In a study presented in a brief report in JAMA Oncology,1 David J. Pinato, MD, PhD, of the Imperial College London, and colleagues found that past—but not concurrent—use of broad-spectrum antibiotic therapy was associated with poorer treatment outcomes in patients receiving immune checkpoint inhibitors for various cancers in routine clinical practice. As stated by the investigators, “Gut dysbiosis impairs response to immune checkpoint inhibitors and can be caused by broad-spectrum antibiotic therapy.”
The study involved 196 patients with non–small cell lung cancer (NSCLC, n = 119), melanoma (n = 38), and other tumor types (n = 39) consecutively treated with immune checkpoint inhibitors in routine clinical practice at two UK academic medical centers (Imperial College NHS Trust and Chelsea and Westminster NHS Foundation Trust) between January 2015 and January 2018. Past broad-spectrum antibiotic use was defined as use within 30 days before the start of therapy with immune checkpoint inhibitors. Disease refractory to immune checkpoint inhibitors was defined as progressive disease 6 to 8 weeks after the first dose of immunotherapy without evidence of pseudoprogression. Most patients were men (70%), had disseminated disease at the start of therapy with immune checkpoint inhibitors (84%), had a performance status of 0 to 1 (81%), had received anti–programmed cell death 1/programmed cell death ligand 1 immune checkpoint inhibitors (96%) as first-line metastatic therapy (62%), and had received no corticosteroid treatment (74%).
Association of Past Antibiotic Use and Outcomes
Overall, 29 patients had used broad-spectrum antibiotics in the past (26 for ≤ 7 days), and 68 received antibiotic treatment concurrently with immune checkpoint inhibitors (39 for ≤ 7 days). Most patients received β-lactam–based antibiotics (20 in the past-treatment group, 46 in concurrent-treatment group). The most common indication for antibiotic use was respiratory tract infection (17 in the past-treatment group and 40 in the concurrent-treatment group). All patients in the past-treatment group received one course of antibiotic treatment; 24 patients in the concurrent-treatment group received more than one course of treatment. Past antibiotic use was not associated with corticosteroid use up to 30 days prior to or during immune checkpoint inhibitor therapy.
Prior antibiotic therapy was associated with significantly poorer overall survival vs no antibiotic therapy (hazard ratio [HR] = 7.4, P < .001). Concurrent antibiotic therapy was not significantly associated with overall survival vs no antibiotic therapy (HR = 0.9, P = .65). The median overall survival was 2 months vs 26 months with prior antibiotic treatment vs no prior antibiotic treatment among all patients. The median overall survival was poorer among patients with vs without prior antibiotic treatment in NSCLC (2.5 vs 26 months, P < .001), melanoma (3.9 vs 14 months, P < .001), and other tumor types (1.1 vs 11, P < .001).
[Past antibiotic] therapy but not [concurrent antibiotic] therapy is associated with a worse treatment response and [overall survival] in unselected patients treated with immune checkpoint inhibitors in routine clinical practice.— David J. Pinato, MD
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Among evaluable patients, poor response to immune checkpoint inhibitors was observed in 81% of those who had used antibiotics in the past vs 44% of those who did not (P < .001). Objective response vs disease progression on Response Evaluation Criteria in Solid Tumors v1.1 was observed in 5 vs 21 patients who had used antibiotics in the past and in 33 vs 33 patients who used antibiotics concurrently (P = .87 vs no use of antibiotics in the past). In the group that had used antibiotics in the past, response to immune checkpoint inhibitors was observed in 5 of 19 patients receiving beta-lactam–based antibiotics and in 0 of 7 receiving other antibiotics.
On multivariate analysis, past antibiotic treatment (HR = 3.4, P < .001) and lack of response to immune checkpoint inhibitors (HR = 8.2, P < .001) were associated with poorer overall survival, independent of tumor site, disease burden, and performance status. In multivariate analysis using a propensity score–weighted model, the respective hazard ratios were 3.3 (P < .001) and 9.0 (P < .001). In multivariate analysis using a propensity score time-dependent model, the respective hazard ratios were 2.6 (P < .001) and 5.5 (P < .001).
The investigators concluded: “Despite being limited by sample size, geographic origin, and the lack of correlative analyses on patients’ gut microbiota, this study suggests that [past antibiotic] therapy but not [concurrent antibiotic] therapy is associated with a worse treatment response and [overall survival] in unselected patients treated with immune checkpoint inhibitors in routine clinical practice. Mechanistic studies are urgently required to investigate [antibiotic]-mediated alterations of gut microbiota as a determinant of poorer outcome following immune checkpoint inhibitor treatment.” ■
DISCLOSURE: The study was supported by the Imperial College National Institute for Health Research Biomedical Research Centre, the Imperial College Tissue Bank, and the Imperial Cancer Research UK Centre. For full disclosures of the study authors, visit jamanetwork.com.
1. Pinato DJ, Howlett S, Ottaviani D, et al: Association of prior antibiotic treatment with survival and response to immune checkpoint inhibitor therapy in patients with cancer. JAMA Oncol. September 12, 2019 (early release online).
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