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Antibiotics are associated with worse outcomes in lung cancer patients treated with chemotherapy and immunotherapy
Arielle Elkrief (Memorial Sloan Kettering Cancer Center, Centre Hospitalier de l’Université de Montréal), Eder Orlando Méndez-Salazar (Centre Hospitalier de l’Université de Montréal, Université de Montréal), Jade Maillou (Centre Hospitalier de l’Université de Montréal, Université de Montréal), Chad Vanderbilt (Memorial Sloan Kettering Cancer Center), Pooja Gogia (Memorial Sloan Kettering Cancer Center), Antoine Desîlets (Centre Hospitalier de l’Université de Montréal), Meriem Messaoudene (Centre Hospitalier de l’Université de Montréal, Université de Montréal), Daniel Kelly (Memorial Sloan Kettering Cancer Center), Marc Ladanyi (Memorial Sloan Kettering Cancer Center), Matthew David Hellmann (Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine), Laurence Zitvogel (Inserm, Université Paris-Saclay), Charles M. Rudin (Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine), Bertrand Routy (Centre Hospitalier de l’Université de Montréal, Université de Montréal), Lisa Derosa (Inserm, Université Paris-Saclay), Adam Jacob Schoenfeld (Memorial Sloan Kettering Cancer Center, Weill Cornell Medicine)
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.