In a systematic review and reconstructed individual-patient meta-analysis reported in The Lancet Oncology, Di Federico et al found that dual CTLA-4 and PD-L1 or PD-1 blockade did not result in improved long-term survival overall vs single PD-L1 or PD-1 blockade in patients with advanced non–small cell lung cancer (NSCLC). However, it was associated with improved survival vs monotherapy in subgroups with PD-L1 tumor proportion score (TPS) < 1% and STK11 mutation.
Study Details
A literature search was performed for randomized phase III trials published through November 2024 that involved PD-L1 or PD-1 inhibitors with or without CTLA-4 inhibitors in patients with advanced NSCLC with data on the outcome measures of interest. The primary outcome measures in the analysis were 5-year overall survival in the overall population and overall survival in subpopulations based on PD-L1 TPS, tumor histology, and mutational status of KRAS and STK11.
Key Findings
Six trials met eligibility criteria. Among the 2,881 patients included in the analysis, 29.1% were female, 1,282 (44.5%) received dual CTLA-4 and PD-L1 or PD-1 blockade, and 1,599 received single PD-L1 or PD-1 blockade.
The overall survival rate at 5 years was 19.8% (95% confidence interval [CI] = 17.7%–22.1%) in the dual blockade group vs 16.3% (95% CI = 14.5%–18.2%) in the single PD-L1 or PD-1 blockade group. Median overall survival was 16.1 months (95% CI = 15.0–17.8 months) vs 16.9 months (95% CI = 15.5–18.3 months), with a hazard ratio (HR) of 0.95 (95% CI = 0.87–1.03, P = .19).
No significant differences in overall survival were observed between groups according to tumor histology or KRAS mutational status.
Median overall survival was significantly longer with dual CTLA-4 and PD-L1 or PD-1 blockade among patients with PD-L1 TPS < 1% (447 vs 512 patients; 15.5 vs 14.5 months, HR = 0.85, 95% CI = 0.74–0.98, P = .021), with a 5-year rate of 16.6% vs 9.3%, and among patients with STK11 mutations (81 vs 120 patients; 13.9 vs 7.8 months, HR = 0.67, 95% CI = 0.49–0.91, P = .012), with a 3-year rate of 28.4% vs 13.4%.
The investigators concluded: “Compared with single PD-L1 or PD-1 inhibition, dual immune checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors was associated with improved overall survival in patients with advanced NSCLC and PD-L1 TPS less than 1% and in those with STK11 mutations, but not in the overall population. Prospective validation of these results in clinical trials is warranted.”
Biagio Ricciuti, MD, PhD, of Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, is the corresponding author of The Lancet Oncology article.
Disclosure: The study was funded by NextGenerationEU. For full disclosures of all study authors, visit thelancet.com.
