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Impact of intestinal dysbiosis-related drugs on the efficacy of immune checkpoint inhibitors in clinical practice

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Abstract

Purpose

Intestinal dysbiosis has emerged as a biomarker of response to immune checkpoint inhibitors (ICIs). It can be caused by antibiotics, although it may also result from the use of other drugs that have been studied to a lesser extent. The objective of our study was to analyze the association between the use of potentially dysbiosis-related drugs and survival in patients treated with ICIs in the clinical practice.

Materials and methods

A retrospective, multicenter, cohort study was conducted. Clinicopathological variables were collected and the concomitant use of drugs was analyzed. A descriptive analysis of variables and overall survival, estimated by the Kaplan–Meier method, was performed, and association with various independent variables was assessed using Cox regression.

Results

We included 253 patients, mainly with non-small cell lung cancer and melanoma. The most commonly used drugs were acid reducers, prescribed to 55.3% of patients, followed by corticosteroids (37.9%), anxiolytic drugs (35.6%), and antibiotics (20.5%). The use of acid reducers (9 vs. 18 months, P < .0001), antibiotics (7 vs. 15 months, P < .017), anxiolytic drugs (8 vs. 16 months, P < .015), and corticosteroids (6 vs. 19 months, P < .00001) was associated with poorer overall survival. Furthermore, the greater the number of drugs used concomitantly with ICIs, the higher the risk of death (1 drug: hazard ratio, 1.88; CI 95%, 1.07–3.30; 4 drugs: hazard ratio, 4.19; CI9 5%, 1.77–9.92; P < .001).

Conclusion

Response to ICIs may be influenced by the use of drugs that lead to intestinal dysbiosis. Although a confirmatory prospective controlled study is required, our findings should be taken into account when analyzing ICI efficacy.

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References

  1. Garrett WS. Cancer and the microbiota. Science. 2015;348(6230):80–6.

    Article  CAS  Google Scholar 

  2. Tan J. Immunotherapy meets microbiota. Cell. 2015;163(7):1561. https://doi.org/10.1016/j.cell.2015.12.009.

    Article  CAS  Google Scholar 

  3. Robert C, Tomas L, Bondarenko I, et al. Ipilimumab plus dacarbacine for previously untreated metastatic melanoma. N Engl J Med. 2011;364:2517–26.

    Article  CAS  Google Scholar 

  4. Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373(13):1270–1.

    Article  Google Scholar 

  5. Ribas A, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–18.

    Article  CAS  Google Scholar 

  6. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:26.

    Article  Google Scholar 

  7. Borghaei H, Paz-Ares L, Horn L. Nivolumab versus docetaxel in advanced nonsquamous non–small-cell lung cancer. N Engl J Med. 2015;373:1627–39.

    Article  CAS  Google Scholar 

  8. Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non– small-cell lung cancer. N Engl J Med. 2015;373(2):123–35.

    Article  CAS  Google Scholar 

  9. Reck M, Rodriguez-Abreu D, Robison A, et al. Pembrolizumab versus chemotherapy for PD-L1 positive non-small-cell lung cancer. N Engl J Med. 2016;10;375(19):1823–33.

    Article  CAS  Google Scholar 

  10. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and necK. N Eng J Med. 2016;375(19):1856–67.

    Article  Google Scholar 

  11. Blank C, Haanen JB, Ribas A, Schumacher TN. The “cancer immunogram”. Science. 2016;353:658–60.

    Article  Google Scholar 

  12. Viaud S, Saccheri F, Mignot G, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6.

    Article  CAS  Google Scholar 

  13. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079–84.

    Article  Google Scholar 

  14. Sivan A, Corrales L, Hubert N, et al. Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science. 2015;350(6264):1084–9.

    Article  CAS  Google Scholar 

  15. Routy B, Le Chatelier E, Derosa L, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epitelial tumors. Science. 2018;359(6371):91–7.

    Article  Google Scholar 

  16. Derosa L, Hellmann MD, Spaziano M, et al. Negative association of antibiotics on clinical activity of immune check-point inhibitors in patients with advanced renal cell and non-small-cell lung cancer. Ann Oncol. 2018;29:1437–44.

    Article  CAS  Google Scholar 

  17. Iida N, Dzutsev A, Stewart CA, et al. Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science. 2013;342(6161):967–70.

    Article  CAS  Google Scholar 

  18. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature. 2018;555:623–8.

    Article  CAS  Google Scholar 

  19. Rogers MAM, Aronoff DM. The influence of nonsteroidal anti-inflammatory drugs on the gut microbiome. Clin Microbiol Infect. 2016;22:178.e1–9.

    Article  CAS  Google Scholar 

  20. Jacckson MA, Goodrich JK, Maxan ME, et al. Proton pump inhibitors alter the composition of the gut microbiota. Gut. 2016;65:749–56.

    Article  Google Scholar 

  21. Dominianni C, Sinha R, Goedert J, et al. Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PLoS ONE. 2015;10(4):e0124599.

    Article  Google Scholar 

  22. Forslund K, Hildebrand F, Nielsen T, et al. Disentangling the effects of type 2 diabetes and metformin on the human gut microbiota. Nature. 2015;528:262–6.

    Article  CAS  Google Scholar 

  23. Matson V, Fessler J, Bao R, et al. The comensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–8.

    Article  CAS  Google Scholar 

  24. Chaput N, Lepage P, Coutzac C, et al. Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab. Ann Oncol. 2017;28(6):1368–79. https://doi.org/10.1093/annonc/mdx108.

    Article  CAS  Google Scholar 

  25. Freeman-Keller M, Kim Y, Cronin H, et al. Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res. 2016;22:886–94.

    Article  CAS  Google Scholar 

  26. Conforti F, Pala L, Bagnardi V, et al. Cancer immunotherapy efficacy and patients’ sex: a systematic review and meta-analysis. Lancet Oncol. 2018;19(6):737–46. https://doi.org/10.1016/S1470-2045(18)30261-4Epub 2018 May 16.

    Article  CAS  PubMed  Google Scholar 

  27. Jakobsson HE, Jernberg C, Andersson AF, et al. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome. PLoS ONE. 2010;5:e9836.

    Article  Google Scholar 

  28. Arbour KC, Mezquita L, Long N, et al. Presented at the ASCO Meeting, Chicago, 2018. J Clin Oncol 36(suppl; abstr 9003).

  29. Scott SC, Pennell NA. Brief report: early use of systemic corticosteroids in patients with advanced NSCLC treated with nivolumab. J Thorac Oncol. 2018. https://doi.org/10.1016/j.jtho.2018.06.004.

    Article  PubMed  Google Scholar 

  30. Kaderbhai C, Richard C, Fumet JD, et al. Antibiotic use does not appear to influence response to nivolumab. Anticancer Res. 2017;37:3195–200.

    CAS  PubMed  Google Scholar 

  31. Horvat TZ, Adel NG, Dang TO, et al. Immune-related adverse events, need for systemic immunosuppression, and effects on survival and time to treatment failure in patients with melanoma treated with ipilimumab at Memorial Sloan Kettering Cancer Center. J Clin Oncol. 2015;33:3193–8.

    Article  CAS  Google Scholar 

  32. Ko HH, et al. Statins: antimicrobial resistance breakers or makers? PeerJ. 2017;5:e3952. https://doi.org/10.7717/peerj.3952.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We appreciate the support of the Research Unit of the Agencia Sanitaria Costa del Sol for the translation of the manuscript.

Funding

None.

Author information

Authors and Affiliations

  1. Oncology Department, Hospital Costa del Sol, Autovía A-7, Km 187, C.P. 29603, Marbella, Málaga, Spain

    E. Pérez-Ruiz & R. Villatoro Roldan

  2. Oncology Department, Hospital Virgen del Rocío, Seville, Spain

    J. Jiménez-Castro & B. Pérez-Valderrama

  3. Interinstitutional Oncology Unit, Institute of Biomedical Research in Málaga (IBIMA), Hospitales Universitarios Regional y Virgen de la Victoria (HURyVV), Malaga, Spain

    M.-A. Berciano-Guerrero & A. Rueda

  4. Oncology Department, Hospital Virgen de las Nieves, Granada, Spain

    J. Valdivia

  5. Oncology Department, Hospital Puerta del Mar, Cádiz, Spain

    S. Estalella-Mendoza

  6. Oncology Department, Hospital Juan Ramón Jiménez, Huelva, Spain

    F. Toscano

  7. Oncology Department, Hospital de Valme, Seville, Spain

    M. Rodriguez de la Borbolla Artacho

  8. Pharmacy Department, Hospital Costa del Sol, Marbella, Spain

    M. Garrido-Siles

  9. Pharmacy Department, Hospital Puerta del Mar, Cádiz, Spain

    M. J. Martínez-Bautista

  10. Research Support Unit, Hospital Costa del Sol, Marbella, Spain

    F. Rivas-Ruiz

  11. Oncology Department, Hospital Virgen Macarena, Seville, Spain

    E. Nogales-Fernández & L. De la Cruz-Merino

  12. Oncology Department, Hospital Reina Sofía, Córdoba, Spain

    C. Morales

Authors
  1. E. Pérez-Ruiz
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  8. M. Garrido-Siles
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Contributions

Conceptualization: EPR, LCM, AR. Data curation: JJC, MABG, JV, SE, FT, MR, MG, RV, MJM, FRR, EN, CM, BPV. Formal analysis: FRR, EPR, AR. Investigation methodology: FRR, EPR, LCM, AR. Validation: EPR; JJC, MABG, JV, SE, FT, MR, MG, RV, MJM, FRR, EN, CM, BPV. Writing original draft: EPR, AR, LCM.

Corresponding author

Correspondence to E. Pérez-Ruiz.

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Conflict of interest

There is no conflict of interest.

Ethical approval

The present study was approved by the Research Ethics Committee of Costa del Sol Hospital.

Informed consent

For this type of study, formal consent is not required.

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E. Pérez-Ruiz, S. Estalella, F. Toscano, E. Nogales, C. Morales, B. Pérez-Valderrama, L. de la Cruz-Merino: On behalf of the Immunotherapy Subcommittee of the Andalusian Clinical Oncology Society (SAOM).

E. Pérez-Ruiz, F. Rivas-Ruiz: Health Service Research Network on Chronic Diseases (REDISSEC).

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Pérez-Ruiz, E., Jiménez-Castro, J., Berciano-Guerrero, MA. et al. Impact of intestinal dysbiosis-related drugs on the efficacy of immune checkpoint inhibitors in clinical practice. Clin Transl Oncol 22, 1778–1785 (2020). https://doi.org/10.1007/s12094-020-02315-9

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  • DOI: https://doi.org/10.1007/s12094-020-02315-9

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