Immunotherapy with immune checkpoint inhibitors (ICIs), either alone or in combination with chemotherapy, is now the established standard of care in the management of advanced non-small cell lung cancer (NSCLC). However, the diversity of the gut microbiome has emerged as a critical determinant of the efficacy of ICIs. Although not definitively proven, mechanistic and epidemiological evidence suggests that prior antibiotic exposure may impact outcomes in patients treated with ICI monotherapy. In addition, recent data indicate that fecal transplantation can reverse immunotherapy resistance in patients with melanoma. This finding further supports the role of a healthy gut microbiome for ICI efficacy. In contrast, there does not appear to be a link between the efficacy of chemotherapy and antibiotic (ATB) use.

A recently published retrospective international study examined if antibiotic (ATB) exposure impacts the efficacy of first-line combination of chemotherapy and immunotherapy in patients with advanced NSCLC. The researchers included 302 patients, treated in eight institutions over 6 years. They evaluated the association between previous antibiotic exposure (pATB) or concurrent antibiotic exposure (cATB) and overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Among the 302 patients with stage IV NSCLC, 47 (15.6%) had received pATB, and 117 (38.7%) received cATB. At chemo-immunotherapy initiation, there were no significant differences in clinicopathologic and molecular characteristics of patients in the pATB group compared with the non pATB group, except for a higher proportion of patients with ECOG performance status (PS) ≥2 in the pATB group (27.7% vs. 8.6%, P=0.0002). There were no statistically significant differences in OS and PFS between the pATB and non-pATB groups. The median OS of patients in the pATB group was 11.2 months and in the non-pATB group 16.6 months (P = 0.0503), while the median PFS was 5.6 months in the pATB group and 6.3 months in the non-pATB group (P=0.2626). Multivariate analysis showed that patients with pATB exposure have similar OS and PFS compared with unexposed patients, regardless of ECOG PS. Similarly, no difference in ORR was found across pATB exposure groups (42.6% vs. 57.4%; P=0.1794). In addition, results of multivariate analysis confirmed that cATB was not associated with an increased risk of progression (HR 1.29; P=0.092) or death (HR 1.30; P=0.125). However, receipt of cATB was associated with smoking status, indicating that active smokers were more susceptible to infections.

This is the first study to evaluate and show no association between ATB exposure and first-line chemo-immunotherapy efficacy in patients with advanced NSCLC. In their discussion, the authors propose that the synergistic interaction between ICIs and chemotherapy may compensate for detrimental ATB effects. Thus, pATB status could be integrated into the treatment decision-making process. For example, in patients with high PD-L1-positive advanced NSCLC and pATB exposure, a combination of ICI and chemotherapy should be considered as first-line therapy rather than a single-agent ICI. Another important finding for practice from this study is that cATB use does not impact clinical outcomes of NSCLC patients on chemo-immunotherapy. This is reassuring, as antibiotics are often prescribed prophylactically for chemotherapy-induced neutropenia and for treatment of febrile neutropenia. The authors acknowledge the limitations of this retrospective analysis and call for future research to further explore the stratification potential for pATB status and the interplay between gut microbiome diversity, systemic antibiotics, and chemotherapy-enhanced anticancer immunity.

Reference:
Cortellini A, et al. Annals of Oncology 2021; Aug 13 [Online ahead of print].