Efficiency and safety of sintilimab-based induction therapy in potentially resectable stage III non-small cell lung cancer (LungMate-009): an open-label, phase 2 trial.

Background: Approximately 30% of patients with non-small-cell lung cancer (NSCLC) have initially resectable disease. This trial aimed to evaluate the safety and feasibility of administering sintilimab-based induction therapy for potentially resectable stage III NSCLC to offer a more advantageous therapeutic strategy. Methods: This investigator-initiated, open-label, phase 2 trial (NCT04728724) aimed to explore the efficacy and safety of sintilimab-based induction therapy in patients with potentially resectable stage III NSCLC on the basis of tumour PD-L1 expression. Eligible patients with PD-L1 expression in at least 50% of tumour cells received four cycles of sintilimab (200 mg every 3 weeks) as monotherapy, and patients with PD-L1 expression in less than 50% of tumour cells or of unknown status received four cycles of sintilimab combined with carboplatin-based chemotherapy before surgical resection. Evaluation of efficacy was conducted by a multidisciplinary team every two cycles. Surgical resection was performed within 21-28 days of the last dose. The primary endpoint was the major pathological response rate. Additionally, bulk RNA sequencing of baseline and surgical samples was conducted to investigate the tumour microenvironment and identify potential biomarkers. Findings: 100 patients were enrolled between November 16, 2022, and September 11, 2023, and 97 patients were included in analyses. 75 (77%) of 97 patients completed four cycles of neoadjuvant treatment (range 1-6 cycles). An overall response was observed in 80 patients (82%; 95% CI 75-90), and all had a partial response. Surgery was performed in 58 patients (60%), and all patients had R0 resection. 38 (66%, 95% CI 53-78) of 58 patients had a major pathological response. As of September 24, 2025, the median follow-up duration was 31.0 months (IQR 27.5-32.6), and median progression-free survival and overall survival were not reached. 24-month progression-free survival was 78% (95% CI 71-87), and 24-month overall survival was 88% (81-94). Grade 3 or higher treatment-related adverse events occurred in 40 (41%) of 97 patients, and the most common grade 3-4 treatment-related adverse events were neutropenia (n = 35 [36%]), leukopenia (n = 18 [19%]). Immune-related adverse events occurred in 51 (53%) of 97 patients receiving study treatment. Differential gene expression analysis in the combination of baseline and surgical tumour samples revealed the upregulation of immune-related genes in responders to neoadjuvant immune checkpoint blockade, and the upregulation of metabolism-related genes in non-responders. Interpretation: Sintilimab-based induction treatment strategy could be a feasible option for potentially resectable NSCLC patients with stage III disease. Notably, we found that increased plasma cell signatures were predictive of response, while elevated AKR1C family gene expression substantially correlated with resistance to immune checkpoint blockade. Funding: This work was supported by the National Natural Science Foundation of China (No. 82430053); Shanghai Science and Technology Committee, China (Grant No. 24SF1904500); Innovation Program of Shanghai Municipal Education Commission, China (Grant No. 2023ZKZD33, Grant No. AI for Science); Tongji University Medicine-X Interdisciplinary Research Initiative, China (Grant No. 2025-0554-ZD-03); and Foundation of Shanghai Pulmonary Hospital, China (Grant No. LYRC202402, FKLY20004).