A combination of sintilimab, anlotinib, and chemotherapy as neoadjuvant treatment has demonstrated promising efficacy in patients with resectable non-small cell lung cancer (NSCLC). The study, which included 45 patients, reported a pathological complete response (pCR) rate of 57.8% and an objective response rate (ORR) of 71.1%. These findings suggest a potential new approach to improve outcomes in this patient population.
The study, published in Nature, enrolled patients with stage II or III NSCLC. Participants received sintilimab (an anti-PD-1 antibody) and anlotinib (a multi-target tyrosine kinase inhibitor) concurrently with platinum-based doublet chemotherapy. The primary endpoint was pCR, while secondary endpoints included major pathological response (MPR), ORR, disease control rate (DCR), event-free survival (EFS), and safety.
Treatment Response and Pathological Outcomes
The results showed that 26 out of 45 patients (57.8%) achieved pCR, and 30 patients (66.7%) achieved MPR. The ORR was 71.1% (32/45), with two patients achieving complete response (CR) and 30 achieving partial response (PR). The DCR was remarkably high at 97.8% (44/45), indicating disease stabilization in nearly all patients. Specifically, in the PP set, pCR occurred in 63.4%, and MPR occurred in 73.2%.
Survival Outcomes
With a median follow-up duration of 22.8 months, the estimated 24-month event-free survival (EFS) rate was 81.5%. The median EFS was not reached. The estimated 12-month survival rate was 97.7%, and the median overall survival (OS) was also not reached. These survival outcomes suggest a durable benefit from the neoadjuvant treatment regimen.
Safety Profile
All patients experienced treatment-related adverse events (TRAEs) during the neoadjuvant treatment period, with 55.6% experiencing grade 3 or 4 TRAEs. The most frequent grade 3 or 4 TRAEs were white blood cell count decrease (11.1%), neutrophil count decrease (11.1%), and vomiting (8.9%). Immune-related adverse events (irAEs) occurred in 15.6% of patients during the neoadjuvant phase and 34.1% during the adjuvant phase. Postoperative complications occurred in 34.1% of patients, with pleural effusion, pneumonia, and pneumothorax being the most common.
Tumor Microenvironment Modulation
Multiplex immunohistochemistry (mIHC) analysis revealed significant changes in the tumor microenvironment (TME) following neoadjuvant treatment. There was a notable decrease in VEGF+ cells in patients who achieved pCR, while those who did not achieve pCR showed a slight increase. The ratio of CD31+/NG2+ cells, indicative of vascular normalization, significantly decreased in the pCR group. Furthermore, perivascular CD4+ T cell infiltration increased significantly in the pCR group.
Implications for Clinical Practice
These findings suggest that the combination of sintilimab, anlotinib, and chemotherapy is a promising neoadjuvant strategy for patients with resectable NSCLC. The high pCR rate, ORR, and DCR, along with encouraging survival outcomes, warrant further investigation in larger, randomized controlled trials. The modulation of the TME observed in this study provides insights into the potential mechanisms of action of this combination therapy.
