Comparative Analysis of Antibiotic Exposure Association with Clinical Outcomes of Chemotherapy Versus Immunotherapy Across Three Tumour Types

In solid tumours, antibiotic use during immune checkpoint inhibitor (ICI) treatment is associated with shorter survival. Following allogeneic haematopoietic cell transplantation (allo-HCT), antibiotic-induced gut microbiome alterations are associated with risk of relapse and mortality.

These findings suggest that the gut microbiota can modulate antitumour immune response across tumour types, though it is not clear if the impact on outcomes is specific to immune therapy. An important limitation of previous studies is that the analysis combined all antibiotic exposures irrespective of the antibiotic spectrum of activity. Whether antibiotic exposure during induction chemotherapy in acute myeloid leukaemia (AML) affects risk of relapse is also unknown.

We performed a single-centred retrospective analysis of antibiotic exposures in metastatic/advanced non-small cell lung cancer (NSCLC) and renal cell cancer (RCC) receiving ICI and newly diagnosed AML patients receiving induction chemotherapy achieving a complete remission 1. Antibiotic use within 4 weeks before and 6 weeks after the ICI initiation were included. In AML patients, antibiotic exposures between days 1 and 28 of induction were collected. Antibiotics were a priori stratified based on spectrum of activity. Primary outcomes of interest were progression-free survival (PFS), overall survival (OS) in NSCLC and RCC and relapse-free survival (RFS) in AML.

140 patients with NSCLC, 55 with RCC and 143 with AML were included. In multivariable analysis, PFS and OS were shorter in NSCLC patients who received broad-spectrum anti-anaerobes (PFS, HR=3.2, 95% CI 1.6 to 6.2, p<0.01; OS, HR=1.7, 95% CI 0.8 to 3.6, p=0.19) or 'other' antibiotics (vancomycin-predominant) (PFS, HR=2.4, 95% CI 1.3 to 4.6, p<0.01; OS, HR=2.4, 95% CI 1.2 to 4.7, p=0.01). In RCC, patients who received penicillins/penicillin-class/early-generation cephalosporins had shorter PFS (HR=3.6, 95% CI 1.7 to 7.6, p<0.01) but similar OS (p=0.37). In the AML cohort, none of the exposures were associated with RFS.

In contrast to AML, antibiotic exposures in solid tumours affected clinical outcomes. The presence of an allogeneic effect (allo-HCT) or an augmented immune system (checkpoint blockade) may be necessary for microbiota mediation of relapse risk.

Key questions

What is already known?
  • Antibiotics have been previously shown to negatively affect treatment outcomes of immune checkpoint blockers in solid tumours and associated with risk of leukaemia relapse post-allogeneic haematopoietic cell transplant.

What does this study add?
  • We tested the effect of exposure to different antibiotic subclasses based on spectrum of activity on clinical outcomes of immune checkpoint blocker in non-small cell lung cancer (NSCLC) and renal cell cancer (RCC) and tested the risk of relapse-free survival (RFS) in acute myeloid leukaemia (AML) following induction chemotherapy.
  • We found that NSCLC patients who received broad-spectrum anti-anaerobes (most commonly piperacillin-tazobactam) or intravenous vancomycin had shorter progression-free survival (PFS) and overall survival.
  • RCC patients who received penicillins, penicillin-class or early-generation cephalosporins had the greatest impact on PFS. In AML, none of the antibiotic exposures were associated with RFS.

How might this impact on clinical practice?

  • Antibiotics-induced gut microbiome dysbiosis can influence clinical outcomes of immunotherapy in solid tumours. The impact might be dependent on the type of antibiotic used and its spectrum of activity.

ESMO open. 2020 Sep [Epub]

Amit A Kulkarni, Maryam Ebadi, Shijia Zhang, Mohamad A Meybodi, Alaa M Ali, Todd DeFor, Ryan Shanley, Daniel Weisdorf, Charles Ryan, Sumithira Vasu, Armin Rashidi, Manish Ramesh Patel

Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA., Hematology, Oncology and Transplantation, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA., Biostatistics Core, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA., Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota, USA .

Source: Kulkarni AA, Ebadi M, Zhang S, et alComparative analysis of antibiotic exposure association with clinical outcomes of chemotherapy versus immunotherapy across three tumour typesESMO Open 2020;5:e000803. doi: 10.1136/esmoopen-2020-000803