Antibiotics may hamper the effectiveness of immune checkpoint inhibitors for patients with metastatic renal cell carcinoma, according to a small, retrospective study. Using antibiotics within 1 month of starting a checkpoint inhibitor was associated with significantly shorter progression-free survival, as well as a trend toward shorter overall survival, in a study of 80 patients with metastatic renal cell carcinoma.

Although the mechanism remains unknown, the prevailing theory is that antibiotics adversely alter the composition of the gut microbiome, and in so doing, slash the ability of beneficial bacteria to boost efficacy of immune checkpoint blockade.

“The data I presented today are just preliminary. But the results are really important because there is a kind of connection between the microbiome, antibiotics, and immune checkpoint blockade,” Lisa Derosa, MD, of Paris-Sud University, Villejuif, France, said during a press briefing prior to the 2017 genitourinary cancers symposium sponsored by the American Society of Clinical Oncology, ASTRO, and the Society of Urologic Oncology.

Dr. Derosa and her colleagues retrospectively assessed 80 people with metastatic renal cell carcinoma enrolled in prospective trials at Gustave Roussy Cancer Institute. The patients were treated with the PD1/PD-L1 inhibitors alone or in combination. The researchers compared survival of 16 patients who also received broad-spectrum antibiotic therapy within 1 month of their first dose of immunotherapy with 64 others who did not receive antibiotics.

Progression-free survival was significantly shorter for patients in the antibiotic group, 2.3 months versus 8.1 months for the nonantibiotic group (P less than .001) on Kaplan-Meier curves. The statistical significance persisted even after the researchers controlled for age, gender, International Metastatic Renal-Cell Carcinoma Database Consortium (IMDC) risk classification, tumor burden, and PPI use in a multivariate analysis. Similarly, the objective response rate to checkpoint inhibition therapy was significantly lower among patients in the antibiotic group (P less than .002).

“There was no significant difference, however, between these groups in overall survival,” Dr. Derosa said.

Despite the findings, Dr. Derosa said it’s too soon to say antibiotics are contraindicated in this patient population. “It may be important to pay attention to these antibiotics in patients treated with immune response inhibitors, but the data are still preliminary.”

“I would propose this data is very intriguing, but it was retrospectively generated, so I consider it hypothesis-generating,” said Sumanta Pal, MD, of City of Hope Medical Center in Duarte, Calif., and moderator of the press briefing. “One has to consider the fact that antibiotics are used under circumstances of medical necessity. I wouldn’t forgo treatment of any active infection … I would use as medically necessary.”

Beta-lactamases and fluoroquinolones comprised the majority of antibiotics in the study. The majority, 67 patients, received immune monotherapy with single-agent PD-1 or PD-L1 inhibitors. Another 10 patients received a combination of a PD-1 inhibitor and a CTLA-4 inhibitor, and 3 were treated with a PD-L1 inhibitor and bevacizumab.

“This is the first analysis evaluating impact of antibiotics on outcome of advanced renal carcinoma patients treated in the era of immune checkpoint blockade,” Dr. Derosa said. “We have a lot of work to do.” She and her colleagues plan to continue enrolling patients in the study. They also plan to evaluate whether alteration of the microbiome composition does play a role in diminishing the effectiveness of immunotherapy, and if so, which types of bacteria are the most likely culprits.


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