Immune checkpoint inhibitors (ICIs) are a key component of different stages of hepatocellular carcinoma (HCC) treatment, particularly in the first line of treatment. A lesson on the primary resistance which hampers their efficacy and activity was learned from the failure of the trials which tested them as first-line mono-therapies. Despite the combination of anti-PD(L)1 agents with anti-VEGF, anti CTLA4, or TKIs demonstrating relevant improvements in efficacy, the “doublets strategy” still shows room for improvement, due to a limited overall survival benefit and a high rate of progressive disease as best response. In this review, we discuss the results from the currently tested doublet strategies (i.e., atezolizumab+bevacizumab, durvalumab+tremelimumab with a mention to the newly presented ICIs/TKIs combinations), which highlight the need for therapeutic improvement. Furthermore, we examine the rationale and provide an overview of the ongoing trials testing the treatment intensification strategy with triplet drugs: anti-PD1+anti-CTLA4+anti-VEGF/TKIs and anti-PD1+anti-VEGF+alternative immunity targets. Lastly, we report on the alternative strategy to integrate ICIs into the new paradigm of immune therapeutics constituted by CAR-T and anti-cancer vaccines. This review provides up-to-date knowledge of ongoing clinical trials of the aforementioned strategies and critical insight into their mechanistic premises.

Claudin 18.2 (CLDN18.2) is highly expressed in up to 40% of gastroesophageal adenocarcinomas (GEA) and represents an emerging therapeutic target for these tumors. However, its distribution across molecular subtypes and its prognostic and predictive roles remain insufficiently studied. This ambispective, multicenter study included 563 patients with GEA diagnosed between 2019 and 2025 across 17 European institutions. Tumor samples were analyzed for CLDN18.2, human epidermal growth factor receptor 2 (HER2), mismatch repair, Epstein-Barr virus (EBV), and programmed death-ligand 1 [PD-L1; combined positive score (CPS)] using immunohistochemistry and/or in situ hybridization. Molecular alterations were characterized using next-generation sequencing. Associations between molecular features and clinical outcomes, such as overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS), were evaluated. High CLDN18.2 expression was observed in 48.3% of tumors, correlating with diffuse-type histology and peritoneal involvement (P < 0.01). Its prevalence varied across molecular subtypes: 33.9% in deficient mismatch repair, 62.5% in EBV-positive, 41.9% in HER2-positive tumors, and 47.2% in tumors with PD-L1 CPS ≥5. Among patients treated with first-line chemotherapy, CLDN18.2 status did not affect mPFS [hazard ratio (HR) 0.90; P = 0.50] or mOS (HR 1.06; P = 0.80). However, among HER2-positive patients, CLDN18.2-high tumors were associated with improved outcomes with HER2-targeted therapy (mPFS 17.0 versus 8.9 months, HR 0.42; P = 0.03; mOS 43.0 versus 23.0 months, HR 0.40; P = 0.07). By contrast, in patients with CLDN18.2-high tumors receiving an immunotherapy-based regimen (IO), there was a trend toward lower ORR (51% versus 64%; P = 0.15), shorter mPFS (8.9 versus 14.0 months; HR 1.47; P = 0.14), and reduced mOS (16.0 versus 43.0 months; HR 2.04; P = 0.052). Combined analyses of CLDN18.2 and PD-L1 showed poorer survival outcomes in CLDN18.2-high tumors across PD-L1 thresholds. CLDN18.2-high GEA was more prevalent than previously reported in pivotal trials and showed substantial overlap across molecular subtypes. It was associated with a greater benefit from HER2-targeted therapy but a trend toward poorer outcomes with IO, underscoring the need for biomarker-guided therapeutic strategies in GEA.

Extended molecular profiling (EMP) is recommended to tailor targeted treatment for advanced cholangiocarcinoma (CCA). However, neither the impact of EMP nor the availability of targeted therapies has been extensively described in a real-world setting. ANITA is an observational (retrospective and prospective) study enrolling 621 patients with CCA from 10 tertiary Italian cancer centers between 2017 and 2023. Current analyses are focused on access to EMP, evolving rates of EMP over time, access to targeted treatments and respective outcomes. Moreover, we explore the prognostic and predictive role of major driver molecular alterations. EMP was performed in 79.9% of patients with advanced CCA. The rate of EMP increased significantly over time (2017-2023: +25.8%). Overall, 139 patients harbored ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) I-III alterations, and 18.7% of these patients received matched targeted therapies. No differences were seen in overall survival (OS) and progression-free survival (PFS) according to EMP availability. Patients receiving targeted therapies had the best OS, which was significantly longer than that of patients who did not receive targeted treatments (hazard ratio 0.49, 95% CI 0.28-0.86) or those without EMP available (hazard ratio 0.34, 95% CI 0.21-0.54). Among ESCAT I-III-positive cases, 42 patients had FGFR2 fusions/rearrangements and 59 had IDH1 mutations. After excluding patients treated with targeted therapies, only FGFR2 fusions/rearrangements retained a prognostic association with OS. Despite the increasing availability of EMP in advanced CCA, patient access to targeted therapies remains suboptimal. Our findings demonstrate that targeted treatments can markedly improve OS. Therefore, strategies to increase access to - and accelerate the availability of - targeted therapies are warranted. ANITA is the largest observational, retrospective and prospective, study exploring the impact of molecular profiling and matched targeted treatment in a large cohort of patients with advanced cholangiocarcinoma. While the availability of molecular profiling has increased in recent years, access to targeted therapy is still limited in routine practice. Administration of targeted treatment has a significant impact on overall survival, highlighting the importance of promoting timely and early access to new agents in this disease. ESR-21-21387.

Programmed death-ligand 1 (PD-L1) expression serves as a predictive biomarker for response to immune checkpoint inhibitors (ICIs) in metastatic gastroesophageal adenocarcinoma (mGEA). The peritoneum is one of the most common metastatic sites and is associated with a poor prognosis and apparently lower clinical efficacy of ICIs. We investigated the heterogeneity of PD-L1 expression in mGEA by examining its concordance between primary tumors and matched peritoneal metastases (PMs), and before and after systemic treatment. PD-L1 expression was assessed using combined positive score (CPS) by immunohistochemistry with VENTANA PD-L1 (SP263) assays on formalin-fixed paraffin-embedded tumor tissues. Results were reported using CPS cut-offs of 1 and 5. Twenty-two primary tumor and matched PM specimens from patients with mGEA were analyzed. The concordance of PD-L1 CPS was 54.5% with a CPS cut-off of 1 and 72.7% with a CPS cut-off of 5, highlighting spatial heterogeneity. Notably, none of the PD-L1-positive primary tumor samples tested positive in the matched PM specimens using the CPS ≥5 cut-off. Potential temporal heterogeneity of PD-L1 expression related to chemo(immuno)therapy administration was also observed, with a 55.6% concordance rate using the CPS ≥5 cut-off. PD-L1 expression in PMs from mGEA is characterized by both spatial and potentially temporal heterogeneity, with the variability being more pronounced at lower CPS cut-off values. This variability complicates its role as a predictive biomarker for ICI outcomes. The high intrapatient discordance rate in PD-L1 CPS expression between positive primary tumor samples and matched PM specimens suggests that peritoneal specimens should not be used as the only source for PD-L1 assessment if representative tissue from other disease sites is available.

Prognosis in advanced gastric cancer (aGC) is predicted by clinical factors, such as stage, performance status, metastasis location, and the neutrophil-to-lymphocyte ratio. However, the role of body composition and sarcopenia in aGC survival remains debated. This study aimed to evaluate how abdominal visceral and subcutaneous fat volumes, psoas muscle volume, and the visceral-to-subcutaneous (VF/SF) volume ratio impact overall survival (OS) and progression-free survival (PFS) in aGC patients receiving first-line palliative chemotherapy. We retrospectively examined CT scans of 65 aGC patients, quantifying body composition parameters (BCPs) in 2D and 3D. Normalized 3D BCP volumes were determined, and the VF/SF ratio was computed. Survival outcomes were analyzed using the Cox Proportional Hazard model between the upper and lower halves of the distribution. Additionally, response to first-line chemotherapy was compared using the χ² test. Patients with a higher VF/SF ratio (N = 33) exhibited significantly poorer OS (p = 0.02) and PFS (p < 0.005) and had a less favorable response to first-line chemotherapy (p = 0.033), with a lower Disease Control Rate (p = 0.016). Notably, absolute BCP measures and sarcopenia did not predict survival. In conclusion, radiologically assessed VF/SF volume ratio emerged as a robust and independent predictor of both survival and treatment response in aGC patients.

Liver transplantation (LT) represents the primary curative option for HCC. Despite the extension of transplantation criteria and conversion with down-staging loco-regional treatments, transplantation is not always possible. The introduction of new standards of care in advanced HCC including a combination of immune checkpoint inhibitor-based therapies led to an improvement in response rates and could represent a promising strategy for down-staging the tumor burden. In this review, we identify reports and series, comprising a total of 43 patients who received immune checkpoint inhibitors as bridging or down-staging therapies prior to LT. Overall, treated patients registered an objective response rate of 21%, and 14 patients were reduced within the Milan criteria. Graft rejection was reported in seven patients, resulting in the death of four patients; in the remaining cases, LT was performed safely after immunotherapy. Further investigations are required to define the duration of immune checkpoint inhibitors, their minimum washout period and the LT long-term safety of this strategy. Some randomized clinical trials including immunotherapy combinations, loco-regional treatment and/or tyrosine kinase inhibitors are ongoing and will likely determine the appropriateness of immune checkpoint inhibitors’ administration before LT.