What question did this study set out to answer?

This trial aims to assess whether fecal microbiota transplantation can counteract resistance to treatment in unresectable hepatocellular carcinoma.

May 30, 2026

Fecal microbiota transplantation to reverse resistance to TKI plus PD-1 inhibitors in unresectable hepatocellular carcinoma: A phase 2 clinical trial.

Key Points

This trial aims to assess whether fecal microbiota transplantation can counteract resistance to treatment in unresectable hepatocellular carcinoma.
Prospective, single-arm phase 2 trial (ChiCTR2200058471).
Treatment-naïve and previously treated patients received respective regimens with TKI and PD-1 inhibitors.
Oral FMT was administered post-progression to evaluate its effects on treatment response.
In the first-line cohort (n=18), ORR was 33.3%, DCR 88.9%, median PFS 7.9 months (95% CI: 4.5–16.0).
In the second-line cohort (n=19), ORR was 0%, DCR 31.6%, median PFS 2.3 months (95% CI: 1.6–4.2).
Among 13 patients receiving FMT post-progression, 8 achieved SD, yielding a DCR of 61% and median PFS of 5.1 months (95% CI: 2.3–8.3).

Abstract

e16205 Background: Tyrosine-kinase inhibitors (TKIs) and immune-checkpoint inhibitors (ICIs) improve survival in unresectable hepatocellular carcinoma (uHCC), but acquired resistance limits benefit. Fecal microbiota transplantation (FMT) has shown potential to reverse immunotherapy resistance. This study evaluated the efficacy of TKI + ICI in patients with uHCC and explored whether FMT post-progression overcome resistance. Methods: This prospective, single-arm phase 2 trial (ChiCTR2200058471) enrolled HCC patients with Child-Pugh A, BCLC-B/C, and ECOG PS 0–1. Treatment-naïve patients received first-line lenvatinib + PD-1 inhibitor, while previously treated patients received second-line regorafenib + tislelizumab. Patients who achieved CR, PR, or SD continued their respective regimens until radiologically confirmed disease progression. Upon progression, oral FMT capsules (30 g daily for 3 days, q3w×3 cycles) were added to the original treatment regimen. The primary endpoint was the DCR post-FMT. Secondary endpoints included ORR, PFS, OS, and safety post-FMT. Results: Between Aug 2022 and Mar 2025, 37 patients were enrolled. As of Jan 22, 2026, in the first-line cohort (n = 18), the ORR was 33.3%, DCR was 88.9%, median PFS was 7.9 months (95% CI: 4.5–16.0), and median OS not reached (95% CI: 16.7 In the second-line cohort (n = 19), the ORR was 0%, DCR was 31.6%, median PFS was 2.3 months (95% CI: 1.6–4.2), and median OS of 9.8 months (95% CI: 5.9–18.1). Across both cohorts, 13 patients received FMT post-progression. Among them, 8 achieved SD, resulting in a DCR of 61%. The median PFS was 5.1 months (95% CI: 2.3–8.3), and median OS remained unreached (95% CI: 8.5–NE). Treatment-related adverse events (AEs) occurred in 86.5 % of all patients, with grade ≥3 AEs observed in 11.8 %. FMT-related toxicity was mild, limited to one grade 1 fever and two grade 1 diarrhoea events. Longitudinal metagenomic analysis of HCC patients across different phases of targeted immunotherapy (with and without FMT) revealed that fluctuations in the abundance of Bacteroides caccae and Phocaeicola plebeius were closely synchronized with mirrored changes in therapeutic efficacy, showing a significant positive correlation. This dynamic association suggests that these microbial taxa contributes to sustaining treatment response and mediates the transient reversal of resistance following FMT. Conclusions: TKI combined with ICI demonstrated favorable efficacy and safety in advanced HCC. FMT post-progression achieved 61% DCR with tolerable toxicity, supporting its potential to overcome TKI-ICI resistance. Bacteroides caccae and Phocaeicola plebeius may be biomarkers of efficacy. Larger RCTs are needed to validate these findings and clarify microbiota-related mechanisms. Clinical trial information: ChiCTR2200058471.

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