Association between antibiotic exposure and survival in patients with hepatocellular carcinoma treated with nivolumab.

Abstract

e16186 Background: Nivolumab, an immune checkpoint inhibitor, has improved the outcomes of patients with hepatocellular carcinoma (HCC). It is approved for HCC patients previously treated with sorafenib. Outcomes have been reported in previous studies, in malignancies other than HCC, to be worse when patients have been exposed to antibiotics while receiving immune checkpoint inhibitors. We aimed to evaluate the effects of antibiotics on survival in HCC patients treated with nivolumab. Methods: We performed a retrospective review of 59 patients with advanced HCC that have been treated with nivolumab in two academic centers in Saudi Arabia. Patient characteristics, tumor data, antibiotic use (2 weeks prior, during, and 4 weeks after nivolumab therapy), survival data, and other factors were collected. Log-rank test analysis was performed to test the difference in overall survival (OS) time with and without antibiotics use. Results: The majority of patients were males (n=51, 85%), and 38 were Child-Pugh A (64%). A large number of patients had Barcelona Clinic Liver Cancer (BCLC) stage C tumors (n=42, 71%), and 20 patients (34%) used antibiotics. Most patients received nivolumab as second-line therapy after exposure to sorafenib (n=49, 83%). In patients who received nivolumab as first- or second-line therapy (n=57) and did not receive antibiotics, the median OS was double that of patients who received antibiotics (10 vs. 4.5 months, P=0.04). In child A patients who received nivolumab as second-line therapy (n=32), those who were exposed to antibiotics had a statistically significant shorter median OS compared to those who did not (5.5 vs. 20 months, P=0.04). More patients achieved partial response, or complete response (as per modified RECIST criteria) in the cohort that did not receive antibiotics compared to patients who received antibiotics (21% vs. 15%) but that was not statistically significant (P=0.6). Conclusions: This study shows that HCC patients receiving nivolumab have worse survival if they received antibiotics. Antibiotic mediated alteration of the gut microbiome may impact nivolumab response and shorten patient survival. Although this finding may warrant a prospective larger study but it is consistent with other previous studies. Antibiotics should be used very cautiously when treatment with checkpoint inhibitors is considered.

Antibiotic Therapy is Associated with Worse Outcome in Patients with Hepatocellular Carcinoma Treated with Sorafenib

“…Indeed, recent evidence supports a negative association between ABT and clinical outcomes in cancer patients treated with TKIs, 17 , 24 chemotherapy 31 and ICI therapy. 13 , 19 , 20 , 23 , 35 While concomitant therapy with antibiotics and epidermal growth factor receptor (EGFR)-TKIs in patients with advanced non-small cell lung cancer (NSCLC) was associated with shorter PFS, there were no changes in ORR or DCR in another study. 24 In patients with metastatic renal cell carcinoma (mRCC) treated with VEGF-targeting therapies among others, antibiotic users had a shorter PFS and lower ORR compared to antibiotic nonusers, while OS was not negatively impacted by ABT in the group of patients receiving anti-VEGF therapy.…”

“… 16–19 Mice with a favourable composition of the commensal microbiome experienced a greater therapeutic activity from ICI therapy. 19 , 20 While modulation of the gut microbiome by fecal microbiota transplant promoted response to ICIs in immunotherapy-refractory melanoma patients, 21 , 22 ABT was associated with shorter survival in patients with different cancer types treated with ICIs 16 , 23 and TKIs. 17 , 24 Patients with advanced chronic liver disease (ACLD) commonly suffer from intestinal dysbiosis and bacterial translocation, which may promote immune dysfunction via the gut–liver axis.…”

Utilizing Gut Microbiota to Improve Hepatobiliary Tumor Treatments: Recent Advances

“…Patients who received antibiotics had a shorter median overall survival than those who did not ( P = 0.04). This suggests that patients with HCC receiving nivolumab have worse survival rates if they receive antibiotics, and that antibiotics should be used carefully during ICI treatments ( 75 ). In some other tumor types, multiple clinical trials have also demonstrated that early exposure to antibiotics was associated with poorer outcomes and reduced clinical benefits following ICI treatment, such as worse overall survival and increased disease refractory risk ( 76 , 77 ).…”

“…antibiotics should be used carefully during ICI treatments (75). In some other tumor types, multiple clinical trials have also demonstrated that early exposure to antibiotics was associated with poorer outcomes and reduced clinical benefits following ICI treatment, such as worse overall survival and increased disease refractory risk (76,77).…”

Antibiotic therapy is associated with worse outcome in patients with hepatocellular carcinoma treated with sorafenib

“…[16][17][18][19] Mice with a favourable composition of the commensal microbiome experienced a greater therapeutic activity from ICI therapy. 19,20 While modulation of the gut microbiome by fecal microbiota transplant promoted response to ICIs in immunotherapy-refractory melanoma patients, 21,22 ABT was associated with shorter survival in patients with different cancer types treated with ICIs 16,23 and TKIs. 17,24 Patients with advanced chronic liver disease (ACLD) commonly suffer from intestinal dysbiosis and bacterial translocation, which may promote immune dysfunction via the gut-liver axis.…”