In the anti-PD-1 antibody cohort (n = 2605), 749 (28.6%) patients received antibiotics in the 3 months prior to anti-PD-1 initiation. In the targeted therapy cohort (n = 1527), 460 (30.1%) patients received antibiotics in the 3 months prior to targeted therapy initiation. Age, sex, metastatic sites, previous surgery or radiotherapy, and comorbidities were reported for the ICI and targeted therapy cohorts. After overlap weighting, standardized mean differences between patients receiving or not receiving antibiotics were close to zero for all covariates (Table 1; Supplementary Table 2, available online). All the characteristics measured were thus well balanced across groups within the pseudo-populations.
Antibiotic Exposure Before First-line Antimelanoma Treatment
In the anti-PD-1 antibody cohort, 749 patients received 954 antibiotic prescriptions in the 3 months prior to their first-line treatment. In the targeted therapy cohort, there were 583 antibiotic prescriptions for 460 patients. The main antibiotics prescribed were amoxicillin and clavulanate (28.9%), amoxicillin (19.8%), pristinamycin (10.3%), and ofloxacin (4.5%). Primary infections requiring hospitalization were urinary tract (26.3%), respiratory tract (22.6%), skin and skin-associated structures infections (22.9%), and fever of undetermined cause (16.7%). The proportion of patients receiving an antibiotic prescription each day was estimated in the 2 years before the initiation of the first-line antimelanoma treatment. The incidence of antibiotic prescriptions rose steadily from 12 months before the first-line treatment in both cohorts (Figure 1).
Evolution of antibiotic use according to the progression of melanoma disease over time. The proportion of patients initiating an antibiotic course in the 2 years before the initiation of the first anticancer treatment line is shown for the anti-PD-1 cohort and the targeted therapy cohort. The 95% confidence band for the proportion of antibiotic prescriptions is shown in gray. The time frame for antibiotics exposure in the main analysis is circled.
Association Between Antibiotic use in the 3 Months Prior to Antimelanoma Treatment and Outcome
In the anti-PD-1 antibody cohort, 956 (36.7%) patients had died, and 1602 (61.5%) had discontinued their first treatment line by December 31, 2017. Antibiotic exposure was not associated with shorter OS (wHR = 1.01, 95% CI = 0.88 to 1.17) or TTD (wHR = 1.00, 95% CI = 0.89 to 1.11). Kaplan-Meier curves were superimposed according to antibiotic receipt in the pseudo-populations (Figure 2, A and B).
Kaplan-Meier curves for overall survival and time-to-treatment discontinuation according to antibiotic treatment in pseudo-populations of patients receiving anti-PD-1 antibody or targeted therapy as a first-line treatment for metastatic melanoma. Pseudo-populations are obtained using overlap weighting from the initial anti-PD-1 antibody cohort (A and B) and targeted therapy cohort (C and D). Patients receiving antibiotics in the 3 months prior to anti-PD-1 antibody or targeted therapy are compared to nonexposed patients. Overall survival is shown in panels A and C and time-to-treatment discontinuation in panels B and D. Weighted log-rank tests are provided. The numbers of at-risk individuals correspond to fictive weighted individuals. All the study participants from the anti-PD-1 antibody cohort (n = 2605) and the targeted therapy cohort (n = 1527) were included. All statistical tests were 2-sided.
In the targeted therapy cohort, 701 (45.9%) patients had died, and 1074 (70.3%) had discontinued their first treatment line by December 31, 2017. Antibiotic exposure was not associated with OS (wHR = 1.08, 95% CI = 0.92 to 1.27) or TTD (wHR = 1.04, 95% CI = 0.91 to 1.18) (Figure 2, C and D).
As the impact of antibiotic treatment was suspected to be more detrimental in the month prior to ICI initiation, a first sensitivity analysis was performed, narrowing the antibiotic time frame to 1 month. No statistically significant association between antibiotic treatment and OS or TTD was evidenced in either cohort (Figure 3).
Forest plot summarizing the analyses performed in both cohorts of patients receiving anti-PD-1 antibody or targeted therapy as a first-line treatment for metastatic melanoma. Main analysis investigated the impact of antibiotics in the 3 months prior to antimelanoma treatment on overall survival and time-to-treatment discontinuation. In the first sensitivity analysis, the antibiotic time frame was narrowed to 1 month prior to antimelanoma treatment initiation. In the second sensitivity analysis, antibiotic exposure was restricted to antibiotics having a high impact on the gut microbiota (fluoroquinolones, second- and third-generation cephalosporins, and penicillin associated with β-lactamase inhibitors). In the third sensitivity analysis, patients with infections requiring hospitalization were excluded. The error bars represent the 95% confidence intervals (CIs). ATB = antibiotics; HR = hazard ratio.
As high-impact antibiotics (fluoroquinolones, penicillin associated with β-lactamase inhibitors, and second- and third-generation cephalosporins) induce more profound gut dysbiosis (21–24), a second sensitivity analysis restricted the analysis to these antibiotics. In both the anti-PD-1 antibody and targeted therapy cohorts, no statistically significant association between high-impact antibiotics and OS or TTD was evidenced (Figure 3).
In a third sensitivity analysis, patients hospitalized with a diagnosis of infection were excluded, as antibiotics administered during hospital stays are not recorded in the SNDS database. OS and TTD were not associated with antibiotic treatment after exclusion of these patients in either the anti-PD-1 antibody or the targeted therapy cohort (Figure 3).
Crude hazard ratios (resulting from analyses in the initial nonweighted populations) and weighted hazard ratios (obtained from pseudo-populations) for the main and sensitivity analyses are provided in Supplementary Table 3 (available online).
J Natl Cancer Inst. 2022;114(5):686-694. © 2022 Oxford University Press