PurposeImmune checkpoint blockade therapy is the standard treatment for metastatic or refractory non-small cell lung cancer (NSCLC). However, it is associated with immune-related adverse events (irAEs). irAEs are sometimes fatal; however, an efficient method for early irAEs detection has not been developed because their onset timing varies. We examined the significance of non-specific symptoms as a prodrome of irAEs in patients with NSCLC.MethodsWe reviewed consecutive patients who received nivolumab at a dosage of 3 mg/kg every 2 weeks for metastatic NSCLC between December 2015 and August 2017. Patient demographics, irAEs and signal symptoms were recorded. Non-specific symptoms (fever and fatigue) occurred 7 days or earlier before the onset of irAEs were considered signal symptoms. For statistical analyses, the association between irAEs and clinical information, including signal symptoms, was evaluated using Fisher’s exact test and logistic regression.ResultsA total of 200 patients received nivolumab; 131 (65.5%) were male, their median age was 63 years (range 30–83), 174 (87.0%) had performance status of 0–1. Signal symptoms occurred in 38 (19.0%) of the 77 patients (38.5%) who experienced irAEs, and were positively associated with the occurrence of irAEs (P< 0.01). Multivariate analysis showed that the occurrence of irAEs was significantly higher in patients with PS 0–1 [odds ratio (OR) 7.01; 95% confidence intervals (CI), 1.69–29.13] and patients experienced signal symptoms (OR 17.30; 95% CI, 6.51–45.99).ConclusionThe occurrence of signal symptoms could be used in the early detection and management of irAEs in patients during immune checkpoint blockade therapy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00432-022-04205-9.