Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy

Abstract

Anti-PD(L)-1 inhibition combined with platinum doublet chemotherapy (Chemo-IO) has become the most frequently used standard of care regimen in patients with non-small cell lung cancer (NSCLC). The negative impact of antibiotics on clinical outcomes prior to anti-PD(L)-1 inhibition monotherapy (IO) has been demonstrated in multiple studies, but the impact of antibiotic exposure prior to initiation of Chemo-IO is controversial. We assessed antibiotic exposures at two time windows: within 60 days prior to therapy (-60 d window) and within 60 days prior to therapy and 42 days after therapy (-60 + 42d window) in 2028 patients with advanced NSCLC treated with Chemo-IO and IO monotherapy focusing on objective response rate (ORR: rate of partial response and complete response), progression-free survival (PFS), and overall survival (OS). We also assessed impact of antibiotic exposure in an independent cohort of 53 patients. Univariable and multivariable analyses were conducted along with a meta-analysis from similar studies. For the -60 d window, in the Chemo-IO group (N = 769), 183 (24%) patients received antibiotics. Antibiotic exposure was associated with worse ORR (27% vs 40%, p = 0.001), shorter PFS (3.9 months vs. 5.9 months, hazard ratio [HR] 1.35, 95%CI 1.1,1.6, p = 0.0012), as well as shorter OS (10 months vs. 15 months, HR 1.50, 95%CI 1.2,1.8, p = 0.00014). After adjusting for known prognostic factors in NSCLC, antibiotic exposure was independently associated with worse PFS (HR 1.39, 95%CI 1.35,1.7, p = 0.002) and OS (HR 1.61, 95%CI 1.28,2.03, p < 0.001). Similar results were obtained in the -60 + 42d window, and also in an independent cohort. In a meta-analysis of patients with NSCLC treated with Chemo-IO (N = 4) or IO monotherapy (N = 13 studies) antibiotic exposure before treatment was associated with worse OS among all patients (n = 11,351) (HR 1.93, 95% CI 1.52, 2.45) and Chemo-IO-treated patients (n = 1201) (HR 1.54, 95% CI 1.28, 1.84). Thus, antibiotics exposure prior to Chemo-IO is common and associated with worse outcomes, even after adjusting for other factors. These results highlight the need to implement antibiotic stewardship in routine oncology practice.

Fig. 1. Association between antibiotic exposure and outcomes to combination platinum-doublet chemotherapy and immunotherapy in patients with non-small cell lung cancer.

A Objective response rate, B Progression-free survival, C Overall survival in antibiotics vs. no antibiotics group. D Multivariable cox model for PFS and (E). OS for antibiotics vs. no antibiotics while adjusting for standard prognostic features in non-small cell lung cancer. mPFS, median progression-free survival; mOS, median overall survival; HR, hazard ratio; 95%CI, 95% confidence interval. Median survival times given and numbers in parentheses represent 95% confidence intervals.

Fig. 2. Association between antibiotic exposure and outcomes to immunotherapy alone in patients with non-small cell lung cancer.

A Objective response rate, B Progression-free survival, C Overall survival in antibiotics vs. no antibiotics group. D Multivariable cox model for PFS and (E). OS for antibiotics vs. no antibiotics while adjusting for standard prognostic features in non-small cell lung cancer. mPFS, median progression-free survival; mOS, median overall survival; HR, hazard ratio; 95%CI, 95% confidence interval. Median survival times given and numbers in parentheses represent 95% confidence intervals.

Fig. 3. Meta-analysis of all studies examining the association of antibiotic exposure on overall survival to Immunotherapy (IO) alone or platinum doublet Chemo-IO in non-small cell lung cancer; strictly before initiation of IO or Chemo-IO.

A literature review described in the Methods was performed to gather all available retrospective and prospective clinical studies evaluating the association between antibiotic exposure and outcome to either IO alone or Chemo-IO. Each included study is listed by row, with hazard ratios (HRs), study weightings (inverse variance), the total number of patients and the subset of antibiotic (ATB)-exposed patients denoted. RE model with representation of the p-value for heterogeneity between studies, random effects model; df, degrees of freedom. A For Chemo-IO and IO studies; B For Chemo-IO studies.