TY - JOUR
T1 - Early Antibiotic Exposure Is Not Detrimental to Therapeutic Effect from Immunotherapy in Hepatocellular Carcinoma
AU - Fessas, Petros
AU - Naeem, Muntaha
AU - Pinter, Matthias
AU - Marron, Thomas U.
AU - Szafron, David
AU - Balcar, Lorenz
AU - Saeed, Anwaar
AU - Jun, Tomi
AU - Dharmapuri, Sirish
AU - Gampa, Anuhya
AU - Wang, Yinghong
AU - Khan, Uqba
AU - Muzaffar, Mahvish
AU - Navaid, Musharraf
AU - Lee, Pei Chang
AU - Bulumulle, Anushi
AU - Yu, Bo
AU - Paul, Sonal
AU - Nimkar, Neil
AU - Bettinger, Dominik
AU - Hildebrand, Hannah
AU - Abugabal, Yehia I.
AU - Pressiani, Tiziana
AU - Personeni, Nicola
AU - Nishida, Naoshi
AU - Kudo, Masatoshi
AU - Kaseb, Ahmed
AU - Huang, Yi Hsiang
AU - Ang, Celina
AU - Pillai, Anjana
AU - Rimassa, Lorenza
AU - Naqash, Abdul Rafeh
AU - Sharon, Elad
AU - Cortellini, Alessio
AU - Pinato, David J.
N1 - Publisher Copyright:
© 2021
PY - 2021/11/8
Y1 - 2021/11/8
N2 - Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within -30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.
AB - Background and Rationale: Immune checkpoint inhibitor (ICI) therapy is an expanding therapeutic option for hepatocellular carcinoma (HCC). Antibiotics (ATB) taken prior to or early during ICI therapy can impact immunotherapy efficacy across indications; however, the effect of ATB is undefined in HCC. Methods: In a large international cohort of 450 ICI recipients from Europe, North America, and Asia, we categorized patients according to timing of ATB focusing on exposure within -30 to +30 days from ICI (early immunotherapy period [EIOP]). EIOP was evaluated in association with overall survival (OS), progression-free survival (PFS), and best radiologic response using RECIST 1.1 criteria. Results: Our study comprised mostly cirrhotic (329, 73.3%) males (355, 79.1%) with a Child-Turcotte Pugh class of A (332, 73.9%), receiving ICI after 1 therapy line (251, 55.9%) for HCC of Barcelona clinic liver cancer stage C (325, 72.4%). EIOP (n = 170, 37.9%) was independent of baseline clinicopathologic features of HCC and correlated with longer PFS (6.1 vs. 3.7 months, log-rank p = 0.0135). EIOP+ patients had similar OS, overall response, and disease control rates (DCRs) compared to EIOP. The effect of EIOP persisted in landmark time analyses and in multivariable models, confirming the independent predictive role of EIOP in influencing PFS following adjustment for covariates reflective of tumor burden, liver function, and ICI regimen administered. In patients receiving programmed cell death-1 receptor/ligand inhibitors monotherapy, EIOP was also associated with higher DCRs (61.4% vs. 50.9%, p = 0.0494). Conclusions: Unlike other oncological indications, ATB in the 30 days before or after ICI initiation is associated with improved benefit from immunotherapy, independent of disease and treatment-related features. Evaluation of the immune microbiologic determinants of response to ICI in HCC warrants further investigation.
KW - Antibiotics
KW - Cancer immunotherapy
KW - Gut microbiota
KW - Hepatocellular carcinoma
KW - Immune checkpoint inhibitors
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U2 - 10.1159/000519108
DO - 10.1159/000519108
M3 - Article
C2 - 34950181
AN - SCOPUS:85117493140
SN - 2235-1795
VL - 10
SP - 583
EP - 592
JO - Liver Cancer
JF - Liver Cancer
IS - 6
ER -