Efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy in potentially resectable stage IIIA/IIIB non-small cell lung cancer: Neo-Pre-IC, a single-arm phase 2 trial.

Background: Some locally advanced (IIIA/IIIB) non-small cell lung cancers (NSCLCs) might have surgical options available. However, information regarding the effectiveness of neoadjuvant immunotherapy for potentially resectable IIIA/IIIB NSCLC is limited. The intent of this investigation was to offer a more favourable alternative to the standard approach of chemoradiotherapy (concurrent or sequential chemoradiotherapy) followed by immunotherapy for potentially resectable stage III NSCLC. Methods: This prospective, single-arm, phase 2 clinical trial (NCT04326153) enrolled treatment-naïve patients with 'potentially resectable' IIIA/IIIB NSCLC who were deemed unsuitable for complete (R0) resection upon initial diagnosis. The study period was between March 20, 2020, and August 20, 2021. Patients underwent neoadjuvant chemoimmunotherapy (sintilimab combined with nab-paclitaxel and carboplatin) for two to three cycles prior to surgical resection of the lung carcinoma and systematic nodal dissection within 30-45 days. The primary endpoint was the 2-year disease-free survival (DFS) rate, with secondary endpoints encompassing major pathological response (MPR) rate, pathological complete response (pCR) rate, overall survival, objective response rate (ORR), downstaging rate, and adverse events (AEs). Tumour immune cell infiltrates, identified via immunohistochemistry, were assessed as biomarkers at baseline and after surgery. Findings: Among 30 patients who received neoadjuvant chemoimmunotherapy, 20 underwent complete resection. The disease control rate was 96.7% (95% CI: 90.3%-99.99%), with an ORR of 55% (95% CI: 37.2%-72.8%) and a downstaging rate of 80% (95% CI: 65.7%-94.3%). In the subgroup of 20 patients who underwent surgery, the MPR rate was 65% (95% CI: 43.3%-82.9%), and the pCR rate was 40% (95% CI: 21.2%-46.3%). The 2-year DFS rate in the surgical group was 75% (95% CI 56%-94%). Notably, the MPR group demonstrated significantly prolonged DFS compared with the non-MPR group (p = 0.00024). A significant increase in pretreatment CD8 expression correlated with improved DFS (p = 0.00019). Three patients (10%) experienced grade 3 or higher immune-related AEs-one case of grade 3 elevated myocardial enzymes, one case of grade 3 interstitial pneumonia, and one case of grade 5 bronchopleural fistula. Interpretation: Neoadjuvant immunotherapy markedly enhanced the rate of pathological response and 2-year DFS in patients with potentially resectable IIIA/IIIB NSCLC. Overexpression of CD8 before treatment (H score≥3) may serve as a potential predictive biomarker for DFS. Consequently, the treatment landscape for potentially resectable IIIA/IIIB NSCLC could undergo changes. Funding: This study did not receive any financial support.