The Adjuvant-Phase Dilemma After Neoadjuvant Chemoimmunotherapy in Resectable NSCLC: Evidence and Response-Guided Strategies

Background/Objectives: Perioperative chemoimmunotherapy has become an important curative-intent strategy for selected patients with resectable non-small cell lung cancer (NSCLC). However, most pivotal trials evaluate neoadjuvant therapy, surgery, and postoperative immune checkpoint inhibitor (ICI) treatment as an integrated regimen. Whether continued postoperative immunotherapy provides independent incremental benefit for all patients after effective neoadjuvant chemoimmunotherapy and complete resection remains unresolved. This review focuses on the adjuvant-phase dilemma and discusses how postoperative treatment may be refined according to response and residual risk. Methods: We performed a narrative review of major neoadjuvant and perioperative chemoimmunotherapy trials, indirect comparative analyses, pathological-response studies, circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) evidence, immune biomarker studies, and emerging data in driver-positive and real-world populations. Particular attention was given to evidence informing postoperative continuation, de-escalation, or intensification after neoadjuvant chemoimmunotherapy. Results: Current phase III perioperative trials demonstrate clinically meaningful activity but do not isolate the independent contribution of the adjuvant ICI phase. Pathological response provides the most accessible postoperative risk signal: pathologic complete response identifies the deepest-response group, major pathologic response represents an intermediate state, and non-major pathologic response or persistent nodal disease suggests higher relapse risk. ctDNA-based MRD offers dynamic risk refinement and may help identify patients with residual systemic disease, although prospective validation is required before it can guide routine treatment omission or escalation. Programmed death-ligand 1 (PD-L1), tumor mutational burden, tertiary lymphoid structures, B-cell signatures, radiomics, and pathomics may provide complementary information but are not sufficient as standalone decision tools. Driver-positive disease requires molecularly stratified perioperative strategies rather than unselected extrapolation from epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK)-negative trials. Conclusions: The key question in resectable NSCLC is shifting from whether perioperative immunotherapy is active to which patients truly require postoperative immunotherapy. Future trials should prospectively test response-guided strategies integrating pathological response, ctDNA-based MRD, immune contexture, baseline risk, and treatment feasibility.