Liver and Bile
J Hepatol. 2025;82(3):512-522
Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: The multicenter VITALITY study
Background and aims: The use of immune checkpoint inhibitors (ICIs) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention-to-treat (ITT) outcomes in the peri-transplant setting are currently based on small and heterogenous single-center reports. Methods: This first multiregional US study (2016–2023) included 117 consecutive patients with HCC assessed for liver transplantation (LT) and treated preoperatively with ICIs. ITT and survival analyses were conducted with evaluation of post-LT rejection rates. Results: In total, 86 (73.5%) patients exceeded Milan criteria (MC) and 65 (75.6%) were successfully downstaged within a median of 5.6 months; 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) who were initially beyond but were downstaged. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4–5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included being beyond MC (p < 0.001), alpha-fetoprotein doubling from baseline (p = 0.014) and radiographic responses (p < 0.001). The 3-year ITT survival rate was 71.1% (73.5% within MC vs. 69.7% beyond MC, p = 0.329), with a 3-year post-LT survival rate of 85%. Post-LT rejection occurred in 7 patients, 6 received their last dose of ICI less than 3 months prior to LT, resulting in 1 graft loss.
Conclusions: The first multicenter evaluation of patients with hepatocellular carcinoma receiving immune checkpoint inhibitors pre-liver transplantation demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of alpha-fetoprotein levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes.
DOI: 10.1016/j.jhep.2024.09.003
PD Dr. Michael Schultheiß
Head of the Interdisciplinary Ultrasound Center and Clinical Head of the TIPS Section, Department of Internal Medicine II, University Medical Center Freiburg (Germany)
Immune checkpoint inhibitors in hepatocellular carcinoma before liver transplantation: risk or new strategy?
In the US VITALITY study, Tabrizian et al. investigated a very important but possibly neglected area of hepatocellular carcinoma (HCC) therapy: the neoadjuvant administration of immune checkpoint inhibitor (ICI) therapy prior to liver transplantation (LTX).
The necessary bridge-to-transplant treatment of HCC patients listed for LTX is a major concern for every HCC practitioner. Since the first approval of sorafenib as a systemic therapy for HCC in 2007, numerous studies on neoadjuvant and adjuvant therapy have been conducted. Therefore, it is perhaps surprising that such a study is only now being published. Unfortunately, the study was not conducted in a randomized setting, but as a prospective observational study, making for a very heterogeneous patient population:
– In contrast to a European collective, the cause of the liver disease was very “virus-dominated,” with 47.9% hepatitis C virus-related, 19.7% hepatitis B virus-related, and only 12% alcohol-related hepatopathies.
– In 59.8% of patients, HCC was initially present within the MILAN criteria; 40.2% were above this.
– Locoregional therapy (LRT) was initially performed in 94% of patients, mostly entailing transarterial radioembolization (41%) or transarterial chemoembolization (36.8%), with between 1 (23.1%) and more than 4 (25.6%) interventions.
The use of ICI as a bridge-to-transplant or as part of a downstaging approach was also based on individual decisions by the multidisciplinary HCC boards of the respective hospitals. The heterogeneous distribution of ICI was 58.1% nivolumab, 20.5% atezolizumab, 18% pembrolizumab, and 3.4% tremelimumab + durvalumab.
Nevertheless, the study represents a very important contribution for LTX-listed HCC patients and will potentially influence their management in the future. Perhaps the most relevant aspect of the study is the data on treatment safety. There were no grade 4 and only 0.9% grade 3 toxicities. Seven (16.7%) patients developed rejection after LTX, of which 3 patients suffered severe courses with significant hepatic necrosis. One patient therefore had to be retransplanted. Among the 7 patients who experienced rejection, 6 had received the last ICI administration less than 3 months before LTX. The therapeutic success of ICI is once again remarkable: 22.6% showed a complete response in the evaluation according to mRECIST, and 34.2% a partial response. Of 86 patients who were outside the MILAN criteria during their illness, 65 (75.6%) were successfully downstaged back to the MILAN criteria!
Most patients in this cohort received ICI in response to an only partial or incomplete response to LRT. However, the basic combination of ICI + LRT may also be useful due to immunological effects. Further studies are therefore needed to determine the exact (timed) value of ICI for HCC patients in the neoadjuvant setting before LTX.