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Antibiotic Treatment Prior to Immune Checkpoint Inhibitor Therapy Shows Detrimental Effect on Response and Survival


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USE OF ANTIBIOTICS prior to checkpoint blockade therapy may attenuate anticancer activity, according to data presented at the 2019 ASCO–Society for Immunotherapy of Cancer (SITC) Clinical Immuno-Oncology Symposium.1 Results of the multicenter study suggest that antibiotic therapy administered within 1 month prior to treatment with immune checkpoint inhibitors exerts an independent detrimental effect on response and survival. A retrospective analysis of unselected patients treated in routine clinical practice showed that those with prior antibiotic exposure had significantly worse median overall survival following immune checkpoint blockade compared to antibiotic-naive patients (2 months vs 26 months, P < .001).


“These data are quite interesting in showing an independent detrimental effect [of antibiotics] both on response and survival in unselected patients treated with immune checkpoint inhibitors in routine clinical practice….”
— David J. Pinato, MD, PhD, MRCP

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“These data are quite interesting in showing an independent detrimental effect [of antibiotics] both on response and survival in unselected patients treated with immune checkpoint inhibitors in routine clinical practice,” said David J. Pinato, MD, PhD, MRCP, Senior Clinical Lecturer and Consultant Medical Oncologist in the Department of Surgery and Cancer at Imperial College, London. “In addition, the lack of prognostic effect for concurrent antibiotic treatment suggests that the timing of antibiotic exposure is crucial, as though there is a ‘priming effect’ toward the immune system. Finally, these data suggest the safety of concurrent antibiotic treatment in patients treated with immunotherapy.”

Patient Selection Is Key

AS DR. PINATO explained, immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and many other key regulators of the immune system, have revolutionized cancer care by affording good overall response and prolongation of survival across multiple tumor types. However, the pharmacodynamics of these agents are still poorly understood and the efficacy of this treatment is limited to a fraction of patients. Patient selection is therefore key, said Dr. Pinato, to spare patients from potentially life-threatening immunotoxicity in the absence of therapeutic benefit.

“We know that part of the efficacy of immune checkpoint inhibitors strongly relies on the influence of the microbiome and that gut microbial diversity enhances mucosal immunity, dendritic cell function, and antigen presentation,” he observed. “In addition, there have been numerous reports in the literature suggesting that enrichment in a particular type of stool microbiota can enhance the potency of immune checkpoint inhibitors by facilitating tumor rejection. We also know that broad-spectrum antibiotics can completely abrogate such microbial diversity and induce protracted gut dysbiosis.”

Despite these connections, the impact of antibiotic-induced dysbiosis on outcomes from immune checkpoint inhibitors has never been prospectively tested in routine clinical practice. Investigators thus sought to analyze whether broad-spectrum antibiotic exposure might impact responsiveness irrespective of tumor sites and whether there would be any time dependency in such a phenomenon between antibiotic exposure and response to checkpoint inhibitors.

Study Design

FOR THIS observational study, Dr. Pinato and colleagues used a prospectively maintained data set of patients treated with immune checkpoint inhibitors between 2015 and 2018 at 2 tertiary academic centers in London (N = 196). The majority of enrolled patients had non–small cell lung cancer (NSCLC; n = 119), but patients with melanoma (n = 38) as well as urologic and head and neck cancers were also included in the analysis. The researchers qualified prior antibiotic exposure using a time frame of 30 days from the first day of immune checkpoint inhibitor treatment or concurrent antibiotic treatment from the first day of immune checkpoint inhibitor treatment until cessation.

Most patients had metastatic disease at checkpoint inhibitor initiation, and the median number of metastatic sites was 2 (range = 0–7). The vast majority of patients (96%) received anti–PD-1/programmed cell death ligand 1 (PD-L1) therapy alone. Prior to checkpoint inhibitor therapy, 29 patients (15%) received antibiotics, whereas 68 patients (35%) received antibiotics concurrently.

 

ANTIBIOTICS AND IMMUNOTHERAPY

  • Results of a multicenter study suggest that antibiotic therapy administered within 1 month prior to treatment with immune checkpoint inhibitors exerts an independent detrimental effect on response and survival in unselected patients treated in routine clinical practice.
  • However, antibiotic treatment administered concurrently with immune checkpoint inhibitors was not associated with worse overall survival.

Beta-lactams were the most prevalent antibiotic class, and they were given mostly for a short course (less than 7 days) and, in all cases, in a single course. When antibiotics were administered concurrently with immunotherapy, said Dr. Pinato, patients tended to be treated longer and with multiple courses. Respiratory infections were the most common indication for both prior and concurrent antibiotic treatment.

Antibiotics Linked to Impact on Survival

AS DR. PINATO reported, the analysis showed that prior antibiotic treatment had a significant adverse effect on overall survival, with a median survival of only 2 months for those with prior exposure vs 26 months for antibiotic-naive patients (hazard ratio [HR] = 7.4, P < .001). In patients who had received prior antibiotic treatment, the likelihood of primary refractoriness to immune checkpoint inhibitors increased from 44% to 81% (P < .001). An additional subanalysis also indicated that signals for worse overall survival were preserved irrespective of tumor site. Prior antibiotic treatment was associated with worse overall survival in NSCLC (26 vs 2.5 months, P < .001), melanoma (14 vs 3.9 months, P < .001), and other tumors (11 vs 1.1 months, P < .001).

However, antibiotic treatment administered concurrently with immune checkpoint inhibitors was not associated with worse overall survival. According to the authors, mechanistic studies are urgently required to investigate antibiotic-mediated alterations of gut microbiota as a determinant of poorer outcome following treatment with immune checkpoint inhibitors.

“We need to investigate not just the prognostic role of antibioticmediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity.”
— David J. Pinato, MD, PhD, MRCP

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“Alexander Fleming, who discovered penicillin in St. Mary’s Hospital, one of the Imperial College–affiliated hospitals, said ‘never neglect an extraordinary appearance or happening,’” Dr. Pinato concluded. “We need to investigate not just the prognostic role of antibiotic-mediated dysbiosis, but perhaps transform this into an actual driver of antitumor immunity.”

DISCLOSURE: Dr. Pinato has received research funding from Bristol-Myers Squibb, Merck Sharp & Dohme and is a paid speaker for ViiV Healthcare.

REFERENCE

1. Pinato DJ, Howlett S, Ottaviani D, et al: Antibiotic treatment prior to immune checkpoint inhibitor therapy as a tumor-agnostic predictive correlate of response in routine clinical practice. 2019 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 147. Presented March 1, 2019.


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