Long-term overall survival with dual CTLA-4 and PD-L1 or PD-1 blockade and biomarker-based subgroup analyses in patients with advanced non-small-cell lung cancer: a systematic review and reconstructed individual patient data meta-analysis.

BACKGROUND: Immune checkpoint inhibitors targeting PD-L1 or PD-1 as monotherapy or combined with CTLA-4 inhibitors or chemotherapy (or both) are the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, it remains unclear which patients benefit from the addition of CTLA-4 inhibitors. We aimed to evaluate whether dual checkpoint blockade with CTLA-4 and PD-L1 or PD-1 inhibitors provides similar efficacy to PD-L1 or PD-1 inhibitor monotherapy, or whether these strategies produce distinct outcomes across NSCLC subpopulations. METHODS: We conducted a search of PubMed, MEDLINE, and Embase for randomised phase 3 trials published from database inception to Nov 21, 2024, that investigated PD-L1 or PD-1 inhibitors, with or without CTLA-4 inhibitors, in patients with advanced NSCLC. We focused on studies reporting Kaplan-Meier survival data at 5 years or biomarker analyses based on PD-L1, KRAS, and STK11 mutational status. Individual patient data were extracted from Kaplan-Meier curves with WebPlotDigitizer version 5 and reconstructed with the IPDfromKM method. The primary endpoint of the study was 5-year overall survival in the overall population and in subpopulations based on PD-L1 tumour proportion score (TPS), tumour histology, and mutational status (mutant vs wild-type) of KRAS and STK11. This study was registered with PROSPERO, CRD420251081707. FINDINGS: The initial search yielded 1026 results, and six randomised clinical trials met the eligibility criteria and were included. Among the 2881 patients eligible for analysis (838 [29·1%] female and 2043 [70·9%] male), 1282 received dual CTLA-4 and PD-L1 or PD-1 blockade and 1599 received single PD-L1 or PD-1 blockade. Patients treated with dual CTLA-4 and PD-L1 or PD-1 blockade had similar median overall survival compared with those treated with single PD-L1 or PD-1 inhibition (16·1 months [95% CI 15·0-17·8] vs 16·9 months [15·5-18·3]; HR 0·95 [95% CI 0·87-1·03], p=0·19). Median overall survival was significantly longer with dual CTLA-4 and PD-L1 or PD-1 blockade among patients with PD-L1 TPS less than 1% versus those treated with single PD-L1 or PD-1 inhibition (15·5 months [95% CI 13·6-18·5] vs 14·5 months [13·4-15·9]; HR 0·85 [95% CI 0·74-0·98], p=0·021), with 5-year overall survival rates of 16·6% (95% CI 13·4-20·6) versus 9·3% (7·0-12·3), respectively. Median overall survival in patients with tumours harbouring STK11 mutations was also significantly longer with dual CTLA-4 and PD-L1 or PD-1 blockade compared with single PD-L1 or PD-1 inhibition (13·9 months [95% CI 9·8-20·8] vs 7·8 months [6·4-12·9]; HR 0·67 [95% CI 0·49-0·91], p=0·012). However, no significant differences in overall survival were found between treatment groups by tumour histology (squamous vs non-squamous NSCLC) or by KRAS mutational status. INTERPRETATION: 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. FUNDING: NextGenerationUE.