Introduction: The relative efficacies of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) for the treatment of recurrent non-small cell lung cancer (NSCLC) after surgery remain unclear. Methods: Among 801 patients with NSCLC who underwent pulmonary resection at Kanazawa Medical University between 2017 and 2021, sixty-four patients had recurrence. We retrospectively compared the efficacies of EGFR-TKIs and ICIs in these patients with recurrent NSCLC who underwent pulmonary resection. Results: The 3-year overall survival rates after recurrence were 79.3% in patients who received EGFR-TKIs, 69.5% in patients who received ICIs, and 43.7% in patients who received cytotoxic agents. There was no significant difference in overall survival between patients treated with EGFR-TKIs and ICIs (p = 0.14) or between patients treated with ICIs and cytotoxic agents (p = 0.23), but overall survival was significantly higher in patients treated with EGFR-TKIs compared with cytotoxic agents (p < 0.01). The probabilities of a 2-year response were 88.5%, 61.6%, and 25.9% in patients treated with EGFR-TKIs, ICIs, and cytotoxic agents, respectively. There was no significant difference in response periods between patients treated with EGFR-TKIs and ICIs (p = 0.18), but the response period was significantly better in patients treated with EGFR-TKIs (p < 0.01) or ICIs (p = 0.03) compared with cytotoxic agents. Percent-predicted vital capacity (p = 0.03) and epidermal growth factor receptor gene mutation (p < 0.01) were significant factors affecting the overall response to chemotherapy in multivariate analysis. Conclusion: EGFR-TKIs and ICIs are effective for treating recurrent NSCLC after surgery. Although adjuvant chemotherapy for completely resected pathological stage II to IIIA NSCLC, atezolizumab or osimertinib, has also been recently approved as adjuvant chemotherapy, there is a risk that patients who relapse after adjuvant chemotherapy will have less choice.

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