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Integrated analysis of concomitant medications and oncological outcomes from PD-1/PD-L1 checkpoint inhibitors in clinical practice
Open accessAbstract
Background: Concomitant medications, such as steroids, proton pump inhibitors (PPI) and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors. Methods: We conducted a multicenter observational retrospective study aimed at evaluating the impact of concomitant medications on clinical outcomes, by weighing their associations with baseline clinical characteristics (including performance status, burden of disease and body mass index) and the underlying causes for their prescription. This analysis included consecutive stage IV patients with cancer, who underwent treatment with single agent antiprogrammed death-1/programmed death ligand-1 (PD-1/PD-L1) with standard doses and schedules at the medical oncology departments of 20 Italian institutions. Each medication taken at the immunotherapy initiation was screened and collected into key categories as follows: corticosteroids, antibiotics, gastric acid suppressants (including proton pump inhibitors - PPIs), statins and other lipid-lowering agents, aspirin, anticoagulants, non-steroidal anti-inflammatory drugs (NSAIDs), ACE inhibitors/Angiotensin II receptor blockers, calcium antagonists, β-blockers, metformin and other oral antidiabetics, opioids. Results: From June 2014 to March 2020, 1012 patients were included in the analysis. Primary tumors were: non-small cell lung cancer (52.2%), melanoma (26%), renal cell carcinoma (18.3%) and others (3.6%). Baseline statins (HR 1.60 (95% CI 1.14 to 2.25), p=0.0064), aspirin (HR 1.47 (95% CI 1.04 to 2.08, p=0.0267) and β-blockers (HR 1.76 (95% CI 1.16 to 2.69), p=0.0080) were confirmed to be independently related to an increased objective response rate. Patients receiving cancer-related steroids (HR 1.72 (95% CI 1.43 to 2.07), p<0.0001), prophylactic systemic antibiotics (HR 1.85 (95% CI 1.23 to 2.78), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.09 to 1.53), p=0.0021), PPIs (HR 1.26 (95% CI 1.07 to 1.48), p=0.0050), anticoagulants (HR 1.43 (95% CI: 1.16 to 1.77), p=0.0007) and opioids (HR 1.71 (95% CI 1.28 to 2.28), p=0.0002) were confirmed to have a significantly higher risk of disease progression. Patients receiving cancer-related steroids (HR 2.16 (95% CI 1.76 to 2.65), p<0.0001), prophylactic systemic antibiotics (HR 1.93 (95% CI 1.25 to 2.98), p=0.0030), prophylactic gastric acid suppressants (HR 1.29 (95% CI 1.06 to 1.57), p=0.0091), PPI (HR 1.26 (95% CI 1.04 to 1.52), p=0.0172), anticoagulants (HR 1.45 (95% CI 1.14 to 1.84), p=0.0024) and opioids (HR 1.53 (95% CI 1.11 to 2.11), p=0.0098) were confirmed to have a significantly higher risk of death. Conclusion: We confirmed the association between baseline steroids administered for cancer-related indication, systemic antibiotics, PPIs and worse clinical outcomes with PD-1/PD-L1 checkpoint inhibitors, which can be assumed to have immune-modulating detrimental effects.
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“As previously reported, they also link PPI use with fecal microbiota oralization32 and adverse outcomes in response to anti-PD-1 therapy33.”
From Intestinal microbiota signatures of clinical response and immune-related adverse events in melanoma patients treated with anti-PD-1 (2022) · cites this paper as [33]
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BackgroundInfluentialMorphine treatment restricts response to immunotherapy in oral squamous cell carcinoma
McIlvried, L. A., Matos, A. A. M., Yuan, M. M., Atherton, M. A., Obuekwe, F., Nilsen, M. L., Nikpoor, A. R., Talbot, S., Bruno, T. C., Taggart, D. N., et al. (2024) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-009962 · Cited by 25
“46 To extend these findings, our in silico bioinformatic analysis found that HNSCC tumor-infiltrating OPRM1 - expressing CD8 + T cells exhibited differential transcriptomic phenotype compared with OPRM1 - negative cells suggesting dysfunc-tionality, decreased cytokine expression and increased…”
van Dorst, D. C. H., van Doorn, L., Colafella, K. M. M., Manintveld, O. C., Hassing, H. C., Danser, A. H. J., Mathijssen, R. H. J., & Versmissen, J. (2021) · Clinical Science · doi:10.1042/cs20200300 · Cited by 25
Mechanisms of Resistance to Immunotherapy in Hepatocellular Carcinoma
Manfredi, G. F., Celsa, C., John, C., Jones, C., Acuti, N., Scheiner, B., Fulgenzi, C. A. M., Korolewicz, J., Pinter, M., Gennari, A., et al. (2023) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s291553 · Cited by 30
“Concomitant use of these three drug types has been associated with poor patient outcomes in retrospective analyses, 168,169 with some evidence that they have a cumulative effect on predicting OS and PFS in patients with advanced cancer receiving ICI therapy.”
BackgroundSelf-citationParisi, C., Abdayem, P., Tagliamento, M., Besse, B., Planchard, D., Remón, J., Minuti, G., Cappuzzo, F., & Barlési, F. (2024) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2024.102845 · Cited by 28
Statin use improves the efficacy of nivolumab in patients with advanced renal cell carcinoma
Santoni, M., Massari, F., Matrana, M. R., Basso, U., Giorgi, U. D., Aurilio, G., Buti, S., Incorvaia, L., Rizzo, M., Martignetti, A., et al. (2022) · European Journal of Cancer · doi:10.1016/j.ejca.2022.04.035 · Cited by 23
Chiang, C., Chen, Y., Chiang, C., Chen, C.-Y., Chang, Y.-C., Wang, S., See, X. Y., Horng, C., Peng, C.-Y., Hsia, Y. P., et al. (2023) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-022-03363-6 · Cited by 24
Shen, J., Hou, H. Y., Liang, B., Guo, X., Chen, L., Yang, Y., & Wang, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1155104 · Cited by 24
“Cortellini et al 2020 (37) Article RP Europe 313/1012 (30.”
BackgroundRodríguez‐Berriguete, G., Puliyadi, R., Machado, N., Barberis, A., Prevo, R., McLaughlin, M., Buffa, F. M., Harrington, K. J., & Higgins, G. S. (2024) · Cell Death and Disease · doi:10.1038/s41419-023-06405-8 · Cited by 25
Acute Kidney Injury Induced by Immune Checkpoint Inhibitors
Tian, R., Liang, J., Li, R., & Zhou, X. (2022) · Kidney Diseases · doi:10.1159/000520798 · Cited by 22
Cani, M., Bironzo, P., Garetto, F., Buffoni, L., & Cotogni, P. (2022) · Healthcare · doi:10.3390/healthcare11010116 · Cited by 22
“tumour burden and may therefore represent another confounding factor [3].”
BackgroundInternò, V., Sergi, M. C., Metta, M. E., Guida, M., Trerotoli, P., Strippoli, S., Circelli, S., Porta, C., & Tucci, M. (2023) · Cancers · doi:10.3390/cancers15051542 · Cited by 22
Self-citationCao, T., Zhou, X., Wu, X., & Zou, Y. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1207544 · Cited by 24
Liao, Y., Lin, Y., Ye, X., & Shen, J. (2025) · JCO Oncology Practice · doi:10.1200/op-24-00583 · Cited by 22
Impact of the ONCOBIOME network in cancer microbiome research
Zitvogel, L., Derosa, L., Routy, B., Loibl, S., Heinzerling, L., de Vries, I. J. M., Engstrand, L., ONCOBIOME Network, Silva, C. A. C., Barbieri, D., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-03608-8 · Cited by 23
“…between broad-spectrum antibiotic use and prognosis was, at least initially, independent of possible confounding factors including age, performance status and comorbidities 3,4 and was observed in patients receiving immunotherapy-based regimens but not in those receiving chemotherapy alone 91,92 .”
Zhao, S., Lu, Z., Zhao, F., Tang, S., Zhang, L., & Feng, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1538969 · Cited by 24
“Immune checkpoint inhibitors (ICIs) dramatically altered the landscape of cancer treatment, and markedly improved the prognosis (1 – 3), particularly for patients with melanoma and non-small cell lung cancer (NSCLC) (4 – 6).”
InfluentialJu, M., Gao, Z., Liu, X., Zhou, H., Wang, R., Zheng, C., Dong, D., Zhu, Z., & Li, K. (2022) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-022-04513-0 · Cited by 21
Bar-Hai, N., Ben‐Betzalel, G., Stoff, R., Grynberg, S., Schachter, J., Shapira‐Frommer, R., & Asher, N. (2023) · Cancers · doi:10.3390/cancers15113041 · Cited by 20
“medication concordantly related to a poorer response rate, PFS and OS in 1012 patients [39].”
BackgroundVos, W. G., Lutgens, E., & Seijkens, T. T. P. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-005611 · Cited by 20
Concomitant Medication Effects on Immune Checkpoint Inhibitor Efficacy and Toxicity
Sieber, B., Strauss, J., Li, Z., & Gatti-Mays, M. E. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.836934 · Cited by 19
“(37) evaluated the effect of ACEi/ARBs in patients with solid tumors, while Failing et al.”
BackgroundResultInfluentialRassy, E., Dalban, C., Colomba, É., Derosa, L., Silva, C. A. C., Négrier, S., Chevreau, C., Gravis, G., Oudard, S. M., Laguerre, B., et al. (2022) · Clinical Genitourinary Cancer · doi:10.1016/j.clgc.2022.07.003 · Cited by 19
Yu, X., Wu, R., Ji, Y., Huang, M., & Feng, Z. (2022) · Diagnostics · doi:10.3390/diagnostics12123157 · Cited by 21
“However, systemic prophylactic antibiotic use greatly reduces the progression-free survival and overall survival of patients treated with ICPis, possibly by mechanisms related to antibiotic-induced alterations in the intestinal flora and effects on the body’s immunity [23].”
BackgroundPizzutilo, E. G., Romanò, R., Roazzi, L., Agostara, A. G., Oresti, S., Zeppellini, A., Giannetta, L. G., Cerea, G., Signorelli, D., Siena, S., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-0161 · Cited by 20
Yuan, M., Han, S., Jia, Y., Feng, J., Liu, D., Su, Z., & Liu, X. (2022) · International Journal of Clinical Practice · doi:10.1155/2022/4938539 · Cited by 18
Wu, L. Y., Hyfte, G. V., Özbek, U., Reincke, M., Gampa, A., Mohamed, Y. I., Nishida, N., Wietharn, B., Amara, S., Lee, P., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1128569 · Cited by 18
Self-citationHatanaka, T., Kakizaki, S., Hiraoka, A., Tada, T., Hirooka, M., Kariyama, K., Tani, J., Atsukawa, M., Takaguchi, K., Itobayashi, E., et al. (2023) · Hepatology Research · doi:10.1111/hepr.13905 · Cited by 18
“A study evaluated 1512 patients with NSCLC based on the pooled data from phase II and phase III studies, revealing that patients treated with PPIs and antibiotics showed significantly shorter PFS and OS in patients receiving atezolizumab monotherapy.16 Another study investigated the association between the concomitant…”
BackgroundInfluentialCoschi, C. H., & Juergens, R. A. (2023) · Current Oncology · doi:10.3390/curroncol31010001 · Cited by 23
“The mechanisms by which they are thought to do so are via direct or indirect effects on the host immune system [69,72,73].”
BackgroundStatin therapy: a potential adjuvant to immunotherapies in hepatocellular carcinoma
Wang, J., Liu, C., Hu, R., Wu, L., & Li, C. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1324140 · Cited by 19
Santini, D., Zeppola, T., Russano, M., Citarella, F., Anesi, C., Buti, S., Tucci, M., Russo, A., Sergi, M. C., Adamo, V., et al. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-02937-9 · Cited by 18
Self-citationBouferraa, Y., Chedid, A., Amhaz, G., Lakkiss, A. E., Mukherji, D., Temraz, S. N., & Shamseddine, A. I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22158036 · Cited by 18
“In a multicenter observational study involving 1012 treated with CPIS, PPIs were shown to be associated with a significantly higher risk of disease progression and death [88].”
BackgroundA Forgotten Corner in Cancer Immunotherapy: The Role of Lipids
Yu, Y., Gao, L., Wang, Y., Xu, B., Maswikiti, E. P., Li, H., Peng, Z., Tao, P., Xiang, L., Gu, B., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.751086 · Cited by 18
Kött, J., Zell, T., Zimmermann, N., Rünger, A., Smit, D. J., Abeck, F., Geidel, G., Hansen, I., Heidrich, I., Weichenthal, M., et al. (2024) · European Journal of Cancer · doi:10.1016/j.ejca.2024.115159 · Cited by 17
Statins and renal cell carcinoma: Antitumor activity and influence on cancer risk and survival
Santoni, M., Monteiro, F. S. M., Massari, F., Abahssain, H., Aurilio, G., Molina‐Cerrillo, J., Myint, Z. W., Ortego, I., Battelli, N., & Grande, E. (2022) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2022.103731 · Cited by 17
Deng, R., Zhang, H., Li, Y., & Shi, Y. (2022) · Journal of Immunotherapy · doi:10.1097/cji.0000000000000442 · Cited by 17
Association of Pulmonary Sepsis and Immune Checkpoint Inhibitors: A Pharmacovigilance Study
Xia, S., Gong, H., Zhao, Y., Guo, L., Wang, Y., Zhang, B., Sarangdhar, M., Noguchi, Y., & Yan, M. (2022) · Cancers · doi:10.3390/cancers15010240 · Cited by 17
“Previous studies [18,19] showed that concomitant medications, such as steroids, proton pump inhibitors (PPI), and antibiotics, might affect clinical outcomes with immune checkpoint inhibitors.”
BackgroundColard‐Thomas, J., Thomas, Q. D., & Viala, M. (2023) · Cancers · doi:10.3390/cancers15082276 · Cited by 18
“03) in a 1012-patient retrospective study [114].”
ResultMevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA
Zhang, W., Pan, X., Xu, Y., Guo, H., Zheng, M., Chen, X., Wu, H., Luan, F., He, Q., Ding, L., et al. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.04.002 · Cited by 17
Scarpa, J. R., Montagna, G., Plitas, G., Gulati, A., Fischer, G. W., & Mincer, J. S. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1267532 · Cited by 17
Statin Use With Immune Checkpoint Inhibitors and Survival in Nonsmall Cell Lung Cancer
Marrone, M. T., Reuss, J. E., Crawford, A., Neelon, B., Liu, J. O., Brahmer, J. R., & Platz, E. A. (2024) · Clinical Lung Cancer · doi:10.1016/j.cllc.2024.12.008 · Cited by 17
Cesano, A., Augustin, R. C., Barrea, L., Bedognetti, D., Bruno, T. C., Carturan, A., Hammer, C., Ho, W. S., Kather, J. N., Kirchhoff, T., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-008876 · Cited by 20
Recent advances in primary resistance mechanisms against immune checkpoint inhibitors
Li, Y.-Z., & Zhang, H.-M. (2021) · Current Opinion in Oncology · doi:10.1097/cco.0000000000000802 · Cited by 17
Rebuzzi, S. E., Banna, G. L., Murianni, V., Damassi, A., Giunta, E. F., Fraggetta, F., Giorgi, U. D., Cathomas, R. L., Rescigno, P., Brunelli, M., et al. (2021) · Cancers · doi:10.3390/cancers13215517 · Cited by 17
Leveraging beneficial microbiome-immune interactions via probiotic use in cancer immunotherapy
Jani, C., Edwards, K., Bhanushali, C. D., Zheng, X. X., Salazar, A. S., Lopes, G. D. L., Jr., & Watson, D. C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1713382 · Cited by 19
Cardiovascular Effects of Immune Checkpoint Inhibitors: More Than Just Myocarditis
Inno, A., Tarantini, L., Parrini, I., Spallarossa, P., Maurea, N., Bisceglia, I., Silvestris, N., Russo, A. D., & Gori, S. (2023) · Current Oncology Reports · doi:10.1007/s11912-023-01411-7 · Cited by 17
Self-citationChorti, E., Kowall, B., Hassel, J. C., Schilling, B., Sachse, M., Gutzmer, R., Loquai, C., Kähler, K. C., Hüsing, A., Gilde, C., et al. (2024) · European Journal of Cancer · doi:10.1016/j.ejca.2024.113536 · Cited by 16
Metadata
- Authors
- Cortellini, A., Tucci, M., Adamo, V., Stucci, L. S., Russo, A., Tanda, E. T., Spagnolo, F., Rastelli, F., Bisonni, R., Santini, D., Russano, M., Anesi, C., Giusti, R., Filetti, M., Marchetti, P., Botticelli, A., Gelibter, A., Occhipinti, M. A., Marconcini, R., Vitale, M. G., Nicolardi, L., Chiari, R., Bareggi, C., Nigro, O., Tuzi, A., De Tursi, M., Petragnani, N., Pala, L., Bracarda, S., Macrini, S., Inno, A., Zoratto, F., Veltri, E., Di Cocco, B., Mallardo, D., Vitale, M. G., Pinato, D. J., Porzio, G., Ficorella, C., & Ascierto, P. A.
- Affiliations
- University of L'Aquila (IT)
- Istituto Tumori Bari (IT)
- University of Messina (IT)
- University of Bari Aldo Moro (IT)
- Ospedale Policlinico San Martino (IT)
- Medical Oncology, ASUR District Area 4 Fermo, Fermo, Italy
- Università Campus Bio-Medico (IT)
- Azienda Ospedaliera Sant'Andrea (IT)
- Policlinico Umberto I (IT)
- Sapienza University of Rome (IT)
- Azienda Ospedaliera Universitaria Pisana (IT)
- Azienda Ospedaliero-Universitaria di Modena (IT)
- UOC Oncologia Padova Sud, Azienda ULSS 6 Euganea, Padova, Italy
- Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT)
- Ospedale di Circolo e Fondazione Macchi (IT)
- Department of Medical, Oral and Biotechnological Sciences, Gabriele d'Annunzio University of Chieti and Pescara, Chieti, Italy
- University of Chieti-Pescara (IT)
- European Institute of Oncology (IT)
- Medical Oncology, Azienda Ospedaliera S. Maria, Terni, Italy
- Azienda Ospedaliera S.Maria (IT)
- Ospedale Sacro Cuore Don Calabria (IT)
- Ospedale Santa Maria Goretti (IT)
- Medical Oncology, Santa Maria Goretti Hospital, Latina, Italy
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- Hammersmith Hospital (GB)
- Medical Oncology, St. Salvatore Hospital, L'Aquila, Italy
- Corresponding author
- Cortellini, Alessio
- ORCID
- Cortellini, Alessio
- Tucci, Marco
- Adamo, Vincenzo
- Stucci, Luigia Stefania
- Russo, Alessandro
- Tanda, Enrica Teresa
- Spagnolo, Francesco
- Bisonni, Renato
- Santini, Daniele
- Russano, Marco
- Giusti, Raffaele
- Filetti, Marco
- Marchetti, Paolo
- Botticelli, Andrea
- Gelibter, Alain
- Occhipinti, Mario Alberto
- Marconcini, Riccardo
- Vitale, Maria Giuseppa
- Nicolardi, Linda
- Chiari, Rita
- Nigro, Olga
- Petragnani, Nicola
- Pala, Laura
- Macrini, Serena
- Inno, Alessandro
- Zoratto, Federica
- Veltri, Enzo
- Mallardo, Domenico
- Vitale, Maria Grazia
- Pinato, David James
- Porzio, Giampiero
- Ficorella, Corrado
- Ascierto, Paolo Antonio
- Venue
- Journal for ImmunoTherapy of Cancer
- Publisher
- BMJ
- Published
- 2020-11
- Volume
- 8
- Issue
- 2
- Pages
- e001361
- ISSN
- 2051-1426 (ISSN-L)
- PMC
- PMC7646355
- OpenAlex
- W3097304584
- Cited by
- 275
- References
- 58
- Citations by year
- 2026: 36 · 2025: 46 · 2024: 50 · 2023: 56 · 2022: 50 · 2021: 36 · 2020: 1
- FWCI
- 12.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by-nc)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by-nc)
- Funders
- Institute for Translational Medicine and Therapeutics
- Wellcome Trust (PS3416)
- Cancer Research UK
- National Institute for Health and Care Research
- Imperial Experimental Cancer Medicine Centre
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Ferroptosis and cancer prognosis
- Health Sciences › Medicine › Oncology › COVID-19 and healthcare impacts
- Keywords
- PD-1/PD-L1 inhibitors, immune checkpoint inhibitors, concomitant medications, drug-drug interactions, corticosteroids, proton pump inhibitors, statins, aspirin, beta-blockers, antibiotics, objective response rate, progression-free survival, overall survival, non-small cell lung cancer, melanoma, renal cell carcinoma, stage IV cancer, immunotherapy safety
- MeSH terms
- Immune Checkpoint Inhibitors, Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Retrospective Studies, Young Adult
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