Comparing immunotherapy re-challenge plus chemoradiotherapy versus chemoradiotherapy alone in metastatic esophageal squamous cell carcinoma after first-line immunotherapy failure

BACKGROUND: Immunotherapy (IO) re-challenge for cancer patients has sparked widespread discussion and attention in recent years. The optimal second-line treatment strategies for patients with metastatic esophageal squamous cell carcinoma (ESCC) after first-line IO failure remains to be further explored. This study aimed to compare the real-world safety and efficacy of IO re-challenge combined with chemoradiotherapy (CRT) versus CRT alone in metastatic ESCC patients. METHODS: We conducted a real-world retrospective study on 59 patients with ESCC who received second-line therapy after first-line IO failure at the Cancer Center of Renmin Hospital of Wuhan University from September 2019 to December 2023. Patients were divided into the IO plus CRT group (n = 34) and CRT alone group (n = 25). Clinical efficacy and adverse events (AEs) were analyzed and compared. Primary outcomes included median overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and safety. Subgroup analysis was also performed. RESULTS: Compared with the CRT alone, IO re-challenge combined with CRT showed significantly improved median OS (11.4 months vs. 6.2 months; adjusted HR = 0.48; 95% CI: 0.25-0.90; P = 0.022), PFS (6.8 months vs. 3.9 months; adjusted HR = 0.50; 95% CI: 0.27-0.94; P = 0.031), and higher ORR (35.3% vs. 16.0%) and DCR (88.2% vs. 68.0%). Patients with the following characteristics: male, stage III-IV, primary tumor located in the middle esophagus, with regional lymph node metastasis and/or distant metastasis, and first-line PFS > 6 months were more likely to obtain OS benefit from IO re-challenge combined with CRT. The incidence of grade ≥ 3 AEs in the two groups of patients were 44.1% and 40.0%, respectively, and mainly including leukopenia, neutropenia, anemia, thrombocytopenia, fatigue and loss of appetite. CONCLUSIONS: Second-line IO re-challenge combined with CRT provided significant survival benefits and controllable safety compared with CRT alone for ESCC patients who had disease progression after first-line IO failure. Further prospective study is needed.