Surrogacy of Pathologic Complete Response in Trials of Neoadjuvant Chemo-Immunotherapy in Resectable NSCLC: A Critical Analysis of Strengths, Weaknesses, and Misinterpretations

Background : Pathological complete response (pCR) has emerged as key endpoint in neoadjuvant and perioperative chemo-immunotherapy (CT-IO) trials in resectable non-small cell lung cancer (NSCLC). While increased pCR rates have correlated with improved event-free survival (EFS) in several trials, the prognostic value of different pathological responses in the neoadjuvant and perioperative setting remains unclear. Methods : We performed a critical review of prospective phase 2 and 3 clinical trials investigating CT-IO in stage II-III resectable NSCLC, focusing on pCR as a surrogate endpoint. Data were extracted from, CheckMate 816, CheckMate 77T, AEGEAN, KEYNOTE-671, NADIM and NADIM II, and NeoTORCH-trials. We analyzed trial design, pCR, EFS and overall survival (OS), with specific focus on the correlation between pCR and survival outcomes. Results: All evaluated trials demonstrated improved pCR rates with the addition of immune checkpoint inhibitors (ICIs) to chemotherapy with pCR rates ranged from 17.3 to 36.8% in the combination of chemotherapy and immunotherapy and consistently correlated with EFS improvements (HR range 0.49-0.68). Biological heterogeneity, differences in trial stagings systems, pathological assessment and biomarker stratification limit the generalizability of these findings. Conclusions: pCR is a promising, yet unvalidated, surrogate endpoint for survival in respectable NSCLC treated with chemo-immunotherapy. While associated with improved EFS in multiple trials, its role as a surrogate for long-term outcomes is not absolute. Standardization of pathology assessment and integration of complementary biomarkers such as circulating tumor DNA (ctDNA) are needed to enhance its predictive utility. Until further validated, pCR should be interpreted within a composite clinical and molecular framework to guide treatment decisions and regulatory approvals. Publication History Article published online: 04 March 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany