Pseudoprogression after neoadjuvant immunotherapy for resectable NSCLC: Incidence, PET/CT patterns, and differentiation.

Abstract

8032 Background: Neoadjuvant immunotherapy combined with chemotherapy is now the standard of care for resectable non-small cell lung cancer (NSCLC). However, evaluating treatment response remains challenging due to the unique response pattern of pseudoprogression associated with immune checkpoint inhibitors (ICIs), which may lead to unnecessary cancellation of curative surgeries. This study aimed to characterize pseudoprogression and investigate strategies for distinguishing pseudoprogression from true tumor progression in the neoadjuvant ICI setting. Methods: This retrospective study included 283 patients with resectable NSCLC who underwent neoadjuvant ICI therapy (n=235) or targeted therapy (n=48) between January 2021 and December 2023. PET-CT scans were acquired at baseline and before surgery. Radiological and metabolic responses were evaluated using RECIST 1.1 and EORTC criteria, respectively. Pathological responses were assessed according to IASLC guidelines. Multivariate logistic regression and receiver operating characteristic analyses were performed to identify predictors of pseudoprogression and evaluate diagnostic performance. Results: Among 283 patients (ICI 235, TKI 48), 9.2% (26 patients) were classified as having progressive disease (PD) by RECIST 1.1, all in the ICI cohort. According to EORTC on PET-CT, progression increased to 25.1% (71 patients). Despite radiologic progression, all 26 patients underwent R0 resection; pCR and MPR rates were 53.8% and 11.6%. Among patients without radiologic progression, pCR and MPR were 30.0% and 19.1%, with no differences in R0 rate or pathological response (p = 1.00 and 0.06). Among 71 patients with progressive metabolic disease (PMD) on PET/CT, 69 (97.2%) achieved R0 resection; 27 (38.0%) achieved pCR and 12 (16.9%) achieved MPR, with similar outcomes by PMD status (p = 1.00 and 0.53). In both the ICI cohort and overall population, primary tumor progression was associated with lower MPR rates than lymph node or distant progression (16.7%, 61.2%, and 100%; p = 0.001) and worse EFS and OS. In the TKI cohort, imaging-defined progressive or stable disease was associated with lower MPR and worse survival. Pseudoprogression occurred in 7.2% by CT, increasing to 16.2% with PET-CT, predominantly nodal. A ≥53.1% reduction in primary-tumor SUVmax identified pseudoprogression (AUC 0.865; sensitivity 73.8%; specificity 88.6%). A multivariable model combining ΔSUVmax, longest diameter change (%), smoking status, and histology showed excellent discrimination (AUC 0.935). Conclusions: Pseudoprogression is common in resectable NSCLC treated with neoadjuvant ICI therapy, presenting as nodal or distant lesions without primary tumor progression. A multifactorial model incorporating primary tumor SUVmax changes provides a robust tool for distinguishing pseudoprogression and guiding clinical decision-making.