[Evolution of Perioperative Immunotherapy Paradigms in Non-small Cell Lung Cancer: From Adjuvant Dilemma to...

The application of immune checkpoint inhibitors (ICIs) has reshaped the perioperative treatment pattern of resectable non-small cell lung cancer (NSCLC). Currently, three treatment paradigms have emerged: adjuvant, neoadjuvant alone, and 'sandwich' (neoadjuvant+surgery+adjuvant). Although IMpower010 and KEYNOTE-091 achieved positive results in adjuvant immunotherapy, the negative results of two large phase III studies, BR.31 and ANVIL, raised questions about the generalizability of this model. In contrast, neoadjuvant immunotherapy has shown efficacy in multiple phase III studies. This advantage may stem from the preservation of the intact tumor antigen repertoire and draining lymph node architecture, enabling chemo-immunotherapy to elicit more robust systemic immune responses. Currently, both neoadjuvant alone and 'sandwich' models are recommended by guidelines, but the 5-year overall survival (OS) rates of CheckMate-816 and KEYNOTE-671 are nearly identical (65.4% vs 64.6%), and the pathological complete response (pCR) rate of CheckMate-77T (25.3%) is comparable to that of CheckMate-816 (24%), suggesting that the incremental benefit of extending neoadjuvant cycles and adding postoperative adjuvant immunotherapy in the 'sandwich' model is very limited. In the future, an individualized decision-making model based on pCR and molecular residual disease (MRD) status, such as de-escalation to observation for those achieving pCR with negative MRD, and intensification for those with residual disease or positive MRD, is expected to optimize the balance between treatment intensity and survival benefit. In summary, the existing evidence favors the adoption of a 'neoadjuvant first' strategy for resectable NSCLC. Based mainly on cross-trial indirect comparisons, the neoadjuvant alone model offers comparable efficacy to the 'sandwich' approach with potential cost-effectiveness advantages, and may be preferred as the initial strategy. Individualized post-neoadjuvant management represents the future direction of this field.
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