Antibiotic Use May Damper the Efficacy of Checkpoint Inhibitors

Use of antibiotics up to a month before treatment with a checkpoint inhibitor may decrease the efficacy of the immunotherapy agent, results of a retrospective analysis show. The analysis, presented during a presscast of the 2017 Genitourinary Cancers Symposium, raised suspicion of the relationship between gut microbiota and antibiotics and their effect on immune checkpoint blockade agents.¹

In patients with metastatic renal cell carcinoma (mRCC), patients who had received broad-spectrum antibiotics had a shorter median progression-free survival (PFS) rate when treated with checkpoint inhibitor immunotherapy than those who had not received antibiotics of 2.3 versus 8.1 months, respectively (P <.001).

Previous preclinical studies using mouse models have suggested an association between antibiotics and the efficacy of immune checkpoint blockade agents.² “This is the first analysis evaluating the impact of antibiotics on outcome in mRCC patients treated in the era of immune checkpoint blockade,” said investigator Lisa Derosa, MD, PhD candidate, of the Gustave Roussy Cancer Institute, Paris-Sud University in Villejuif, France.

Researchers analyzed 80 patients with mRCC who were being treated with checkpoint inhibitors on trials at the Gustave Roussy institute. Immunotherapy treatments included single-agent anti—PD-1/PD-L1 therapy (n = 67), a combination of a PD-1 inhibitor and a CTLA-4 inhibitor (n = 10), and a combination of anti–PD-L1 therapy and bevacizumab (Avastin; n = 3).

A majority of the enrolled patients were male (65%), 88% had a clear-cell histology, and 80% of the patients had prior nephrectomy. Twenty-one percent had favorable disease by International mRCC Database Consortium (IMDC) risk standards, 57% had intermediate IMDC risk, and 22% had poor-risk disease. Sixteen patients (20%) had received antibiotics up to 1 month prior to starting treatment with immunotherapy, including mostly beta-lactamases or fluoroquinolones.

At a median follow-up of 6 months, overall survival (OS) results were not yet able to be reached in the overall population, but a negative trend was already noted for patients who received prior antibiotics. The objective response rate also favored patients who had not received antibiotics (P <.002).

In a subgroup of 62 patients who were treated with nivolumab (Opdivo) monotherapy, patients who had not taken antibiotics showed a greater PFS rate, which also achieved statistical significance (P <.009). OS in the nivolumab monotherapy subgroup was also significantly higher in patients who had not taken recent antibiotics (P <.003).

“Derosa shows that antibiotic therapy may have a direct impact on how well the PD-1 inhibitor nivolumab works in patients with kidney cancer,” said Sumanta K. Pal, MD, who moderated the presentation.

A multivariate analysis for prognostic risk factors showed a hazard ratio of 4.17 (95% CI, 1.92-9.08) for patients who had not received antibiotics compared with those that had taken antibiotics (P <.001). Patients with a lower Karnofsky performance statuses also showed an increased hazard ratio (HR, 5.23; 1.57-17.4; P <.005).

“Immune based therapies for cancer may have a complex interplay with the host’s microbiome,” commented Pal, an assistant clinical professor in the Department of Medical Oncology and Therapeutics Research and co-director of the Kidney Cancer Program at City of Hope in Duarte, California. “Antibiotics may influence the bacterial composition of our gut, and this could in turn impact how effective immune therapy is.”

Derosa stated that the data was preliminary but that it encouraged longer follow-up and further studies to confirm the hypothesis of the study.

“The observations that Derosa makes have some consistency with preclinical observation,” Pal said. “We may be able to offer some insights as to whether or not bacterial composition of the gut could affect clinical outcomes and that might help us guide antibiotic usage.” Pal also suggested that these findings are not yet mature enough to impact clinical practice. The researchers plan to enroll additional patients in this study to investigate the mechanism of action. Other studies exploring the relationship between antibiotics and the efficacy of immunotherapy agents in lung cancer and kidney cancer are ongoing.

References

1. Derosa L, Routy B, Enot D, et al. Impact of antibiotics on outcome in patients with metastatic renal cell carcinoma treated with immune checkpoint inhibitors. Presented at: 2017 Genitourinary Cancers Symposium; February 16-18, 2017; Orlando, FL. Abstract 462.
2. Vétizou M, Pitt JM, Daillère R, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350(6264):1079-1084. doi: 10.1126/science.aad1329.

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