Perioperative nivolumab combined with chemotherapy significantly improves event free survival and pathological response in patients with stage III non-small-cell lung cancer, including those with N2 nodal disease, according to an exploratory phase III analysis.
Study Context and Rationale
Patients with non-small-cell lung cancer (NSCLC) and metastases to ipsilateral mediastinal or subcarinal lymph nodes, known as N2 disease, have traditionally faced poor long-term outcomes. Whether modern immunotherapy can overcome this adverse prognosis remains a critical question. Investigators conducted an exploratory analysis of a randomised phase III trial comparing perioperative nivolumab plus chemotherapy with chemotherapy alone in resectable stage III NSCLC, with outcomes assessed according to nodal status.
Trial Design and Treatment Strategy
Participants with stage III NSCLC were randomly assigned to receive neoadjuvant nivolumab plus chemotherapy followed by surgery and adjuvant nivolumab, or neoadjuvant chemotherapy followed by surgery and adjuvant placebo. Outcomes were evaluated in patients with N2 disease, including those with multistation nodal involvement, as well as in those with non-N2 stage III disease. Key endpoints included event free survival, defined as the time from randomisation to disease progression or death, and pathological complete response, indicating the absence of viable tumour cells after surgery.
Efficacy in N2 and Multistation Disease
Among patients with N2 disease, perioperative nivolumab led to markedly better outcomes than placebo. The one year event free survival rate was 70% with nivolumab versus 45% with placebo, corresponding to a hazard ratio of 0.46; 95% CI: 0.30–0.70. Pathological complete response rates were also higher at 22.0% versus 5.6%. Definitive surgery was performed in 77% of patients receiving nivolumab and 73% receiving placebo, with most undergoing simple lobectomy. In patients with multistation N2 disease, benefits were even more pronounced, with one year event free survival rates of 71% versus 46% and pathological complete response rates of 29.0% versus 2.7%. Among those who underwent surgery, nodal downstaging occurred in 67% of nivolumab treated patients compared with 59% in the placebo group.
Broader Implications for Stage III NSCLC
In patients with stage III non-N2 NSCLC, median event free survival was not reached with nivolumab and was 17.0 months with placebo, with a one year event free survival rate of 74% versus 62%. No new safety signals were identified. These findings suggest that perioperative nivolumab may mitigate the historically poor prognosis associated with N2 disease and support its use as an effective treatment strategy in resectable stage III NSCLC.
Reference
Provencio M et al. Clinical outcomes with perioperative nivolumab by nodal status in patients with stage III resectable NSCLC: phase 3 CheckMate 77T exploratory analysis. Nature Cancer. 2026; https://doi.org/10.1038/s43018-025-01104-z.
