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. 2025 Sep 2:88:103482.
doi: 10.1016/j.eclinm.2025.103482. eCollection 2025 Oct.

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

Sara Oresti  1 , Fabio Salomone  2 , Antonio Nuccio  1   3 , Francesca Rita Ogliari  1   3 , Silvia Teresa Riva  1 , Ludovica Mollica  1   3 , Alessandra Bulotta  1 , Maria Grazia Viganò  1 , Francesco Maria Venanzi  1   3 , Francesco Passaretti  1   3 , Ludovica Papotto  1   3 , Anna Di Lello  1   3 , Michele Ferrara  1 , Giorgia Foggetti  1   3   4 , Giuseppe Damiano  1   3 , Alberto Servetto  2 , Raffaele Califano  5 , Massimo Di Maio  6 , Biagio Ricciuti  7 , Alessio Cortellini  8   9   10 , Martin Reck  11 , Michela Cinquini  12 , Valter Torri  12 , Giuseppe Viscardi  13 , Roberto Ferrara  1   3
Affiliations

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

Sara Oresti et al. EClinicalMedicine. .

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.

Keywords: Acquired resistance; CTLA-4 inhibitors; Immunotherapy; Non-small cell lung cancer; Platinum-based chemotherapy.

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Conflict of interest statement

Sara Oresti reports Speaker’s fee from AstraZeneca and Roche; Support for attending meetings and/or travel from Jannses, Johnson & Johnson and Takeda. Francesca Rita Ogliari reports Speaker’s fee from Roche, Sanofi, Amgen; Support for attending meetings and/or travel from Amgen, Johnson & Johnson. Raffaele Califano reports grants or contracts from Merck Sharp & Dohme, Roche, PharmaMar, GSK, Janssen, AstraZeneca, Taiho, ArriVent and OSE Immunotherapeutics; consulting fees from Pfizer, Merck Sharp & Dohme, PharmaMar, ArriVent, Roche, Bristol Myers Squibb, AstraZeneca, Biontech, Janssen, GSK and Takeda; payment or honoraria from Beigene, Regeneron, AstraZeneca, Janssen, GSK, Takeda; support for attending meetings and/or travel from Janssen, Takeda; participation on a data safety monitoring board or advisory board for PharmaMar, Janssen, Astrazeneca, Arrivent; leadership or fiduciary role for ESMO Educational Publication Working Group; stock or stock options with Supportive Care UK and LOC at the Christie Private Care. Bulotta Alessandra reports honoraria for a role as consultant and advisory board for Roche, BMS, AstraZeneca and speaker fees for BMS, MSD, AstraZeneca, Ely Lilly. Biagio Ricciuti reports speaker fees from Targeted Oncology, consultancy or participation to advisory board from Regeneron, AstraZeneca, Amgen, Guidepoint Inc. Alessio Cortellini reports grants for consultancies/advisory boards from MSD, BMS, IQVIA, AstraZeneca, REGENERON, Amgen, Daiichi-Sankyo, Access Infinity, Ardelis Health, Alpha Sight, Guidepoint, Roche and Alira Health; speaker fees from AstraZeneca, Pierre-Fabre, MSD, Sanofi/REGENERON; payment for writing/editorial activity from BMS, MSD, Roche; travel support from Sanofi/REGENERON, MSD. Martin Reck reports speaker fees from Amgen, AstraZeneca, Beigene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Mirati, Merck, MSD, Lily, Novartis, Pfizer, Sanofi, Roche, and Regeneron; consultancy or participation to advisory board from Daiichi Sankyo and Sanofi. Alberto Servetto reports honoraria from Eli Lilly, MSD, and Janssen and travel support from Bristol-Myers Squibb and AstraZeneca. Massimo Di Maio reports honoraria from Pfizer, Takeda, AstraZeneca, Janssen, Eisai, Novartis, Roche, Astellas Pharma, MSD Oncology, Boehringer Ingelheim, Viatris, Ipsen; consultancy or participation to advisory boards and direct research funding from AstraZeneca, Pfizer, Takeda, Janssen, Eisai, Novartis, Roche, MSD, Viatris, Ipsen; Research Funding from Tesaro/GlaxoSmithKline. Giuseppe Viscardi reports travel support from AstraZeneca, MSD, Novartis, Sanofi; honoraria for advisory board from Amgen, MSD, Novartis. Ferrara Roberto reports honoraria for advisory board from MSD, Beigene, AstraZeneca, BMS, Sanofi, Johnson & Johnson.

Figures

Fig. 1
Fig. 1
PRISMA diagram.
Fig. 2
Fig. 2
Alluvial plot of acquired resistance rates at 12 months according to treatment regimens (17 RCTs). ICI, immune checkpoint inhibitors; PCT, platinum-based chemotherapy.
Fig. 3
Fig. 3
Indirect comparisons of AR risk at 6 and 12 months for PCT-containing versus PCT free regimens (A and B) and for CTLA-4 inhibitors containing versus CTLA-4 inhibitors free regimens (C and D). Abbreviations: RR, risk ratio; ICI, immune checkpoint inhibitors; PCT, platinum-based chemotherapy.
Fig. 4
Fig. 4
IPD reconstructed Kaplan–Meier curves comparing median duration of response between mono-ICI + PCT versus mono-ICI (A), combo-ICI + PCT versus combo-ICI (B), mono-ICI + PCT versus combo-ICI + PCT (C), mono-ICI versus combo-ICI (D). Abbreviations: DoR, duration of response; ICI, immune checkpoint inhibitors; HR, hazard ratio; PCT, platinum-based chemotherapy.
See this image and copyright information in PMC

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