麻豆传媒

ORLANDO -- Recent antibiotic therapy had a significant association with worse progression-free survival (PFS) in patients with metastatic renal cell carcinoma (mRCC) treated with an immune checkpoint inhibitor, a retrospective analysis of clinical trial records showed.

Patients who received antibiotics within a month before the start of anti-PD-1/PD-L1 therapy had a median PFS 2.3 months as compared with 8.1 months for patients without recent antibiotic therapy. The association remained significant in a multivariate analysis that controlled for a variety of demographic and clinical factors.

Overall survival data for the patients remained immature, but a trend toward worse survival emerged in the antibiotic group, according to a preliminary analysis, as reported at the (GUCS).

"This is the first analysis evaluating the impact of antibiotics on outcome in metastatic renal cell carcinoma patients treated in the era of immune checkpoint blockade," , of Gustave Roussy Institute in Villejuif, France, said during a press briefing prior to GUCS, which begins here Thursday. "The mechanisms behind this negative effect are under exploration. Further studies are warranted to investigate whether the alteration of gut microbiota compositions is responsible for this different outcome."

Investigators believe that antibiotics may worsen outcome in immunotherapy-treated cancers by "wiping out the good bacteria" in the gut, she said.

The data are thought provoking and warrant further evaluation in a larger number of patients and across different tumor types, said , of Dana-Farber Cancer Institute in Boston.

"The link to the microbiota could be real but is also very complex," said Choueiri, who was not involved in the study. "There are data that the intestinal microbiota modulates the (Yervoy), another immune checkpoint blocker. Antibiotics can change the microbiota composition and kill some bacteria important for the activity of the drug."

Asked whether the results might apply only to mRCC, Choueiri added, "It is hard to justify that this is just related to RCC only because of the biology of RCC, compared to melanoma or other tumors."

Derosa agreed. "This research may be relevant to more than just kidney cancers, as antibiotics are commonly prescribed t4o patients with cancer to prevent or treat infections related to cancer treatment or a weakened immune system," she said.

The rationale for investigating the impact of antibiotics on immune checkpoint inhibitor efficacy came from several lines of evidence. Prescription antibiotics alter the gut microbiota and decrease bacterial diversity. Studies involving preclinical models suggested an interrelationship between antibiotics and the efficacy of immune checkpoint blockade, said Derosa.

The potential mechanism of interaction between antibiotics and immune checkpoint blockade remained unclear, she continued. To learn more about the relationship, investigators evaluated the effect of recent antibiotic treatment on the activity of PD-1/PD-L1 inhibitors in patients with mRCC.

The findings came from a retrospective review of 80 patients with mRCC enrolled in various clinical trials of PD-1/PD-L1 inhibitors (primarily nivolumab [Opdivo], n=62). Some patients received single-agent immunotherapy and others received a PD-1 inhibitor plus a CTLA-4 inhibitor (such as ipilimumab) or bevacizumab (Avastin).

Derosa said 16 patients had received antibiotic treatment in the 30 days before starting an immune checkpoint inhibitor. Beta-lactamases and fluoroquinolones accounted for most of the antibiotics used.

The outcomes of interest were PFS, objective response rate, and overall survival (OS) between patients who received antibiotics before starting immunotherapy and those who did not. The PFS data showed a striking and statistically significant four-fold higher PFS in patients who did not receive antibiotics (P<0.001). An analysis limited to subgroup of patients treated with nivolumab also showed a clear separation of survival curves favoring patients without recent antibiotic therapy.

In the analysis of all patients, OS did not differ significantly between patients with and without prior antibiotics. However, in the nivolumab subgroup, prior antibiotic therapy already exhibited a significant adverse effect on survival, as no patient with prior antibiotics lived as long as 12 months.

By multivariate analysis, prior antibiotic therapy increased the hazard for disease progression or death more than four-fold (HR 4.17, 95% CI 1.92-9.08, P<0.001). The only other factor that significantly influenced PFS was baseline Karnofsky Performance Status.

"It's remarkable that antibiotic use could have such a negative impact on the efficacy of immunotherapy," said press briefing moderator , an American Society of Clinical Oncology expert and genitourinary oncologist at City of Hope in Duarte, Calif. "This study suggests that patient antibiotic use should be considered carefully so that the possible benefits of immunotherapy are not compromised."

Choueiri saw an analogy in clinical experience with corticosteroids in patients with cancer.

"Perhaps like with corticosteroid use, antibiotic use should be done cautiously in patients on immune checkpoint blockade and reserved for patients with clinical symptoms of bacterial infection, rather than a potential simple 'cold' or mild viral illness," he said. "At the end of the day, the patient is not receiving intense chemotherapy, where the neutrophil counts would drop and put them at risk for an infection."

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