Pembrolizumab, a PD-1 inhibitor, demonstrated anti-tumour activity and tolerability in patients treated with sorafenib and with advanced hepatocellular carcinoma in KEYNOTE-224. Longer-term efficacy and safety after ∼2.5 years of additional follow-up are reported. Adults with confirmed hepatocellular carcinoma who experienced progression after or intolerance to sorafenib treatment received pembrolizumab 200 mg every 3 weeks for ≤35 cycles or until confirmed progression, unacceptable toxicity, withdrawal of consent or investigator decision. The primary end-point was objective response rate assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumours v1.1. The secondary end-points included duration of response, disease control rate, time to progression, progression-free survival, overall survival and adverse events. Efficacy and safety were assessed in 104 patients. The median time from first dose to data cutoff was 45.1 months (range, 41.3-49.3). Objective response rate was 18.3% (95% CI: 11.4-27.1), and median duration of response was 21.0 months (range, 3.1 to 39.5+). Disease control rate was 61.5%, and median time to progression was 4.8 months (95% CI: 3.9-7.0). Median progression-free survival was 4.9 months (95% CI: 3.5-6.7) and median overall survival was 13.2 months (95% CI: 9.7-15.3). Of 104 patients, 76 (73.1%) patients reported treatment-related adverse events; most were low grade in severity (grade 3-4, n = 26 [25.0%]; grade 5, n = 1 [1.0%]). Immune-mediated hepatitis occurred in 3 patients (all grade 3). No viral-induced hepatitis flares occurred. After ∼2.5 years of additional follow-up, pembrolizumab continued to provide durable anti-tumour activity and no new safety concerns were identified. NCT02702414.

Backgrounds and Aims: Even if no systemic treatment is currently validated for unresectable hepatocellular-cholangiocarcinoma (cHCC-CCA), tyrosine kinase inhibitors (TKIs) and platinum-based chemotherapy are frequently used in clinical practice. Our study aims to describe the effectiveness of first-line systemic treatments in patients with cHCC-CCA. Patients and Methods: Patients with histological diagnosis of unresectable or metastatic cHCC-CCA confirmed by a centralized review (WHO classification 2019) and who received systemic treatment from 2009 to 2020 were included retrospectively in 11 centers. The outcomes of patients with cHCC-CCA were compared with patients with hepatocellular carcinoma (HCC) treated by sorafenib (n = 117) and with intrahepatic cholangiocarcinoma (iCCA, n = 94) treated mainly by platinum-based chemotherapy using a frailty Cox model. The efficacy of TKIs and platinum-based chemotherapies in patients with cHCC-CCA was assessed using a doubly robust estimator. Results: A total of 83 patients with cHCC-CCA were included and were predominantly male (72%) with underlying cirrhosis (55%). 67% of patients had extrahepatic metastases and 31% macrovascular tumor invasion. cHCC-CCAs were more often developed on cirrhosis (55.4%) than iCCA (26.6%) but less frequently than HCC (80.2%) (p < 0.001). Both HCC (36.8% and cHCC-CCA (66.2%) had less frequent extrahepatic metastases than iCCA (81%) (p < 0.001). Unadjusted overall survival (OS) was better in iCCA (13 months) compared to cHCC-CCA (12 months) and HCC (11 months) (p = 0.130). In multivariable analysis, after adjustment by a Cox frailty model, patients with cHCC-CCA had the same survival as HCC and iCCA (HR = 0.67, 95% CI: 0.37–1.22, p = 0.189 and HR = 0.66, 95% CI: 0.43–1.02, p = 0.064, respectively). ALBI score (HR = 2.15; 95% CI: 1.23–3.76; p = 0.009), ascites (HR = 3.45, 95% CI: 1.31–9.03, p = 0.013), and tobacco use (HR = 2.29, 95% CI: 1.08–4.87, p = 0.032) were independently associated with OS in patients with cHCC-CCA. Among patients with cHCC-CCA, 25 patients treated with TKI were compared with 54 patients who received platinum-based chemotherapies. Patients treated with TKI had a median OS of 8.3 months compared to 11.9 months for patients treated with platinum-based chemotherapy (p = 0.86). After a robust doubly adjustment on tumor number and size, vascular invasion, ALBI, MELD, and cirrhosis, the type of treatment did not impact OS (HR = 0.92, 95% CI: 0.27–3.15, p = 0.88) or progression-free survival (HR = 1.24, 95% CI: 0.44–3.49, p = 0.67). Conclusions: First-line systemic treatments with TKIs or platinum-based chemotherapies have similar efficacy in patients with unresectable/metastatic cHCC-CCA. The ALBI score predicts OS.

Background and aim: Transarterial chemoembolization with drug-eluting microspheres (DEM-TACE) is recommended for patients with BCLC stage B hepatocellular carcinoma (HCC) and stage 0-A unsuitable for curative treatments. We assessed efficacy and safety along with hepatobiliary toxicities (HBT) of DEM-TACE using a novel microsphere, LifePearl^TM, loaded with anthracyclines. Materials and methods: 97 patients diagnosed with HCC were prospectively enrolled and treated using LifePearl^TM loaded with doxorubicin (77%) or idarubicin (23%). Safety and tolerability were assessed using CTCAE, HBT by CT/MRI scans, and tumor response by applying modified Response Evaluation Criteria in Solid Tumors (mRECIST). Follow-up was after 2 years. Results: Adverse events (AE) were reported in 73.2% of patients, majority being Grade 1–2. Grade ≥ 3 AE reported in 13.4% of patients were mainly related to postembolization syndrome. HBT were observed after 15.5% (29/187) of the DEM-TACEs. Objective response and disease control rates were 81% and 99%, respectively, as the best responses. Survival rates at one and two years were 81% and 66%, respectively, while the median overall survival (OS) was not reached. Median progression free survival was 13.7 months (95% CI: 11.3; 15.6) and median time to TACE untreatable progression was 16.7 months (95% CI: 12.7; not estimable (n.e.)). Conclusions: DEM-TACE using LifePearl^TM provides a high tumor response rate in HCC patients. HBT rates within or below previously reported results for cTACE and DEM-TACE indicate a good safety profile for LifePearl^TM. The trial was registered in National Library of Medicine (ID: NCT03053596).

Purpose: To evaluate survival, efficacy and safety of transarterial chemoembolization (TACE) in the treatment of patients with hepatocellular carcinoma (HCC), through a pooled analysis of patients with BCLC 0, A and B HCC stages, treated with polyethylene glycol drug eluting microspheres (PEG-DEM) TACE. Materials and Methods: Patients from 3 retrospective and 2 prospective registries were included. Overall survival (OS), progression-free survival (PFS), tumour response and safety were evaluated. Multivariate Cox regression analysis was performed to evaluate predictors of OS. Results: A total of 580 patients (72.1% males, mean age 66.9 ± 10.3 years) were included. 43.5% had BCLC A, and 41.0% BCLC B disease stage, and 85.8% were Child–Pugh class A. Complete and partial response (mRECIST or RECIST1.1) were achieved in 60.14% and 27.11% of patients, with overall response and disease control rates of 87.30% and 94.60%, respectively. Median OS was 50.8 months for the total population, and 61.2 and 38.1 months for BCLC 0 + A and BCLC B patients, respectively. Median PFS for the total population, BCLC 0 + A and BCLC B groups was 15.6, 21.6 and 12.7 months, respectively. Conclusions: This multicentric pooled analysis confirmed efficacy and safety of PEG-DEM TACE, with a median OS of 50.8 months.

Purpose: To report response rates (using mRECIST), overall survival (OS), progression-free survival and local tumour recurrence-free survival (LRFS) of balloon-occluded transarterial chemoembolisation (bTACE) for hepatocellular carcinoma (HCC). Materials and Methods: Patients from five European centres treated with conventional or drug-eluting microsphere bTACE for HCC were included, and patients already lost to follow-up before 12 months were excluded. Possible factors contributing to LRFS and OS were evaluated with Cox proportional hazards models. Results: Seventy-three patients were enrolled. The mean number of nodules per patient was 2.07(± 1.68), and the average maximum diameter of the nodules was 37 ± 19.9 mm. The response of the target lesion at 6 months was complete response (CR) in 58.9%, partial response (PR) in 28.8%, stable disease (SD) in 6.8% and progressive disease (PD) in 5.5%. The median follow-up time was 31 months; at the last follow-up, target tumour response was CR in 49.3%, PR in 12.3%, SD in 5.5% and PD 32.9%. Overall response at the last follow-up was CR in 17.8%, PR in 9.6%, SD 2.7% and PD in 69.9% (for new lesions in 37% of patients). Median OS was not reached; mean overall survival was 50.0 months, while median LRFS was 31.0 months. At uni- and multivariable analysis, only tumour maximum diameter was related to LRFS (hazard ratio [HR] = 1.021; 95% CI 1.004–1.038, P = 0.015). Conclusions: bTACE demonstrated high efficacy for HCC, with a complete response in 58.9% of patients, a median local recurrence-free survival of 31.0 months and a mean overall survival of 50.0 months. Graphical

Conventional transarterial embolization (cTACE) has been proven to be effective for intermediate stage hepatocellular carcinoma (HCC), with a recent systematic review showing an overall survival (OS) of 19.4 months. Nevertheless, due to the rapid development of the systemic therapeutic landscape, the place of TACE is becoming questionable. Is there still a niche for TACE in the era of immunotherapy and combination treatments such as atezolizumab–bevacizumab, which has shown an OS of 19.2 months with excellent tolerance? The development of drug-eluting microspheres (DEMs) has led to the standardization of the technique, and along with adequate selection, it showed an OS of 48 months in a retrospective study. In order to increase treatment selectivity, new catheters have also been added to the TACE arsenal as well as the use of cone-beam CT (CBCT), which provides three-dimensional volumetric images and guidance during procedures. Moreover, the TACE indications have also widened. It may serve as a “bridging therapy” for liver transplantation candidates while they are on the waiting list, and it represents a valuable downstaging tool to transplantation criteria. The aim of this review is to explore the current data on the advancements of TACE and its future place amongst the growing panel of treatments.