Pseudoprogression in neoadjuvant immunotherapy for resectable NSCLC: a PET-CT-based study

Neoadjuvant chemoimmunotherapy is standard for resectable non-small-cell lung cancer (NSCLC) but response assessment is challenging due to pseudoprogression, which may lead to unnecessary cancellation of surgery. We characterized pseudoprogression and developed a clinical strategy to distinguish it from true progression after neoadjuvant immune checkpoint inhibitor (ICI) therapy.

We retrospectively analyzed data from 283 patients with resectable NSCLC receiving neoadjuvant ICI (n = 235) or tyrosine kinase inhibitor (n = 48) therapy from January 2021 to December 2023. Positron emission tomography-computed tomography (PET-CT) scans were acquired at baseline and preoperatively. Responses were evaluated using RECIST 1.1 and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Predictors of pseudoprogression were evaluated using multivariable logistic regression. Model performance was assessed in an independent validation cohort (n = 95).

By RECIST 1.1, 26 of 283 patients (9.2%) had progressive disease (PD), all in the ICI cohort. By EORTC criteria, the number with PD increased to 71 of 283 (25.1%). Despite PD, all 26 patients underwent R0 resection; complete pathological response (CPR) and major pathological response (MPR) rates were 53.8% and 65.3% compared with 30.0% and 49.0%, respectively, in patients without PD. Among 71 with progressive metabolic disease, 69 (97.2%) achieved R0; CPR and MPR were 38.0% and 54.9%, respectively. Primary-tumor progression had lower MPR than nodal or distant progression (23.1%, 58.2%, and 73.3%, respectively, P = 0.020). Pseudoprogression occurred in 7.2% based on CT, increasing to 16.2% with PET-CT. A ≥53.1% reduction in primary-tumor maximum standardized update value (SUV_max) identified pseudoprogression [area under the curve (AUC) 0.865, sensitivity 94.7%, specificity 74.1%]. A multivariable model combining change in SUV_max, longest diameter change, smoking status, and histology showed excellent discrimination (AUC 0.935) and remained robust in validation (AUC 0.859).

Imaging-defined progression after neoadjuvant ICI may reflect pseudoprogression, most commonly nodal or distant lesions without primary tumor progression. A validated model incorporating primary-tumor metabolic response and clinical features improves discrimination of pseudoprogression and may support decision making to avoid inappropriate cancellation of potentially curative resection.