Altering the gut microbiome and tumor microenvironment in advanced liver cancer: A phase II study of nivolumab, tadalafil and oral vancomycin in patients with refractory primary hepatocellular carcinoma or liver dominant metastatic cancer from colorectal or pancreatic cancers

A phase II study was conducted in patients with primary hepatocellular carcinoma or liver dominant metastatic cancer from colorectal (CRC) or pancreatic (PDAC) cancers to assess the effect of nivolumab (anti-PD1), oral vancomycin and tadalafil. Patients were treated with 480 mg nivolumab intravenously every 4 weeks, oral 10 mg tadalafil daily and 125 mg vancomycin orally every 6 h days 1–21 of a 28-day cycle. The primary endpoint was best overall response. Secondary endpoints included analysis of the gut microbiota, serum bile acids and immune cells in peripheral blood. A total of 22 patients were enrolled (6 HCC, 7 CRC and 9 PDAC patients). Three out of 16 evaluable patients (2 patients with HCC and 1 patient with CRC) demonstrated stable disease as best response. No unexpected adverse events were observed. A decrease in secondary bile acids along with changes in gut microbiota were observed. Vancomycin/Tadalafil/Nivolumab treatment did not cause any apparent change of major immune cell frequencies in peripheral blood however, a significant change was observed in monocyte subsets. Treatment was well tolerated and led to changes in the gut microbiome along with changes in the bile acid pool and myeloid cells in peripheral blood. No clinical activity was observed.