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Impact of platinum-based chemotherapy and CTLA-4 inhibition on acquired resistance to first-line anti-PD-1/PD-L1 agents in non-small cell lung cancer: a systematic review and reconstructed individual patient data analysis
Oresti, S. Salomone, F. Nuccio, A. Ogliari, F. R. Riva, S. T. Mollica, L. Bulotta, A. Viganò, M. G. Venanzi, F. M. Passaretti, F.
Oresti, S.
Salomone, F.
Nuccio, A.
Ogliari, F. R.
Riva, S. T.
Mollica, L.
Bulotta, A.
Viganò, M. G.
Venanzi, F. M.
Passaretti, F.
Abstract
BACKGROUND: Acquired resistance is defined as disease progression following an initial response to immune checkpoint inhibitors (ICI). The impact of adding platinum-based chemotherapy (PCT) or anti-CTLA-4 agents to PD-(L)-1 inhibitors on acquired resistance is currently unknown. METHODS: Systematic research by January 31, 2025 identified randomized clinical trials (RCTs) evaluating first-line ICI as monotherapy (mono-ICI) or in combination with PCT (mono-ICI + PCT), CTLA-4 inhibitors (combo-ICI), or both (combo-ICI + PCT) in metastatic non-small-cell lung cancer (NSCLC). RCTs reporting duration of response (DoR) data were eligible. Acquired resistance rates at 6 and 12 months were estimated from DoR curves. Aggregate data based on type of regimens were reported with risk ratio (RR) and pooled by random effect model. Primary and secondary endpoints were respectively the indirect comparison of acquired resistance risk between PCT-containing versus PCT-free regimens and between anti-CTLA-4 containing versus anti-CTLA-4 free regimens, respectively. Time-to-event outcomes were retrieved from Kaplan-Meier (KM) curves using individual patient data (IPD) and compared by log rank tests. This study was registered to the PROSPERO online platform (CRD42025639320). FINDINGS: Nineteen RCTs were included. 6- and 12-months acquired resistance rates were 16.5%-34.1% (mono-ICI), 26.4%-47.8% (mono-ICI + PCT), 19.0%-33.0% (combo-ICI), and 28.4%-47.1% (combo-ICI + PCT). A higher risk of acquired resistance was suggested from indirect comparisons of mono-ICI + PCT versus mono-ICI (12-months RR: 1.46, 95% CI 1.23-1.75) and of combo-ICI + PCT versus combo-ICI (12 months RR: 1.36, 95% CI 1.06-1.73). Using the reconstructed patient-level data, median DoR was 5-7 months significantly shorter with PCT-containing compared to PCT-free regimens. The addition of anti-CTLA-4 agents did not impact on acquired resistance. INTERPRETATION: Although insufficient RCTs reported acquired resistance rates stratified by specific factors influencing DoR (i.e., PD-L1, TMB) for such analyses to be included in this report, the increased acquired resistance risk observed with PCT-containing regimens highlights the potential value of tailoring first-line treatment strategies in NSCLC on the basis of individual risk of resistance to ICI. FUNDING: This research did not receive any specific grant from funding agencies.
Authors
Oresti, S.
Salomone, F.
Nuccio, A.
Ogliari, F. R.
Riva, S. T.
Mollica, L.
Bulotta, A.
Viganò, M. G.
Venanzi, F. M.
Passaretti, F.
Papotto, L.
Di Lello, A.
Ferrara, M.
Foggetti, G.
Damiano, G.
Servetto, A.
Califano, R.
Di Maio, M.
Ricciuti, B.
Cortellini, A.
Reck, M.
Cinquini, M.
Torri, V.
Viscardi, G.
Ferrara, R.
Salomone, F.
Nuccio, A.
Ogliari, F. R.
Riva, S. T.
Mollica, L.
Bulotta, A.
Viganò, M. G.
Venanzi, F. M.
Passaretti, F.
Papotto, L.
Di Lello, A.
Ferrara, M.
Foggetti, G.
Damiano, G.
Servetto, A.
Califano, R.
Di Maio, M.
Ricciuti, B.
Cortellini, A.
Reck, M.
Cinquini, M.
Torri, V.
Viscardi, G.
Ferrara, R.
Description
Date
2025
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Article
Citation
Oresti S, Salomone F, Nuccio A, Ogliari FR, Riva ST, Mollica L, et al. Impact of platinum-based chemotherapy and CTLA-4 inhibition on acquired resistance to first-line anti-PD-1/PD-L1 agents in non-small cell lung cancer: a systematic review and reconstructed individual patient data analysis. EClinicalMedicine. 2025 Oct;88:103482. PubMed PMID: 40969680. Pubmed Central PMCID: PMC12441679. Epub 2025/09/19. eng.