Altering the gut microbiome and TME in advanced liver cancers: A phase II study of nivolumab, tadalafil, and oral vancomycin in refractory HCC or liver-dominant metastatic CRC or PDAC.

e14642 Background: The gut-liver axis shapes the environment that promotes liver disease. In murine models of liver cancer, our group showed that altering gut microbiome with oral vancomycin can induce an antitumor effect by modifying bile acids (BA) that then recruit natural killer T cells (NKTC). However, these NKTC were met by an immunosuppressive counter-regulatory response where myeloid-derived suppressor cells (MDSC) accumulated, impairing their cytotoxicity. Tadalafil, a PDE5 inhibitor, can suppress these MDSC in the TME. The aim of this study was to examine if the immunomodulatory effects of oral vancomycin and tadalafil can enhance nivolumab activity in advanced primary liver cancer or liver metastases. Methods: This is a phase II study of adult patients (pts) with refractory hepatocellular carcinoma (HCC) or liver-dominant metastatic colorectal (mCRC) or pancreatic (mPDAC) cancers. Pts received IV nivolumab 480mg on D1, oral vancomycin 125mg every 6 hours on D1-21, and tadalafil 10mg once daily in 28d cycles until disease progression or unacceptable toxicity. Primary endpoint was best overall response (BOR) according to RECIST v1.1. Secondary endpoints included safety/tolerability and mOS. Correlative studies were performed on paired stool, blood, and tumor biopsies. Results: From 6/2019 - 7/2021, 22 heavily pretreated pts were enrolled: 6 HCC, 9 PDAC, 7 CRC. Median age was 63y (41-82), and 27% were female. Molecular testing showed MSS, TMB low to intermediate (1.57-13.35), and frequent mutations in KRAS and TP53. The BOR was SD (3pts, 18.75%), followed by PD (13pts, 81.25%); there were no PR or CR (ORR = 0%). Six pts had symptomatic deterioration prior to restaging scans. At a median follow-up of 4m (0.9-23.0m), all 22 pts had died of progressive disease with mOS of 4m. When stratified by site of origin, mOS was 9.5m (95%CI: 1.3-21.9m) in HCC and 3.6m (95%CI: 1.9-6.6m) in liver metastases (log-rank test, p=0.27). The most common grade 3-4 trAEs were electrolyte disturbances and anemia. The stool microbiome composition of Bacteroides species did not change with treatment as detected by shotgun sequencing. Plasma secondary BA, measured by the mixed meal test, decreased with treatment (p<0.05, n=18, two-way ANOVA). The classical to non-classical monocytes ratio increased with treatment in flow cytometry analysis of PBMC immune cells (p<0.05, n=14, one-way ANOVA). Transcriptomic analysis of treated liver tumor biopsies showed an increase in BA metabolism. Conclusions: Although well tolerated, the combination of oral vancomycin and tadalafil with nivolumab did not produce any meaningful clinical responses. Correlative studies suggested enhanced activation of BA metabolization, but TME immune profiling did not reveal substantial changes in regulatory suppressor cells or NKTC activity. Clinical trial information: NCT03785210 .