Interim analysis of the efficiency and safety of neoadjuvant PD-1 inhibitor (sintilimab) combined with chemotherapy (nab-paclitaxel and carboplatin) in potentially resectable stage IIIA/IIIB non-small cell lung cancer: a single-arm, phase 2 trial

Introduction While some clinical studies have shown that PD-1 and PD-L1 can also be an effective neoadjuvant treatment for early-stage non-small cell lung cancer (NSCLC), no evidence has been available for the use of the PD-1 inhibitor sintilimab combined with chemotherapy as a neoadjuvant treatment for potentially resectable NSCLC in the Chinese population. Methods This prospective, single-center, single-arm, phase 2 clinical trial (registration number: NCT04326153) included treatment-naive patients with potentially resectable NSCLC (stage IIIA/IIIB) who received sintilimab plus nab-paclitaxel and carboplatin for two to three cycles before systematic nodal dissection 30 to 45 days after neoadjuvant treatment. After surgery, patients needed to complete two cycles of adjuvant chemoimmunotherapy (sintilimab + nab-paclitaxel + carboplatin). The primary endpoint was disease-free survival rate at 24 months, whereas secondary endpoints included major pathological response (MPR) and pathologic complete response (pCR) rates, the proportion of patients who achieved tumor downstaging, overall survival, objective response rate (ORR), and adverse effects. PD-L1 status before and after treatment was also determined. Results Among the 20 patients who received neoadjuvant chemoimmunotherapy, 16 underwent radical resection. The disease control rate and ORR were 90% and 70%, respectively. Among the 16 patients who underwent surgery, 10 (62.5%) and 5 (31.25%) achieved MPR and pCR, respectively. Squamous cell NSCLC exhibited superior response rates compared to adenocarcinoma (pCR 35.7% vs. 0%). Moreover, 14 patients (70%) experienced grade 1 or 2 neoadjuvant treatment-related adverse events (TRAEs), whereas 6 (30%) experienced grade 3 TRAEs. Bronchopleural fistula (BPF) was found in the current study as an adverse reaction of concern. The rate of BPF was 20% (4/20), of which three patients were in grade 1-2, and one patient died. The occurrence of BPF had no significant correlation with basic disease history, nutritional status, anemia, hypoalbuminemia, surgical procedure, pathological remission, and PD-L1 expression. However, during neoadjuvant treatment, no adverse events prompted dose reduction, treatment discontinuation, surgery delay, or death. Although PD-L1 expression may change after chemoimmunotherapy, no regular pattern was noted. PD-L1 expression, neither at baseline nor after neoadjuvant chemoimmunotherapy, was associated with pathological remission. Conclusions The current study found similar ORR, slightly lower MPR and pCR rates, and lower grade 3 TRAEs among patients with potentially resectable stage IIIA/IIIB NSCLC compared to the NADIM trial, as well as a greater ORR, MPR rate, pCR rate, and grade 3 TRAEs compared to Gao's study involving sintilimab for Chinese patients with resectable stage IA-IIIB NSCLC. Though neoadjuvant chemoimmunotherapy had been found to promote a high risk of BPF for patients with stage IIIA/IIIB disease, it offered greater potential for radical cure. Therefore, the current study suggests that neoadjuvant chemoimmunotherapy can be a safe approach in increasing the efficiency of treatment and hopefully improving the prognosis of patients with potentially resectable locally advanced NSCLC.