Meta-analysis: similar overall survival with dual vs single checkpoint blockade in NSCLC, subgroup differences reported;

Evidence before this study

First-line therapy for patients with metastatic non-small-cell lung cancer (NSCLC) without actionable genomic drivers include PD-1 or PD-L1 inhibitors as single agents or in combination with platinum-based chemotherapy, with or without CTLA-4 inhibitors. However, although dual CTLA-4 and PD-L1 or PD-1 blockade has shown superiority over platinum-based chemotherapy in patients with metastatic NSCLC, its use remains debated due to the scarcity of comparative studies against single PD-L1 or PD-1-based therapies. In addition, the absence of robust biomarkers of response to dual checkpoint blockade further limits its use in clinical practice.

We conducted a systematic review of randomised phase 3 clinical trials of CTLA-4 and PD-L1 or PD-1 blockade in patients with previously untreated advanced NSCLC and performed an individual patient data meta-analysis by extracting and reconstructing individual patient data from published Kaplan–Meier curves. We searched MEDLINE, PubMed, and Embase for potentially eligible studies published in English from database inception until Nov 21, 2024, using the following terms in full and abbreviated: “non-small cell lung cancer”, “immunotherapy”, “immune checkpoint inhibitor”, “PD-1”, “PD-L1”, “CTLA-4” (and drug names).

We then compared overall survival obtained with dual versus single immune checkpoint blockade overall and in specific subgroups of patients based on PD-L1 tumour proportion score (TPS), histology, and KRAS and STK11 mutational status.

Added value of this study

This meta-analysis provides a comprehensive comparison of long-term survival outcomes between dual and single immune checkpoint blockade, while also identifying biomarkers that might guide the addition of CTLA-4 inhibition to PD-L1 or PD-1 blockade, in patients with advanced NSCLC. Although overall survival was similar across the entire population, dual checkpoint blockade significantly improved overall survival in patients with PD-L1 TPS less than 1% and in those with STK11-mutated tumours compared with PD-L1 or PD-1 inhibition alone. By contrast, no significant overall survival differences were observed based on tumour histology (squamous or non-squamous) or KRAS mutational status, or among patients with PD-L1 TPS 1% or greater or STK11 wild-type tumours.

Implications of all the available evidence

Our study elucidates the clinical benefit of dual checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors compared with PD-L1 or PD-1 inhibition alone and suggests a potential framework for biomarker-driven treatment selection in patients with previously untreated advanced NSCLC. Specifically, our findings support the use of dual checkpoint blockade in patients with PD-L1 TPS less than 1% and those with STK11-mutated tumours, in whom this approach confers a significant survival advantage over single PD-L1 or PD-1 inhibition. Conversely, for patients with PD-L1 TPS 1% or greater or STK11 wild-type tumours, regardless of KRAS mutational status, single-agent PD-L1 or PD-1 inhibition—with or without chemotherapy—remains the preferred approach due to comparable efficacy and reduced toxicity. These results address a key unmet need by providing evidence to inform biomarker-guided use of CTLA-4 blockade in NSCLC, supporting a more personalised and targeted application of dual checkpoint blockade in clinical practice.

Source: The Lancet Oncology