AVOID ANTIBIOTIC USE DURING IMMUNOTHERAPY

Patients with stage III and stage IV melanoma receiving immune checkpoint inhibitors (ICIs) had decreased overall survival (OS) and increased melanoma-specific mortality and risk for moderate to severe colitis if they were treated with antibiotics, according to a large retrospective study (Abstract 56) presented during the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.

“Antibiotics exert a profound effect on the composition of the gut microbiome. In turn, that change can affect the way that patients respond to immunotherapy,” said Brian Chu, of the University of Pennsylvania Perelman School of Medicine, who presented the results on February 7. The study’s senior author was John N. Lukens, MD, also of the University of Pennsylvania.

“Antibiotics exert a profound effect on the composition of the gut microbiome. In turn, that change can affect the way that patients respond to immunotherapy.”—Mr. Brian Chu

Previous reports have suggested that antibiotic exposure could have a negative effect on treatment outcomes with ICIs. Most reports were primarily in patients with stage IV malignancies though, and it was not previously known whether the effect was similar in patients with stage III melanoma.

The new retrospective study included a total of 568 patients with stage III (204 patients) or stage IV (364 patients) melanoma, all treated with ICI therapy (ipilimumab, nivolumab, pembrolizumab, or ipilimumab/nivolumab) between 2008 and 2019. Patients who received a single dose of perioperative antibiotics were excluded. Of the patients with stage III melanoma, 158 had not received antibiotics and 46 patients were exposed to antibiotics within 3 months prior to ICI initiation. Among the patients with stage IV melanoma, 296 had not received antibiotics and 68 had antibiotic exposure.

Baseline characteristics were well balanced, with one exception: in the stage III group, those who were exposed to antibiotics were more likely to have undergone surgical resection (p = 0.0001); this was due to the use of antibiotics for postoperative wound infections.

Patients who received antibiotics had a significantly decreased OS (2.3 years vs. 3.6 years; p = 0.0101), as well as an increased melanoma-specific mortality (p = 0.0278).

Among the entire cohort, the hazard ratio (HR) for OS for those exposed to antibiotics was 1.7 (95% CI [1.3, 2.4]; p = 0.0004). For patients with stage IV melanoma, the HR was 1.6 (95% CI [1.2, 2.3]; p = 0.005); for those with stage III melanoma, the HR was 2.8 (95% CI [1.3, 5.9]; p = 0.008). Specifically among patients stage III disease treated in the adjuvant setting, the HR for those treated with antibiotics was 4.8 (95% CI [1.1, 21.5]; p = 0.038). In a sensitivity analysis that excluded those who received intravenous antibiotics and those who were hospitalized for reasons associated with their antibiotic, the poorer OS persisted, with an HR of 1.7 (95% CI [1.2, 2.4]; p = 0.003).

Patients who were exposed to antibiotics also had an increased risk for moderate to severe colitis, with an HR of 2.1 (95% CI [1.02, 4.52]; p = 0.046).

“We envision validation studies that correlate the receipt of antibiotics with changes in the microbiome,” Mr. Chu said. He added that it has yet to be determined if reconstitution of the microbiome using probiotics, fecal microbial transfer, or other methods could negate the effects observed in this study.

Discussant Jarushka Naidoo, MBBCh, of the Sidney Kimmel Cancer Center at Johns Hopkins University, said these results do confirm previous findings of poorer OS in advanced melanoma as well as lung cancer, and takes a step forward by including stage III melanoma. “The association between antibiotic exposure and high-grade colitis in the stage III population is a new finding, and the authors are to be congratulated on this.”

She added that the study is limited in terms of its sensitivity analysis, which excluded the sickest patients, and that a study examining a larger population including those with an ECOG status of 2 or higher may be warranted. The importance of antibiotic timing is also an outstanding question.

“I think it is very important that this should not be a reason to not give antibiotics to those patients who need it,” she said. “The rationale for giving probiotics as a supplementation may not be valid, as we don’t know which microbes are being depleted by the antibiotics and which need to be supplemented.”