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Cortellini A, Di Maio M, Nigro O, et al. Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy. J Immunother Cancer. 2021;9(4)doi: 10.1136/jitc-2021-002421.
Cortellini, A., Di Maio, M., Nigro, O., Leonetti, A., Cortinovis, D. L., Aerts, J. G., Guaitoli, G., Barbieri, F., Giusti, R., Ferrara, M. G., Bria, E., D'Argento, E., Grossi, F., Rijavec, E., Guida, A., Berardi, R., Torniai, M., Sforza, V., Genova, C., Mazzoni, F., Garassino, M. C., De Toma, A., Signorelli, D., Gelibter, A., Siringo, M., Marchetti, P., Macerelli, M., Rastelli, F., Chiari, R., Rocco, D., Della Gravara, L., Inno, A., Michele, T., Grassadonia, A., Di Marino, P., Mansueto, G., Zoratto, F., Filetti, M., Santini, D., Citarella, F., Russano, M., Cantini, L., Tuzi, A., Bordi, P., Minuti, G., Landi, L., Ricciardi, S., Migliorino, M. R., Passiglia, F., Bironzo, P., Metro, G., Adamo, V., Russo, A., Spinelli, G. P., Banna, G. L., Friedlaender, A., Addeo, A., Cannita, K., Ficorella, C., Porzio, G., & Pinato, D. J. (2021). Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy. Journal for immunotherapy of cancer, 9(4), . https://doi.org/10.1136/jitc-2021-002421
Cortellini, Alessio, et al. "Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy." Journal for immunotherapy of cancer vol. 9,4 (2021). doi: https://doi.org/10.1136/jitc-2021-002421
Cortellini A, Di Maio M, Nigro O, Leonetti A, Cortinovis DL, Aerts JG, Guaitoli G, Barbieri F, Giusti R, Ferrara MG, Bria E, D'Argento E, Grossi F, Rijavec E, Guida A, Berardi R, Torniai M, Sforza V, Genova C, Mazzoni F, Garassino MC, De Toma A, Signorelli D, Gelibter A, Siringo M, Marchetti P, Macerelli M, Rastelli F, Chiari R, Rocco D, Della Gravara L, Inno A, Michele T, Grassadonia A, Di Marino P, Mansueto G, Zoratto F, Filetti M, Santini D, Citarella F, Russano M, Cantini L, Tuzi A, Bordi P, Minuti G, Landi L, Ricciardi S, Migliorino MR, Passiglia F, Bironzo P, Metro G, Adamo V, Russo A, Spinelli GP, Banna GL, Friedlaender A, Addeo A, Cannita K, Ficorella C, Porzio G, Pinato DJ. Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy. J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2021-002421. PMID: 33827906; PMCID: PMC8031700.
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J Immunother Cancer. 2021 Apr;9(4). doi: 10.1136/jitc-2021-002421.

Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy.

Journal for immunotherapy of cancer

Alessio Cortellini, Massimo Di Maio, Olga Nigro, Alessandro Leonetti, Diego L Cortinovis, Joachim Gjv Aerts, Giorgia Guaitoli, Fausto Barbieri, Raffaele Giusti, Miriam G Ferrara, Emilio Bria, Ettore D'Argento, Francesco Grossi, Erika Rijavec, Annalisa Guida, Rossana Berardi, Mariangela Torniai, Vincenzo Sforza, Carlo Genova, Francesca Mazzoni, Marina Chiara Garassino, Alessandro De Toma, Diego Signorelli, Alain Gelibter, Marco Siringo, Paolo Marchetti, Marianna Macerelli, Francesca Rastelli, Rita Chiari, Danilo Rocco, Luigi Della Gravara, Alessandro Inno, De Tursi Michele, Antonino Grassadonia, Pietro Di Marino, Giovanni Mansueto, Federica Zoratto, Marco Filetti, Daniele Santini, Fabrizio Citarella, Marco Russano, Luca Cantini, Alessandro Tuzi, Paola Bordi, Gabriele Minuti, Lorenza Landi, Serena Ricciardi, Maria R Migliorino, Francesco Passiglia, Paolo Bironzo, Giulio Metro, Vincenzo Adamo, Alessandro Russo, Gian Paolo Spinelli, Giuseppe L Banna, Alex Friedlaender, Alfredo Addeo, Katia Cannita, Corrado Ficorella, Giampiero Porzio, David J Pinato

Affiliations

  1. Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK [email protected].
  2. Department of Biotechnology and Applied Clinical Science, University of L'Aquila, L'Aquila, Italy.
  3. Department of Oncology and Medical Oncology, University of Turin and AO Ordine Mauriziano, Turin, Italy.
  4. Medical Oncology, ASST dei Sette Laghi, Varese, Italy.
  5. Medical Oncology, University Hospital of Parma, Parma, Italy.
  6. Medical Oncology, Azienda Ospedaliera San Gerardo, Monza, Italy.
  7. Department of Pulmonary Disease, Erasmus Medical Center, Rotterdam, Netherlands.
  8. Dipartimento di Oncologia ed Ematologia, AOU Policlinico di Modena, Modena, Italy.
  9. Medical Oncology Unit, Sant'Andrea Hospital of Rome, Roma, Italy.
  10. Comprehensive Cancer Center, Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS, Roma, Italy.
  11. Department of Translational Medicine and Surgery, Universitá Cattolica del Sacro Cuore, Roma, Italy.
  12. Division of Medical Oncology, University of Insubria, Varese, Italy.
  13. Medical Oncology, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico, Milan, Italy.
  14. Struttura Complessa di Oncologia Medica e Traslazionale, Azienda Ospedaliera Santa Maria di Terni, Terni, Italy.
  15. Oncology Clinic, Università Politecnica delle Marche, Ospedali Riuniti di Ancona, Ancona, Italy.
  16. Thoracic Medical Oncology, National Cancer Institute IRCCS Pascale Foundation, Napoli, Italy.
  17. Lung Cancer Unit, IRCCS Ospedal Policlinico San Martino, Genova, Italy.
  18. Department of Medical Oncology, Careggi University Hospital, Firenze, Toscana, Italy.
  19. Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
  20. Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.
  21. Medical Oncology Unit B, Policlinico Umberto I, Sapienza University of Rome, Roma, Italy.
  22. Department of Clinical and Molecular Medicine, Sapienza University of Rome, Roma, Italy.
  23. Medical Oncology, University Hospital Santa Maria della Misericordia, Udine, Italy.
  24. Medical Department, ASUR Area Vasta 4, Fermo, Italy.
  25. Medical Oncology, Ospedali riuniti Padova Sud "Madre Teresa Di Calcutta", Monselice, Padova, Italy.
  26. Pneumo-Oncology Unit, Ospedali dei Colli Monaldi Cotugno CTO, Napoli, Italy.
  27. Oncology Unit, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Italy.
  28. Dipartimento di Terapie Innovative in Medicina ed Odontoiatria, Universitá G. D'Annunzio, Chieti-Pescara, Italy.
  29. Clinical Oncology Unit, SS Annunziata Hospital, Chieti, Italy.
  30. Medical Oncology, Azienda Sanitaria Locale Frosinone, Frosinone, Italy.
  31. Medical Oncology, Ospedale Santa Maria Goretti, Latina, Italy.
  32. Medical Oncology, Campus Bio-Medico University, Roma, Italy.
  33. Department of Oncology and Hematology, AUSL della Romagna, Ravenna, Italy.
  34. Pneumo-Oncology Unit, San Camillo Forlanini Hospital, Roma, Italy.
  35. Department of Oncology, San Luigi Gonzaga University Hospital, Orbassano, Italy.
  36. Department of Oncology, San Luigi Hospital, Orbassano, Italy.
  37. Department of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
  38. Medical Oncology and Department of Human Pathology, Azienda Ospedaliera Papardo and Università degli Studi di Messina, Messina, Italy.
  39. UOC Territorial Oncology of Aprilia, AUSL Latina, Sapienza University of Rome, Aprilia, Italy.
  40. Medical Oncology, Portsmouth University Hospitals NHS Trust, Portsmouth, UK.
  41. Oncology Department, University Hospital of Geneva, Geneve, Switzerland.
  42. Medical Oncology, San Salvatore Hospital, L'Aquila, Italy.
  43. Division of Cancer, Department of Surgery and Cancer, Imperial College London, London, UK.
  44. Department of Translational Medicine, Universitá del Piemonte Orientale "A. Avogadro", Novara, Italy.

PMID: 33827906 PMCID: PMC8031700 DOI: 10.1136/jitc-2021-002421

Abstract

BACKGROUND: Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate.

METHODS: We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses.

RESULTS: 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate.

CONCLUSION: In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords: immunotherapy; lung neoplasms

Conflict of interest statement

Competing interests: AC received speaker fees and grant consultancies by Astrazeneca, MSD, BMS, Roche, Novartis, Istituto Gentili and Astellas. RG received speaker fees and grant consultancies by Astr

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