Abstract
BACKGROUND: Combination immunotherapy has become a standard first-line treatment for advanced non-small cell lung cancer (NSCLC). However, its application in patients with checkpoint inhibitor-related pneumonitis (CIP) remains challenging due to the risk of treatment-related pulmonary toxicity. While first-line outcomes in CIP patients are increasingly reported, data on the efficacy and safety of subsequent therapies are lacking. This study aimed to evaluate treatment patterns, survival outcomes, and the risk of pulmonary toxicity associated with second-line therapy in NSCLC patients with prior CIP after first-line immunotherapy. METHODS: This retrospective study analyzed 159 patients with advanced or recurrent NSCLC treated with first-line combination immunotherapy at Fukuoka University Hospital between January 2019 and March 2024, including those who had previously received molecular targeted therapy for driver gene mutations. Patients were stratified based on baseline CIP status. Among them, 91 patients (19 prior CIP and 72 non-prior CIP) who received second-line therapy were evaluated for progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and drug-induced pneumonitis onset during second-line treatment. RESULTS: Baseline CIP was present in 32 patients (20.1%). The transition rate to second-line therapy was 73% in the prior CIP group and 64% in the non-prior CIP group, with no statistically significant difference observed between the two groups (P=0.49), indicating that the presence of prior CIP did not clearly affect the likelihood of receiving secondary therapy. PFS following second-line treatment was similar between patients with and without prior CIP. However, OS tended to be shorter in the prior CIP group (6.4 vs. 10.3 months), although the difference was not statistically significant (P=0.07), a trend that persisted after propensity score matching. Drug-induced pneumonitis development during second-line therapy occurred more frequently in patients with prior CIP (26% vs. 3%, P<0.01). CONCLUSIONS: Second-line cytotoxic chemotherapy following combination immunotherapy may be associated with shorter survival and increased pulmonary toxicity in NSCLC patients with prior CIP. Careful clinical decision-making, multidisciplinary consultation, and close monitoring are essential when initiating second-line treatment in this population.