TY - JOUR
T1 - Differential influence of antibiotic therapy and other medications on oncological outcomes of patients with non-small cell lung cancer treated with first-line pembrolizumab versus cytotoxic chemotherapy
AU - Cortellini, Alessio
AU - Di Maio, Massimo
AU - Nigro, Olga
AU - Leonetti, Alessandro
AU - Cortinovis, Diego L.
AU - Aerts, Joachim G.J.V.
AU - Guaitoli, Giorgia
AU - Barbieri, Fausto
AU - Giusti, Raffaele
AU - Ferrara, Miriam G.
AU - Bria, Emilio
AU - D'Argento, Ettore
AU - Grossi, Francesco
AU - Rijavec, Erika
AU - Guida, Annalisa
AU - Berardi, Rossana
AU - Torniai, Mariangela
AU - Sforza, Vincenzo
AU - Genova, Carlo
AU - Mazzoni, Francesca
AU - Garassino, Marina Chiara
AU - De Toma, Alessandro
AU - Signorelli, Diego
AU - Gelibter, Alain
AU - Siringo, Marco
AU - Marchetti, Paolo
AU - MacErelli, Marianna
AU - Rastelli, Francesca
AU - Chiari, Rita
AU - Rocco, Danilo
AU - Della Gravara, Luigi
AU - Inno, Alessandro
AU - Michele, De Tursi
AU - Grassadonia, Antonino
AU - Di Marino, Pietro
AU - Mansueto, Giovanni
AU - Zoratto, Federica
AU - Filetti, Marco
AU - Santini, Daniele
AU - Citarella, Fabrizio
AU - Russano, Marco
AU - Cantini, Luca
AU - Tuzi, Alessandro
AU - Bordi, Paola
AU - Minuti, Gabriele
AU - Landi, Lorenza
AU - Ricciardi, Serena
AU - Migliorino, Maria R.
AU - Passiglia, Francesco
AU - Bironzo, Paolo
AU - Metro, Giulio
AU - Adamo, Vincenzo
AU - Russo, Alessandro
AU - Spinelli, Gian Paolo
AU - Banna, Giuseppe L.
AU - Friedlaender, Alex
AU - Addeo, Alfredo
AU - Cannita, Katia
AU - Ficorella, Corrado
AU - Porzio, Giampiero
AU - Pinato, David J.
N1 - Publisher Copyright:
© 2021 BMJ Publishing Group. All rights reserved.
PY - 2021/4/7
Y1 - 2021/4/7
N2 - Background Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate. Methods We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses. Results 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate. Conclusion In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.
AB - Background Some concomitant medications including antibiotics (ATB) have been reproducibly associated with worse survival following immune checkpoint inhibitors (ICIs) in unselected patients with non-small cell lung cancer (NSCLC) (according to programmed death-ligand 1 (PD-L1) expression and treatment line). Whether such relationship is causative or associative is matter of debate. Methods We present the outcomes analysis according to concomitant baseline medications (prior to ICI initiation) with putative immune-modulatory effects in a large cohort of patients with metastatic NSCLC with a PD-L1 expression ≥50%, receiving first-line pembrolizumab monotherapy. We also evaluated a control cohort of patients with metastatic NSCLC treated with first-line chemotherapy. The interaction between key medications and therapeutic modality (pembrolizumab vs chemotherapy) was validated in pooled multivariable analyses. Results 950 and 595 patients were included in the pembrolizumab and chemotherapy cohorts, respectively. Corticosteroid and proton pump inhibitor (PPI) therapy but not ATB therapy was associated with poorer performance status at baseline in both the cohorts. No association with clinical outcomes was found according to baseline statin, aspirin, β-blocker and metformin within the pembrolizumab cohort. On the multivariable analysis, ATB emerged as a strong predictor of worse overall survival (OS) (HR=1.42 (95% CI 1.13 to 1.79); p=0.0024), and progression free survival (PFS) (HR=1.29 (95% CI 1.04 to 1.59); p=0.0192) in the pembrolizumab but not in the chemotherapy cohort. Corticosteroids were associated with shorter PFS (HR=1.69 (95% CI 1.42 to 2.03); p<0.0001), and OS (HR=1.93 (95% CI 1.59 to 2.35); p<0.0001) following pembrolizumab, and shorter PFS (HR=1.30 (95% CI 1.08 to 1.56), p=0.0046) and OS (HR=1.58 (95% CI 1.29 to 1.94), p<0.0001), following chemotherapy. PPIs were associated with worse OS (HR=1.49 (95% CI 1.26 to 1.77); p<0.0001) with pembrolizumab and shorter OS (HR=1.12 (95% CI 1.02 to 1.24), p=0.0139), with chemotherapy. At the pooled analysis, there was a statistically significant interaction with treatment (pembrolizumab vs chemotherapy) for corticosteroids (p=0.0020) and PPIs (p=0.0460) with respect to OS, for corticosteroids (p<0.0001), ATB (p=0.0290), and PPIs (p=0.0487) with respect to PFS, and only corticosteroids (p=0.0033) with respect to objective response rate. Conclusion In this study, we validate the significant negative impact of ATB on pembrolizumab monotherapy but not chemotherapy outcomes in NSCLC, producing further evidence about their underlying immune-modulatory effect. Even though the magnitude of the impact of corticosteroids and PPIs is significantly different across the cohorts, their effects might be driven by adverse disease features.
KW - immunotherapy
KW - lung neoplasms
UR - http://www.scopus.com/inward/record.url?scp=85103905194&partnerID=8YFLogxK
U2 - 10.1136/jitc-2021-002421
DO - 10.1136/jitc-2021-002421
M3 - Article
SN - 2051-1426
VL - 9
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 4
M1 - e002421
ER -