Treatment with antibiotics prior to immune checkpoint inhibitor therapy may confer poorer overall survival and an increased risk of colitis in patients with advanced melanoma, according to data presented at the 2020 ASCO-SITC Clinical Immuno-Oncology Symposium.1
The largest institutional retrospective study to date of antibiotics prior to immunotherapy showed decreased survival in patients with stage III or IV melanoma who received antibiotics within 3 months prior to their first infusion of immune checkpoint inhibitors (which were given in the neoadjuvant or adjuvant setting). Findings also demonstrated reduced survival in patients with stage III disease who received immunotherapy in the adjuvant setting, as well as those with minor infections. Finally, researchers identified an increased incidence of immune-mediated colitis that required intravenous steroids.
Brian Chu, BS
John N. Lukens, MD
“Although these findings need to be explored in preclinical studies, they suggest a degree of gut dysbiosis in patients receiving antibiotics, given the known role of the microbiome in local gut immune tolerance,” said Brian Chu, BS, a medical student at the Perelman School of Medicine at the University of Pennsylvania. John N. Lukens, MD, Assistant Professor of Radiation Oncology at the Hospital of the University of Pennsylvania, was the senior author for the study.
As Mr. Chu reported, antibiotics exert a profound effect on the composition of the gut microbiome, which, in turn, can affect the way patients respond to immunotherapy. Although the negative effect of antibiotics on the response to immunotherapy has been shown preclinically and clinically in patients with advanced cancer, added Mr. Chu, it had been unknown whether patients with stage III melanoma also have similarly worse outcomes after receiving antibiotics.
“These negative effects could be caused by antibiotic-induced dysbiosis or confounding comorbidities, a marker of poor overall health due to infection,” Mr. Chu explained. “It’s also unknown whether antibiotic-induced dysbiosis can exacerbate the effects of the intestinal toxicities of immune checkpoint inhibitors.”
Decreased Overall Survival
For this study, Mr. Chu and colleagues used their institutional database to identify 568 patients with melanoma treated with immune checkpoint inhibitors between 2004 and 2019. Antibiotic exposure was defined as receipt of antibiotics within 3 months before the first infusion of checkpoint inhibitor therapy. The primary outcome was overall survival, and the secondary outcome was immune-mediated colitis requiring intravenous steroids. The researchers analyzed patients with stage III and IV disease separately for the primary analysis.
KEY POINTS
- In patients with stage III/IV melanoma treated with immune checkpoint inhibitors, receipt of antibiotics within 3 months prior to initiation of immunotherapy was associated with an increased incidence of colitis and decreased overall survival.
- The median overall survival was 3.6 years in patients not exposed to antibiotics, dropping to 2.3 years in those exposed to antibiotics.
- The melanoma-specific mortality rate at 2 years was 37% in the antibiotic-naive group, increasing to 47% in those exposed to antibiotics.
- The incidence of severe immune-mediated colitis was doubled in patients who had received antibiotics.
Antibiotics were associated with decreased overall survival and increased melanoma-specific mortality in all patients. Although antibiotic-naive patients had a median overall survival of 3.6 years, patients who received antibiotics prior to checkpoint inhibitors had a median overall survival of 2.3 years (P = .01). Moreover, these survival differences were maintained in prespecified subgroup analyses. Patients with stage III melanoma who were exposed to antibiotics had a hazard ratio of 2.8 (P = .008), for example, and those who received immunotherapy in the adjuvant setting had a hazard ratio of 4.8 (P = .038).
A sensitivity analysis that excluded patients treated given intravenous antibiotics and patients hospitalized for their infection showed a similar decrease in overall survival. The investigators found a survival detriment associated with three major classes of antibiotics including penicillins, cephalosporins, and fluoroquinolones.
Among all study patients, the melanoma-specific mortality rate at 2 years was 37% in the antibiotic-unexposed group and 47% in those receiving antibiotics (P = .03), he further reported.
More Colitis in Antibiotic-Exposed Group
Finally, results showed that the rate of moderate to severe colitis, defined as immune-mediated colitis requiring IV steroids within 1 year of immune checkpoint inhibitors, was twice as high in patients exposed to antibiotics (P = .046).
For future research, Mr. Chu and colleagues are planning validation studies that correlate the receipt of antibiotics with changes in the microbiome. The researchers are also seeking to understand whether the risk posed by antibiotics is potentially modifiable.
“It remains to be seen if the reconstitution of the microbiome after antibiotics, such as with a high-fiber diet or fecal transplants, negates the observed effect that we have found,” Mr. Chu concluded.
DISCLOSURE: Mr. Chu reported no conflicts of interest. Dr. Lukens has received institutional research funding from Merck.
REFERENCE
1. Chu B, Mohiuddin JJ, Facciabene A, et al: Association of antibiotic exposure with overall survival and colitis in patients with stage III and IV melanoma receiving immune checkpoint inhibitors. 2020 ASCO-SITC Clinical Immuno-Oncology Symposium. Abstract 56. Presented February 7, 2020.
