prompted new CAR T studies with various antigen targets. This review examines the preliminary clinical experience in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated with CAR T. Methods: A systematic review examined publications, abstracts, and clinical trials of CAR T therapy patients with NSCLC and SCLC, as of January 7, 2025. Studies of CAR T therapy that included ≥ 3 patients with lung cancer were included. Results: We identified 48 NSCLC and 5 SCLC patients treated with CAR T in 5 publications. More clinical trials are underway; 18 trials were identified for CAR T in NSCLC ± SCLC and another 3 for SCLC only. Of 21 trials, 11 (52%) were classified as “recruiting” or “active not recruiting,” 2 were “not yet recruiting,” 2 were terminated, and 6 had an “unknown” status. Two published trials (NCT03182816, NCT01869166) administered EGFR-CAR T products to treat 9 and 11 patients, respectively. Three patients achieved a partial response (PR), 10 had stable disease (SD), and the remainder had progressive disease (PD). Survival was reported for one EGFR study, with a median overall survival (OS) of 15.53 months (range 8.8-22.0) and median progression-free survival (PFS) of 7.1 months (range 2.7-17.1). Studies of MUC-1-CAR T (NCT03525782) and ROR1-CAR T (NCT02706392) in 28 NSCLC patients showed similar outcomes. For MUC1-CAR T in 20 patients, 11 had SD, and 9 developed PD. In the ROR1-CAR T study with 8 patients, one achieved a PR after receiving a second CAR infusion but had PD after 6 months. The majority (16/18) of patients in the study had SD by day +28, but all 16 patients developed PD by 6 months after CAR infusion. A study of 5 SCLC patients treated with DLL3-directed CAR T AMG 119 (NCT03392064) also showed PR in 1 patient, SD in 2, PD in 1, and not evaluable in 1. All products demonstrated favorable safety profiles, with the most frequent events being low-grade cytokine release syndrome (CRS), fever, chills, and dyspnea. One patient with NSCLC and extensive disease at baseline died of respiratory failure on day +17 after an ROR1-CAR-T. Conclusions: This systemic review of CAR T in advanced lung cancer shows brief, limited responses but with acceptable safety data. The best response has been PR in < 10% of reported patients; this is not encouraging, but the details of individual patients are unclear for a meta-analysis. The results of ongoing clinical trials will be important to inform the direction of future investigations.