NASH limits anti-tumour surveillance in immunotherapy-treated HCC.

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1-5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment.

Molecular Markers of Response to Anti-PD1 Therapy in Advanced Hepatocellular Carcinoma.

BACKGROUND & AIMS: Single-agent anti-PD1 checkpoint inhibitors convey outstanding clinical benefits in a small fraction (∼20%) of patients with advanced hepatocellular carcinoma (aHCC) but the molecular mechanisms determining response are unknown. To fill this gap, we herein analyze the molecular and immune traits of aHCC in patients treated with anti-PD1. METHODS: Overall, 111 tumor samples from patients with aHCC were obtained from 13 centers before systemic therapies. We performed molecular analysis and immune deconvolution using whole-genome expression data (n = 83), mutational analysis (n = 72), and histologic evaluation with an endpoint of objective response. RESULTS: Among 83 patients with transcriptomic data, 28 were treated in frontline, whereas 55 patients were treated after tyrosine kinase inhibitors (TKI) either in second or third line. Responders treated in frontline showed upregulated interferon-γ signaling and major histocompatibility complex II-related antigen presentation. We generated an 11-gene signature (IFNAP), capturing these molecular features, which predicts response and survival in patients treated with anti-PD1 in frontline. The signature was validated in a separate cohort of aHCC and >240 patients with other solid cancer types where it also predicted response and survival. Of note, the same signature was unable to predict response in archival tissue of patients treated with frontline TKIs, highlighting the need for fresh biopsies before immunotherapy. CONCLUSION: Interferon signaling and major histocompatibility complex-related genes are key molecular features of HCCs responding to anti-PD1. A novel 11-gene signature predicts response in frontline aHCC, but not in patients pretreated with TKIs. These results must be confirmed in prospective studies and highlights the need for biopsies before immunotherapy to identify biomarkers of response.

Management of biliary tract cancers in early-onset patients: A nested multicenter retrospective study of the ACABI GERCOR PRONOBIL cohort.

BACKGROUND & AIMS: Accumulating data has shown the rising incidence and poor prognosis of early-onset gastrointestinal cancers, but few data exist on biliary tract cancers (BTC). We aimed to analyse the clinico-pathological, molecular, therapeutic characteristics and prognosis of patients with early onset BTC (EOBTC, age ≤50 years at diagnosis), versus olders. METHODS: We analysed patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder adenocarcinoma between 1 January 2003 and 30 June 2021. Baseline characteristics and treatment were described in each group and compared. Progression-free survival, overall survival and disease-free survival were estimated in each group using the Kaplan-Meier method. RESULTS: Overall, 1256 patients were included, 188 (15%) with EOBTC. Patients with EOBTC demonstrated fewer comorbidities (63.5% vs. 84.5%, p < .0001), higher tumour stage (cT3-4: 50.0% vs. 32.3%, p = .0162), bilobar liver involvement (47.8% vs. 32.1%, p = .0002), and metastatic disease (67.6% vs. 57.5%, p = .0097) compared to older. Patients with EOBTC received second-line therapy more frequently (89.5% vs. 81.0% non-EOBTC, p = .0224). For unresectable patients with BTC, median overall survival was 17.0 vs. 16.2 months (p = .0876), and median progression-free survival was 5.8 vs. 6.0 months (p = .8293), in EOBTC vs. older. In advanced stages, fewer actionable alterations were found in EOBTC (e.g., IDH1 mutations [7.8% vs. 16.6%]; FGFR2-fusion [11.7% vs. 8.9%]; p = .029). CONCLUSIONS: Patients with EOBTC have a more advanced disease at diagnosis, are treated more heavily at an advanced stage but show similar survival. A distinctive molecular profile enriched for FGRF2 fusions was found.

Inflamed and non-inflamed classes of HCC: a revised immunogenomic classification.

OBJECTIVE: We previously reported a characterisation of the hepatocellular carcinoma (HCC) immune contexture and described an immune-specific class. We now aim to further delineate the immunogenomic classification of HCC to incorporate features that explain responses/resistance to immunotherapy. DESIGN: We performed RNA and whole-exome sequencing, T-cell receptor (TCR)-sequencing, multiplex immunofluorescence and immunohistochemistry in a novel cohort of 240 HCC patients and validated our results in other cohorts comprising 660 patients. RESULTS: Our integrative analysis led to define: (1) the inflamed class of HCC (37%), which includes the previously reported immune subclass (22%) and a new immune-like subclass (15%) with high interferon signalling, cytolytic activity, expression of immune-effector cytokines and a more diverse T-cell repertoire. A 20-gene signature was able to capture ~90% of these tumours and is associated with response to immunotherapy. Proteins identified in liquid biopsies recapitulated the inflamed class with an area under the ROC curve (AUC) of 0.91; (2) The intermediate class, enriched in TP53 mutations (49% vs 29%, p=0.035), and chromosomal losses involving immune-related genes and; (3) the excluded class, enriched in CTNNB1 mutations (93% vs 27%, p<0.001) and PTK2 overexpression due to gene amplification and promoter hypomethylation. CTNNB1 mutations outside the excluded class led to weak activation of the Wnt-ßcatenin pathway or occurred in HCCs dominated by high interferon signalling and type I antigen presenting genes. CONCLUSION: We have characterised the immunogenomic contexture of HCC and defined inflamed and non-inflamed tumours. Two distinct CTNNB1 patterns associated with a differential role in immune evasion are described. These features may help predict immune response in HCC.

Evidence-Based Management of Hepatocellular Carcinoma: Systematic Review and Meta-analysis of Randomized Controlled Trials (2002-2020).

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, with a rapidly changing landscape of treatments. In the past 20 years, numerous randomized controlled trials (RCTs) have aimed at improving outcomes across disease stages. We aimed to analyze the current evidence and identify potential factors influencing response to therapies. METHODS: We conducted a systematic review of phase III RCTs (2002-2020) across disease stages. A meta-analysis was designed to examine the relationship between etiology and outcome after systemic therapies with either tyrosine-kinase inhibitor (TKI)/antiangiogenic or immune checkpoint inhibitor (ICI) therapy. RESULTS: Out of 10,100 studies identified, 76 were phase III RCTs. Among them, a rigorous screening algorithm identified 49 with high quality including a total of 22,113 patients undergoing adjuvant (n = 7) and primary treatment for early (n = 2), intermediate (n = 7), and advanced (first-line, n = 21; second-line, n = 12) stages of disease. Nine of these trials were positive, 6 treatments have been adopted in guidelines (sorafenib [2 RCTs], lenvatinib, atezolizumab+bevacizumab, regorafenib, cabozantinib and ramucirumab), but 2 were not (adjuvant CIK cells and sorafenib plus hepatic arterial infusion with FOLFOX). Meta-analysis of 8 trials including 3739 patients revealed ICI therapy to be significantly more effective in patients with viral hepatitis compared with nonviral-related HCC, whereas no differences related to etiology were observed in patients treated with TKI/anti-vascular endothelial growth factor. CONCLUSIONS: Among 49 high-quality RCTs conducted in HCC during 2002-2020, 9 resulted in positive results. A meta-analysis of systemic therapies suggests that immunotherapies may be more effective in viral etiologies.

The emergence of long-term survivors in recurrent and metastatic squamous cell head and neck cancer.

PURPOSE OF REVIEW: The systemic therapies available in recurrent and metastatic head and neck squamous cell carcinoma to date are palliative-intent treatments in most cases. However, a small subgroup of patients derives unconventional benefit and become long-term survivors, achieving cure in some cases. This review focusses on this group of patients, discusses recent literature and suggests plausible molecular hypothesis. RECENT FINDINGS: Human papillomavirus-related disease is known to confer a better prognosis in metastatic patients, probably because of its greater sensitivity to systemic therapies. This group of patients seems to have a greater immune activation, which could partly explain this fact. Moreover, the use of antiepidermal growth factor receptor therapies in the metastatic setting has doubled the prevalence of long-term survivors. One of the most plausible explanations is the immune-modulatory effect of cetuximab mediated by antibody-dependent cell-mediated cytotoxicity.These facts, along with the recent encouraging results of checkpoint inhibitors in this disease, give hope that these therapies will not only improve survival but also increase the prevalence of long-term survivors. SUMMARY: Long-term survivors merit our utmost attention as an in-depth study of these patients could help us to better understand the tumour biology and allow us to develop robust biomarkers and effective targeted therapies, which could in turn lead to a true paradigm shift.

Contrast-enhancement in supratentorial low-grade gliomas: a classic prognostic factor in the molecular age.

BACKGROUND: Contrast enhancement (CE) is found in 10-60% of low-grade gliomas. Its prognostic significance is controversial, and its correlation with IDH mutations and 1p/19q codeletion is elusive. The aim of this study is to investigate whether CE is associated with molecular characteristics of low-grade gliomas and uncover its prognostic value. MATERIALS AND METHODS: All confirmed histological cases of low-grade gliomas diagnosed at our institution between years 2000-2016 were reviewed (n = 102). Spinal and brainstem localization, only-biopsied tumours with ring-like enhancement and incomplete medical records were excluded. RESULTS: Mean age was 42 years ( ± 13.9 years), and 63.6% were male. The median follow-up time was 79.8 months. CE was present on 25% of preoperative MRI, and 25% of patients were considered high-risk according to Pignatti score. Most were astrocytomas (67%) and 87.2% were surgically removed. IDH mutation was found in 64.6% of tumour samples, and 18.8% had a 1p/19q codeletion. No subgroup differences were observed according to CE except for presurgical performance status and postoperative chemotherapy. IDH status and 1p/19q codeletion were evenly distributed. On univariate analysis, age, size > 6 cm, CE, extent of resection, Pignatti score, IDH mutation and 1p/19q codeletion were significantly associated to OS. On multivariate analysis, only CE and IDH status were independently associated to OS. CE remained a significant prognostic factor in IDH-mutant non-codeleted tumours when analysed by tumour subtype. CONCLUSION: CE in low-grade gliomas provides prognostic information in IDH-mutant non-codeleted tumours, although its meaning remains uncertain in IDH-wildtype gliomas.

Clinical value of liquid biopsy in FGFR2 fusion-positive cholangiocarcinoma patients during targeted therapy.

PURPOSE: FGFR2 fusions occur in 10%-15% of intrahepatic cholangiocarcinoma (iCCA) patients, potentially benefiting from FGFR inhibitors (FGFRi). We aimed to assess the feasibility of detecting FGFR2 fusions in plasma and explore plasma biomarkers for managing FGFRi treatment. EXPERIMENTAL DESIGN: We conducted a retrospective study on 18 patients with iCCA and known FGFR2 fusions previously identified in tissue samples from prior FGFRi treatment. Both tissue and synchronous plasma samples were analyzed using a custom hybrid capture gene panel with next-generation sequencing (VHIO-iCCA panel) and validated against commercial vendor results. Longitudinal plasma analysis during FGFRi was performed. Subsequently, we explored the correlation between plasma biomarkers, liver enzymes, tumor volume, and clinical outcomes. RESULTS: Sixteen patients (88.9%) were positive for FGFR2 fusion events in plasma. Remarkably, the analysis of plasma suggests that lower levels of circulating tumor DNA (ctDNA) are linked to clinical benefits from targeted therapy and result in improved progression-free survival and (PFS) overall survival (OS). Higher concentrations of cell-free DNA (cfDNA) before FGFRi treatment were linked to worse OS, correlating with impaired liver function, and indicating compromised cfDNA removal by the liver. Additionally, increased ctDNA or the emergence of resistance mutations allowed earlier detection of disease progression compared to standard radiological imaging methods. CONCLUSIONS: VHIO-iCCA demonstrated accurate detection of FGFR2 fusions in plasma. The integration of information from various plasma biomarkers holds the potential to predict clinical outcomes and identify treatment failure prior to radiological progression, offering valuable guidance for the clinical management of patients with iCCA.

Generation of Metastatic Cholangiocarcinoma Patient-Derived Xenograft Models.

Cholangiocarcinoma (CCA) poses a substantial clinical hurdle as it is often detected at advanced metastatic stages with limited therapeutic options. To enhance our understanding of advanced CCA, it is imperative to establish preclinical models that faithfully recapitulate the disease's characteristics. Patient-derived xenograft (PDX) models have emerged as a valuable approach in cancer research, offering an avenue to reproduce and study the genomic, histologic, and molecular features of the original human tumors. By faithfully preserving the heterogeneity, microenvironmental interactions, and drug responses observed in human tumors, PDX models serve as highly relevant and predictive preclinical tools. Here, we present a comprehensive protocol that outlines the step-by-step process of generating and maintaining PDX models using biopsy samples from patients with advanced metastatic CCA. The protocol encompasses crucial aspects such as tissue processing, xenograft transplantation, and subsequent monitoring of the PDX models. By employing this protocol, we aim to establish a robust collection of PDX models that accurately reflect the genomic landscape, histologic diversity, and therapeutic responses observed in advanced CCA, thereby enabling improved translational research, drug development, and personalized treatment strategies for patients facing this challenging disease.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: A large real-life worldwide population.

BACKGROUND: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes. METHODS: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS). RESULTS: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine. CONCLUSION: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC.

Liquid biopsy after resection of pancreatic adenocarcinoma and its relation to oncological outcomes. Systematic review and meta-analysis.

BACKGROUND: It has been hypothesised that manipulation during surgery releases tumoral components into circulation. We investigate the effect of surgery on plasma-borne DNA biomarkers and the oncological outcomes in resectable pancreatic ductal adenocarcinoma (PDAC). We also compare non-touch isolation techniques (NTIT) with standard techniques. MATERIALS AND METHODS: We performed a systematic review and a meta-analysis of studies analysing liquid biopsy as circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), and messenger RNA (mRNA) in resectable PDAC patients who underwent surgery and its association with overall survival (OS) and disease-free survival (DFS). Research in EMBASE, Web of Science and PubMed was performed. The ctDNA shift negative-to-positive (ctDNA -/+) or ctDNA shift positive-to-negative (ctDNA +/-) before and after surgery was evaluated. RESULTS: Twelve studies comprising 413 patients were included. Shorter OS and DFS were identified in patients with positive ctDNA status before (HR = 2.28, p = 0.005 and HR = 2.16, p = 0.006) or after surgery (HR = 3.88, p < 0.0001 and HR = 3.81, p = 0.03), respectively. Surgical resection increased the rate of ctDNA +/-. There were no differences in OS or DFS in the ctDNA +/- group compared with ctDNA +/+ or ctDNA -/+. However, there was a trend to shorter OS in the ctDNA -/+ group (HR = 5.00, p = 0.09). No differences between NTIT and standard techniques on liquid biopsy status were found. CONCLUSION: Positive ctDNA in the perioperative period is associated with a worse prognosis. Surgical resection has a role in the negativisation of liquid biopsy status. More studies are needed to assess the potential of minimally invasive techniques on ctDNA dynamics.

Clinical and genomic characterisation of early-onset pancreatic cancer.

BACKGROUND: The incidence of early-onset pancreatic cancer (EOPC) has risen dramatically in recent years. We aimed to characterise the clinical and genomic features of EOPC and evaluate their therapeutic implications. METHODS: We performed a comparative, single-centre, retrospective analysis of clinical, germline, and genomic features in EOPC (≤50 years) patients and compared them with a control group of average-onset pancreatic cancer patients (AOPC, ≥70 years). Key molecular findings were compared with an external, publicly available cohort. RESULTS: We reviewed 336 patients who met all inclusion criteria (EOPC N = 139, AOPC N = 197). EOPC was associated with smoking status, lower prevalence of diabetes, better performance status, higher CA19.9 levels, and higher albumin levels at diagnosis. After adjustment for baseline covariates, we observed no differences in overall survival (OS). Age was associated with an increase in the incidence of KRASMUT both in our cohort and the validation cohort. EOPC were enriched in potentially actionable alterations according to ESCAT tiers I-IIIA when compared with AOPC in discovery and validation cohorts (19% versus 14% and 14% versus 8%, respectively). In the first-line metastatic setting, EOPC had a longer progression-free survival (hazard ratio [HR] 0.61, 95% confidence interval (CI) 0.43-0.87) and OS (HR 0.65, 95% CI 0.45-0.95), although there were no differences in response rate. After adjusting for the number of treatment lines, EOPC patients who did receive targeted therapies exhibited longer OS compared with EOPC who did not (HR 0.34, 95% CI 0.12-0.93). CONCLUSIONS: EOPC patients have improved outcomes in the metastatic setting when compared to AOPC and are enriched for targetable alterations that open opportunities for precision oncology-based approaches.

Human Metastatic Cholangiocarcinoma Patient-Derived Xenografts and Tumoroids for Preclinical Drug Evaluation.

PURPOSE: Cholangiocarcinoma (CCA) is usually diagnosed at advanced stages, with limited therapeutic options. Preclinical models focused on unresectable metastatic CCA are necessary to develop rational treatments. Pathogenic mutations in IDH1/2, ARID1A/B, BAP1, and BRCA1/2 have been identified in 30%-50% of patients with CCA. Several types of tumor cells harboring these mutations exhibit homologous recombination deficiency (HRD) phenotype with enhanced sensitivity to PARP inhibitors (PARPi). However, PARPi treatment has not yet been tested for effectiveness in patient-derived models of advanced CCA. EXPERIMENTAL DESIGN: We have established a collection of patient-derived xenografts from patients with unresectable metastatic CCA (CCA_PDX). The CCA_PDXs were characterized at both histopathologic and genomic levels. We optimized a protocol to generate CCA tumoroids from CCA_PDXs. We tested the effects of PARPis in both CCA tumoroids and CCA_PDXs. Finally, we used the RAD51 assay to evaluate the HRD status of CCA tissues. RESULTS: This collection of CCA_PDXs recapitulates the histopathologic and molecular features of their original tumors. PARPi treatments inhibited the growth of CCA tumoroids and CCA_PDXs with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1. In line with these findings, only CCA_PDX and CCA patient biopsy samples with mutations of BRCA2 showed RAD51 scores compatible with HRD. CONCLUSIONS: Our results suggest that patients with advanced CCA with pathogenic mutations of BRCA2, but not those with mutations of IDH1, ARID1A, or BAP1, are likely to benefit from PARPi therapy. This collection of CCA_PDXs provides new opportunities for evaluating drug response and prioritizing clinical trials.

Current and emerging anti-angiogenic therapies in gastrointestinal and hepatobiliary cancers.

Gastrointestinal tumours are a heterogeneous group of neoplasms that arise in the gastrointestinal tract and hepatobiliary system. Their incidence is rising globally and they currently represent the leading cause of cancer-related mortality worldwide. Anti-angiogenic agents have been incorporated into the treatment armamentarium of most of these malignancies and have improved survival outcomes, most notably in colorectal cancer and hepatocellular carcinoma. New treatment combinations with immunotherapies and other agents have led to unprecedented benefits and are revolutionising patient care. In this review, we detail the mechanisms of action of anti-angiogenic agents and the preclinical rationale underlying their combinations with immunotherapies. We review the clinical evidence supporting their use across all gastrointestinal tumours, with a particular emphasis on colorectal cancer and hepatocellular carcinoma. We discuss available biomarkers of response to these therapies and their utility in routine clinical practice. Finally, we summarise ongoing clinical trials in distinct settings and highlight the preclinical rationale supporting novel combinations.

Immunotherapies for hepatocellular carcinoma.

Liver cancer, more specifically hepatocellular carcinoma (HCC), is the second leading cause of cancer-related death and its incidence is increasing globally. Around 50% of patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib in the first line and regorafenib, cabozantinib or ramucirumab in the second line. In the past 5 years, immune-checkpoint inhibitors have revolutionized the management of HCC. The combination of atezolizumab and bevacizumab has been shown to improve overall survival relative to sorafenib, resulting in FDA approval of this regimen. More recently, durvalumab plus tremelimumab yielded superior overall survival versus sorafenib and atezolizumab plus cabozantinib yielded superior progression-free survival. In addition, pembrolizumab monotherapy and the combination of nivolumab plus ipilimumab have received FDA Accelerated Approval in the second-line setting based on early efficacy data. Despite these major advances, the molecular underpinnings governing immune responses and evasion remain unclear. The immune microenvironment has crucial roles in the development and progression of HCC and distinct aetiology-dependent immune features have been defined. Inflamed and non-inflamed classes of HCC and genomic signatures have been associated with response to immune-checkpoint inhibitors, yet no validated biomarker is available to guide clinical decision-making. This Review provides information on the immune microenvironments underlying the response or resistance of HCC to immunotherapies. In addition, current evidence from phase III trials on the efficacy, immune-related adverse events and aetiology-dependent mechanisms of response are described. Finally, we discuss emerging trials assessing immunotherapies across all stages of HCC that might change the management of this disease in the near future.

Objective Response Predicts Survival in Advanced Hepatocellular Carcinoma Treated with Systemic Therapies.

PURPOSE: Because of the increased number of sequential treatments used for advanced hepatocellular carcinoma (HCC), there is a need for surrogate endpoints of overall survival (OS). We analyze whether objective response (OR) is an independent predictor and surrogate endpoint of OS. PATIENTS AND METHODS: A systematic review of randomized clinical trials (RCT) in advanced HCC published between 2010 and 2020 was conducted to explore OS surrogacy of OR by Response Evaluation Criteria in Solid Tumors (RECIST) and modified RECIST (mRECIST). In parallel, RCTs exploring the impact of OR on OS in a time-dependent multivariate analysis were integrated in a meta-analysis. RESULTS: Of 65 RCTs identified in advanced HCC, we analyzed 34 studies including 14,056 patients that reported OS and OR by either RECIST (n = 23), mRECIST (n = 5), or both (n = 6). When exploring surrogacy, the trial-level correlation between OR odds ratio and OS HR was R = 0.677 by mRECIST and R = 0.532 by RECIST. Meta-analysis of five RCTs assessing predictors of survival in multivariate analysis found that patients with OR by mRECIST presented a pooled HR for OS of 0.44 (95% confidence interval, 0.27-0.70; P < 0.001) compared with nonresponders. Responses to atezolizumab-bevacizumab had a greater impact on OS than tyrosine kinase inhibitor responses. CONCLUSIONS: OR-mRECIST is an independent predictor of OS in patients with advanced HCC. Although correlation of OR-mRECIST and OS is better than with OR-RECIST, the level of surrogacy is modest. Thus, it can be used as endpoint in proof-of-concept phase II trials, but the data do not support its use as a primary endpoint of phase III investigations assessing systemic therapies.

Atezolizumab plus Bevacizumab: A Novel Breakthrough in Hepatocellular Carcinoma.

The combination of atezolizumab and bevacizumab increases overall survival compared with sorafenib in advanced hepatocellular carcinoma (HCC). Its approval by the FDA has launched a new era of combination therapies in advanced and earlier settings that are likely to reshape the management of HCC across all disease stages.See related article by Casak et al., p. 1836.

Uveal Melanoma, Angiogenesis and Immunotherapy, Is There Any Hope?

Uveal melanoma is considered a rare disease but it is the most common intraocular malignancy in adults. Local treatments are effective, but the systemic recurrence rate is unacceptably high. Moreover, once metastasis have developed the prognosis is poor, with a 5-year survival rate of less than 5%, and systemic therapies, including immunotherapy, have rendered poor results. The tumour biology is complex, but angiogenesis is a highly important pathway in these tumours. Vasculogenic mimicry, the ability of melanomas to generate vascular channels independently of endothelial cells, could play an important role, but no effective therapy targeting this process has been developed so far. Angiogenesis modulates the tumour microenvironment of melanomas, and a close interplay is established between them. Therefore, combining immune strategies with drugs targeting angiogenesis offers a new therapeutic paradigm. In preclinical studies, these approaches effectively target these tumours, and a phase I clinical study has shown encouraging results in cutaneous melanomas. In this review, we will discuss the importance of angiogenesis in uveal melanoma, with a special focus on vasculogenic mimicry, and describe the interplay between angiogenesis and the tumour microenvironment. In addition, we will suggest future therapeutic approaches based on these observations and mention ways in which to potentially enhance current treatments.