Liver transplantation (LT) is a curative treatment for selected patients with hepatocellular carcinoma (HCC), particularly when tumors meet established transplant criteria. In patients beyond these criteria, downstaging strategies may allow reconsideration for transplantation. With immune checkpoint inhibitors now standard of care in advanced HCC, their role in downstaging prior to transplantation requires prospective evaluation.
The ImmunoXXL study was designed to assess the safety and efficacy of liver transplantation after response to atezolizumab–bevacizumab (Atezo–Bev) in patients with intermediate and advanced HCC beyond extended transplant criteria and not amenable to further locoregional therapies.
The article was published as a Research Article (Articles in Press) in the Journal of Hepatology on February 26, 2026.
Title: Efficacy of liver transplantation after response to atezolizumab-bevacizumab downstaging of intermediate and advanced hepatocellular carcinoma (ImmunoXXL)
Authors: Sherrie Bhoori, Licia Rivoltini, David J. Pinato, Valentina Bellia, Marianna Maspero, Marco Bongini, Jacopo de Cristofaro, Marta Vaiani, Michela Dosi, Elisabetta Vergani, Barbara Vergani, Giuseppe Leoncini, Elena Daveri, Giovanni Di Maio, Nicolò Simonotti, Barbara Cappetti, Agata Cova, Francesca Rini, Stefano Bergamini, Luca Lalli, Carlo Sposito, and Vincenzo Mazzaferro.
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Methods
ImmunoXXL is an investigator-led, prospective, single-center observational study. Eligible patients had intermediate or advanced HCC beyond extended transplant criteria, were not amenable to further locoregional therapies, and achieved partial or complete radiological response to atezolizumab–bevacizumab.
All patients received atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously every three weeks as first-line treatment. Radiological response was assessed every two months using mRECIST criteria. Patients achieving downstaging after a minimum of three cycles were evaluated by a multidisciplinary transplant board. Eligibility required tumor burden and AFP downstaging congruent with an estimated post-transplant survival of at least 60% according to the Metroticket 2.0 calculator.
Immunotherapy was withdrawn prior to transplantation with a planned washout period of 30–90 days. The primary endpoint was post-transplant recurrence-free survival (RFS). Secondary endpoints included safety, efficacy, and overall survival (OS). Longitudinal immune monitoring was performed in tumor tissue and peripheral blood.
Results
Between December 2022 and January 31, 2025, 16 patients were enrolled, listed, and transplanted in the ImmunoXXL study. These patients came from a larger cohort of 61 potentially eligible patients who received Atezo–Bev for intermediate and advanced HCC.
At baseline, the transplanted cohort had substantial tumor burden:
- Median largest tumor size: 6.5 cm (IQR 3–8)
- Median AFP: 283 ng/mL (IQR 6–1080)
- Portal vein tumor thrombosis: 50%
- Previous locoregional therapies: 15 patients (94%)
Downstaging to transplant eligibility was achieved after a median of 4.7 months (IQR 2.4–7.6). The median washout period from the last Atezo–Bev dose to transplantation was 57.5 days (IQR 29–87). Median follow-up after transplantation was 16 months (95% CI 4–22).
Treatment- and transplant-related outcomes showed both efficacy and risk. Pre-transplant immune-related adverse events occurred in 3 patients (19%), while post-transplant acute rejection occurred in 4 patients (25%). Patients who developed rejection had a shorter median pre-transplant washout period than non-rejecting patients (28 days [15.5–43] vs 60 days [37.5–112]; p=0.045). Post-transplant 90-day morbidity was 62.5% (95% CI 35–85), and 90-day mortality was 6.3% (95% CI 0.2–30).
Pathologic assessment confirmed deep responses after downstaging:
- Complete pathological response: 10 patients
- Partial pathological response: 6 patients
- Radiological and pathological responses were significantly correlated: R² 0.88; p<0.001; 95% CI 0.77–0.94
During follow-up, one patient (6.2%) developed post-transplant HCC recurrence. Estimated 2-year recurrence-free survival was 90% (95% CI 62–98%), and 2-year post-transplant overall survival was 94% (95% CI 67–100%).
Immune profiling showed that responding patients harboured a tumour microenvironment with features suggestive of immune activation/extinguishment, correlated with the duration of Atezo–Bev treatment and the length of pre-LT washout. The study also reports that tumour response and graft rejection are closely intertwined, with the PD-1/PD-L1 axis representing a pathway shared by both tumour and graft tolerance.
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Conclusion
In this prospective study, liver transplantation after atezolizumab–bevacizumab downstaging in patients with intermediate and advanced HCC beyond extended transplant criteria was associated with 2-year recurrence-free survival of 90% and overall survival of 94%. Acute rejection appeared increased but remained clinically manageable. The authors conclude that liver transplantation should be considered after HCC response to immunotherapy.
Find out the full article on Journal of Hepatology.