Incidence and Predictors of Esophagogastric Varices Bleeding in Patients with Hepatocellular Carcinoma in Lenvatinib.

Introduction: Lenvatinib is indicated for the forefront treatment of advanced hepatocellular carcinoma (aHCC), but its use may be limited by the risk of esophagogastric varices (EGV) bleeding. This study assessed the prevalence, predictors, and complications of EGV in aHCC patients treated with lenvatinib. Methods: In this multicenter international retrospective study, cirrhotic patients treated with lenvatinib for aHCC, were enrolled if upper-gastrointestinal endoscopy was available within 6 months before treatment. Primary endpoint was the incidence of EGV bleeding during lenvatinib therapy; secondary endpoints were predictors for EGV bleeding, prevalence, and risk factors for the presence of EGV and high-risk EGV at baseline, as well as impact of EGV bleeding on patients' survival. Results: 535 patients were enrolled in the study (median age: 72 years, 78% male, 63% viral etiology, 89% Child-Pugh A, 16% neoplastic portal vein thrombosis [nPVT], 56% Barcelona Clinic Liver Cancer-C): 234 had EGV (44%), 70 (30%) were at high risk and 59 were on primary prophylaxis. During lenvatinib treatment, 17 patients bled from EGV (3 grade 5), the 12-month cumulative incidence being 3%. The only baseline independent predictor of EGV bleeding was the presence of baseline high-risk EGV (hazard ratio: 6.94, 95% confidence interval [CI]: 2.23-21.57, p = 0.001). In these patients the 12-month risk was 17%. High-risk varices were independently associated with Child-Pugh B score (odds ratio [OR]: 2.12; 95% CI: 1.08-4.17, p = 0.03), nPVT (OR: 2.54; 95% CI: 1.40-4.61, p = 0.002), and platelets <150,000/µL (OR: 2.47; 95% CI: 1.35-4.50, p = 0.003). Conclusion: In hepatocellular carcinoma patients treated with lenvatinib, the risk of EGV bleeding was mostly low but significant only in patients with high-risk EGV at baseline.

Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). OBJECTIVE: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. PATIENTS AND METHODS: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. RESULTS: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. CONCLUSION: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

Different Genomic Clusters Impact on Responses in Advanced Biliary Tract Cancer Treated with Cisplatin Plus Gemcitabine Plus Durvalumab.

BACKGROUND: The results reported in the TOPAZ-1 phase III trial led to the approval of the combination of cisplatin and gemcitabine with durvalumab as the new first-line standard of care for patients with locally advanced or metastatic cholangiocarcinoma. OBJECTIVE: We performed a clustering analysis to classify patients into different groups based on their mutation profile, correlating the results of the analysis with clinical outcomes. METHODS: We selected 51 patients with cholangiocarcinoma who were treated with the combination of chemotherapy and durvalumab and who were screened using the next-generation sequencing-based FoundationOne gene panel. We conducted mutation-based clustering of tumors and a survival analysis. RESULTS: Three main clusters were identified. Cluster 1 is mostly characterized by mutations in genes belonging to the chromatin modification pathway, altered in 100% of patients. Cluster 2 is characterized by the alteration of several pathways, among which DNA damage control, chromatin modification, RTK/RAS, cell-cycle apoptosis, TP53, and PI3K were the most affected. Finally, most altered pathways in cluster 3 were RTK/RAS and cell-cycle apoptosis. Overall response rate was 4/13 (31%), 12/24 (50%), and 0/10 (0%) in cluster 1, cluster 2, and cluster 3, respectively, and the difference between the three clusters was statistically significant (p = 0.0188). CONCLUSIONS: By grouping patients into three clusters with distinct molecular and genomic alterations, our analysis showed that patients included in cluster 2 had higher overall response rates, whereas patients included in cluster 3 had no objective response. Further investigations on larger and external cohorts are needed in order to validate our results.

Comparative Genomic Analysis and Clinical Outcomes of BRAF-mutated Advanced Biliary Tract Cancers.

PURPOSE: BRAF mutations are rare in biliary tract cancers (BTC), but are of interest given the recent developments in targeted therapy for BTC. We investigated the clinical outcomes in a cohort of BRAF-mutant advanced BTC treated with first-line chemotherapy. Furthermore, we investigated the genomic landscape of BRAF class I, II, and III mutations in the intrahepatic cholangiocarcinoma (iCCA) subgroup of BTC. EXPERIMENTAL DESIGN: We analyzed two nonoverlapping cohorts. We examined the genomic landscape of BRAF-mutated iCCA in a "genomic cohort" [187 class I, 82 class II, 113 class III BRAF mutants and 8,026 wildtype (WT)]. We also analyzed median progression-free survival (PFS) and overall survival (OS) on first-line chemotherapy in a separate multi-institutional "clinical cohort" of patients with BTC (including iCCA and extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer; 41 class I, 32 class II+III BRAF mutants and 1,042 WT). RESULTS: In the entire BTC clinical cohort, the median PFS was shorter for class I [HR, 2.11 (P < 0.001)] and class II+III [HR, 1.72 (P = 0.007)] as compared with BRAF WT. OS was also shorter in class I [HR, 2.04 (P = 0.011)] and class II+III [HR, 1.86 (P = 0.002)] as compared with BRAF WT. In the iCCA subgroup, class I alterations were mutually exclusive with FGFR2, IDH1/2, ERBB2, and KRAS mutations. Class II+III mutations appear to be mutually exclusive with FGFR2 and KRAS. CONCLUSIONS: In BTC, all classes of BRAF mutations are associated with a worse prognosis. BRAF mutations occur in 5% of iCCA subgroup and may be mutually exclusive with other targetable mutations.

Updated survival outcomes with ivosidenib in patients with previously treated IDH1-mutated intrahepatic-cholangiocarcinoma: an Italian real-world experience.

Background: The results of the phase III ClarIDHy trial led to the FDA approval of ivosidenib as a therapeutic option for patients with locally advanced or metastatic cholangiocarcinoma (CCA) harboring isocitrate dehydrogenase 1 (IDH1) mutations. We recently published the first data on the use of ivosidenib in a real-world setting. Objective: Here we report the updated survival results of 11 patients with locally advanced or metastatic IDH1-mutated CCA who received ivosidenib in clinical practice. Patients and methods: Patients treated with ivosidenib as second- and third-line treatments for advanced CCA have been collected with the aim to evaluate the survival outcomes. A molecular study has been performed by next generation sequencing essay. Results: Overall, 11 patients were included. After a median follow-up of 13.7 months, median progression-free survival from the start of treatment with ivosidenib was 4.4 months (95% CI: 2.0-5.8), whereas median overall survival was 15 months (95% CI: 6.6-15.0) regardless of treatment line. Disease control rate was 63%, with two patients achieving a partial response (18%). Eighteen percent of patients experienced at least one treatment-related adverse events (AEs), but no grade ⩾3 was reported. The most frequently observed grade 2 AEs were prolonged QT interval and hypomagnesemia. A molecular profiling was performed on 8 out of 11 patients, highlighting TP53, BAP1, CDKN2A, and CDKN2B as the most common co-altered genes in these patients. Conclusion: The present update confirms the results of our previous real-world experience on the use of ivosidenib in IDH1-mutated CCA. Real-world evidence on larger numbers of patients is needed to confirm our findings.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real-world setting. METHODS: The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression-free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. RESULTS: From February 2022 to November 2022, 145 patients were enrolled. After a median follow-up of 8.5 months (95% CI: 7.9-13.6), the median PFS was 8.9 months (95% CI: 7.4-11.7). Median OS was 12.9 months (95% CI: 10.9-12.9). The investigator-assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3-4 AEs occurred in 51 patients (35.2%). The rate of immune-mediated AEs (imAEs) was 22.7%. Grades 3-4 imAEs occurred in 2.1% of the patients. In univariate analysis, non-viral aetiology, ECOG PS >0 and NLR ≥3 correlated with shorter PFS. CONCLUSION: The results reported in this first real-world analysis mostly confirmed the results achieved in the TOPAZ-1 trial in terms of PFS, ORR and safety.

Clinical Outcomes After Progression on First-Line Therapies in IDH1 Mutated Versus Wild-Type Intrahepatic Cholangiocarcinoma Patients.

BACKGROUND: Isocitrate dehydrogenase-1 (IDH1) mutations occur in a significant proportion of intrahepatic cholangiocarcinomas (iCCAs). No data are available regarding the prognostic impact of IDH1 mutations in advanced iCCA patients after progression on first-line therapies. OBJECTIVE: We investigated the role of IDH1 mutation in advanced iCCA after progression on first-line therapies. PATIENTS AND METHODS: After progression on first-line therapies for advanced iCCA, consecutive patients were retrospectively collected. The IDH1 status was tested at baseline. This analysis aimed to examine the association between the presence of IDH1 missense mutations and survival outcomes in patients with advanced iCCA treated with a second-line therapy. RESULTS: The analysis included 119 patients; 56/119 (47%) were IDH1 mutated (IDH1m) and 63/119 (53%) were IDH1 wild type (IDH1 WT). At univariate analysis for overall survival (OS), the presence of IDH1 mutation was associated with a worse median OS (mOS; 8.2 vs. 14.1 months; hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.0, p = 0.0047). Patients harboring IDH1 mutations showed a worse objective response rate (ORR) compared with patients without IDH1 mutation, whereas no significant differences in disease control rate (DCR) were found. Multivariate analysis confirmed IDH1 mutations as an independent negative prognostic factor for OS (HR 1.7, 95% CI 1.1-2.7, p = 0.0256). By evaluating only patients receiving FOLFOX as second-line therapy, no statistically significant differences were found in terms of both OS and PFS between IDH1m and IDH1 WT patients. In this subset of patients, those harboring an IDH1 mutation showed a worse ORR and DCR compared with those without. Finally, at univariate analysis for OS from third-line treatment, the presence of an IDH1 mutation was associated with a trend toward a worse mOS (6.0 vs. 11.9 months; HR 1.6, 95% CI 0.8-3.2, p = 0.25). CONCLUSION: The present analysis constitutes the first evidence of a negative prognostic impact of IDH1 mutations in a cohort of patients treated after progression on first-line therapies in contrast to IDH1 inhibitors.

Molecular profile and its clinical impact of IDH1 mutated versus IDH1 wild type intrahepatic cholangiocarcinoma.

IDH1-mutated cholangiocarcinomas (CCAs) are an interesting group of neoplasia with particular behavior and therapeutic implications. The aim of the present work is to highlight the differences characterizing IDH1m and IDH1wt CCAs in terms of genomic landscape. 284 patients with iCCA treated for resectable, locally advanced or metastatic disease were selected and studied with the FOUNDATION Cdx technology. A comparative genomic analysis and survival analyses for the most relevant altered genes were performed between IDH1m and IDH1wt patients. Overall, 125 patients were IDH1m and 122 IDH1wt. IDH1m patients showed higher mutation rates compared to IDH1wt in CDKN2B and lower mutation rates in several genes including TP53, FGFR2, BRCA2, ATM, MAP3K1, NOTCH2, ZNF703, CCND1, NBN, NF1, MAP3KI3, and RAD21. At the survival analysis, IDH1m and IDH1wt patients showed no statistically differences in terms of survival outcomes, but a trend in favor of IDH1wt patients was observed. Differences in prognostic values of the most common altered genes were reported. In surgical setting, in IDH1m group the presence of CDKN2A and CDKN2B mutations negatively impact DFS, whereas the presence of CDKN2A, CDKN2B, and PBRM1 mutations negatively impact OS. In advanced setting, in the IDH1m group, the presence of KRAS/NRAS and TP53 mutations negatively impact PFS, whereas the presence of TP53 and PIK3CA mutations negatively impact OS; in the IDH1wt group, only the presence of MTAP mutation negatively impact PFS, whereas the presence of TP53 mutation negatively impact OS. We highlighted several molecular differences with distinct prognostic implications between IDH1m and IDH1wt patients.

The oncological multidimensional prognostic index is a promising decision-making tool: A real-world analysis in older patients with metastatic colorectal cancer.

BACKGROUND: Approximately 50% of colorectal cancers occur in older patients. International societies recommend geriatric tools to optimise treatment of older patients. Comprehensive Geriatric Assessment (CGA) is a multidimensional assessment used to classify patients as fit, vulnerable, or frail. The CGA-based oncological multidimensional prognostic index (onco-MPI) also classifies patients as high-, intermediate-, or low-risk based on tumour characteristics. We investigated the role of CGA and onco-MPI in older patients with metastatic colorectal cancer (mCRC) in a real-world setting. METHODS: Data for consecutive mCRC patients aged ≥70 years were retrieved from a prospectively maintained database from 2010 to 2020. We analyzed patients' and tumours' characteristics, and the CGA domains. Onco-MPI was calculated by a validated algorithm derived from CGA domains. Pearson's test was used to verify whether onco-MPI scores and chemotherapy administration were correlated. RESULTS: The study included 488 mCRC patients with a mean age of 76.1 years. According to CGA, 52% of patients were fit, 28% vulnerable, and 20% frail. According to onco-MPI, 9% were low, 54% intermediate, and 37% high-risk. The median OS was 22.7 months. The following factors improved OS: 0-1 ECOG PS, low onco-MPI, fit based on CGA, chemotherapy administration, and doublet regimen. Chemotherapy administration significantly correlated with onco-MPI scores, leading to a survival gain regardless of the risk subgroups. First-line regimen had no impact on survival across the CGA and onco-MPI categories. CONCLUSION: CGA and onco-MPI scores confirmed their prognostic impact in older mCRC patients and may aid in decision-making and subgroup stratification in dedicated trials.

Next-generation sequencing analysis of cholangiocarcinoma identifies distinct IDH1-mutated clusters.

BACKGROUND: IDH1-mutated intrahepatic cholangiocarcinomas (IDH1m iCCAs) could be treated with anti-IDH1 drugs, although the high heterogeneity in this class of tumours could limit treatment efficacy. METHODS: We selected 125 IDH1m iCCAs that were treated as resectable, locally advanced, or metastatic and were screened by the NGS-based FoundationOne gene panel. We conducted a mutation-based clustering of tumours and survival analysis. RESULTS: Three main clusters were identified. The most altered pathways in cluster 1 were cell cycle and apoptosis, RTK/RAS, PI3K, and chromatin modification. Of note, CDKN2A/2B were mutated in 41/44 patients of this cluster. In cluster 2, the most affected pathways were as follows: Chromatin modification, DNA damage control, PI3K, and RTK/RAS. In this cluster, the most frequently mutated genes were ARID1A and PBRM1. The most altered pathways in cluster 3 were as follows: Cell cycle and apoptosis, DNA damage control, TP53, and chromatin modification. Importantly, TP53 was mutated only in cluster 3 patients. In the cohort of patients treated with surgery, cluster 2 showed statistically significant better disease-free survival (DFS) and overall survival (OS) compared with patients in cluster 3 and cluster 1 (p = 0.0014 and p = 0.0003, respectively). In the advanced setting, cluster 2 experienced a statistically significant better PFS (p = 0.0012), a tendency toward a better OS from first-line treatment, and a better OS from first-line progression compared with patients in cluster 1 and cluster 3 (p = 0.0017). We proposed an easy-to-use algorithm able to stratify patients in the three clusters on the basis of the genomic profile. CONCLUSION: We highlighted three different mutation-based clusters with prognostic significance in a cohort of IDH1m iCCAs.

Determinants of Treatment Benefit and Post-Treatment Survival for Patients with Hepatocellular Carcinoma Enrolled in Second-Line Trials after the Failure of Sorafenib Treatment.

Second-line treatments are standard care for advanced hepatocellular carcinoma (HCC) patients with preserved liver function who are intolerant of or progress on first-line therapy. However, determinants of treatment benefit and post-treatment survival (PTS) remain unknown. HCC patients previously treated with sorafenib and enrolled in second-line clinical trials were pooled according to the investigational treatment received and the subsequent regulatory approval: approved targeted agents and immune checkpoint inhibitors (AT) or other agents (OT) not subsequently approved. Univariate and multivariate analyses using Cox proportional hazards models established relationships among treatments received, clinical variables, and overall survival (OS) or PTS. For 174 patients (80 AT; 94 OT) analyzed, baseline factors for longer OS in multivariate analysis were second-line AT, absence of both portal vein thrombosis and extrahepatic spread (EHS). Treatment with AT (versus OT) was associated with significantly longer OS among patients with EHS (pinteraction = 0.005) and patients with low neutrophil-to-lymphocyte ratio (NLR; pinteraction = 0.032). Median PTS was 4.0 months (95% CI 2.8−5.3). At second-line treatment discontinuation, alpha-fetoprotein (AFP) levels <400 ng/dl, albumin-bilirubin (ALBI) grade 1, and enrolment onto subsequent trials independently predicted longer PTS. Treatment with AT, PVT, and EHS were prognostic factors for OS, while AFP, ALBI grade and enrolment onto a third-line trial were prognostic for PTS. Presence of EHS and low NLR were predictors of greater OS benefit from AT.

Platinum sensitivity in patients with IDH1/2 mutated vs wild-type intrahepatic cholangiocarcinoma: A propensity score-based study.

Isocitrate dehydrogenase (IDH)1/2 mutations are the most frequent druggable alterations in intrahepatic cholangiocarcinoma (iCCA), reported in ~20% of cases. Preclinical evidence indicates that these mutations are associated with homologous recombination deficiency (HRD), which could be exploited as a target for platinum chemotherapy (ChT) and PARP inhibitors. However, the role of IDH1/2 mutations as surrogate biomarkers for platinum efficacy is unknown. We conducted a multicenter, propensity score-matched analysis to investigate the impact of IDH1/2 mutations on progression-free survival (PFS), overall response rate (ORR) and disease control rate (DCR) in patients with iCCA treated with platinum-based ChT. An exploratory comparison of complex HRD estimates between IDH1/2 mutated and wild-type tumors from TCGA was also performed. A total of 120 cases were matched in a 1:1 ratio (60 IDH1/2 mutant and 60 wild-type). No differences were observed for platinum-based PFS (7.7 vs 7.3 months, P = .970), DCR (66.1% vs 74.1%, P = .361) and ORR (27.8% vs 25.0%, P = .741). IDH1/2 mutations showed mutual exclusivity with genomic alterations in ATM, BRCA2, MST1R, NF1, FGFR2 and CDKN2A/B losses, respectively, with no clear survival and response differences. Among TCGA tumors, IDH1/2 mutated CCA did not show higher HRD compared to wild-type cases. IDH1/2 mutations are not associated with increased sensitivity to platinum-based ChT in iCCA patients. Deeper genomic sequencing is needed to elucidate the HRD phenotype in IDH1/2 mutant iCCA and exploit its therapeutic vulnerabilities.

Simultaneous Care in Oncology: A 7-Year Experience at ESMO Designated Centre at Veneto Institute of Oncology, Italy.

Benefits of early palliative care referral in oncology are well-validated. At the Veneto Institute of Oncology-IRCCS, a simultaneous-care outpatient clinic (SCOC) has been active since 2014, where patients with advanced cancer are evaluated by an oncologist together with a palliative care team. We prospectively assessed SCOC patients' characteristics and SCOC outcomes through internal procedure indicators. Data were retrieved from the SCOC prospectively maintained database. There were 753 eligible patients. The median age was 68 years; primary tumor sites were gastrointestinal (75.2%), genitourinary (15.0%) and other sites (9.8%). Predominant symptoms were psychological issues (69.4%), appetite loss (67.5%) and pain (65.9%). Dyspnea was reported in 53 patients (7%) in the referral form, while it was detected in 226 patients (34.2%) during SCOC visits (p < 0.0001). Median survival of patients after the SCOC visit was 7.3 months. Survival estimates by the referring oncologist were significantly different from the actual survival. Psychological intervention was deemed necessary and undertaken in 34.6% of patients, and nutritional support was undertaken in 37.9% of patients. Activation of palliative care services was prompted for 77.7% of patients. Out of 357 patients whose place of death is known, 69.2% died at home, in hospice or residential care. With regard to indicators' assessment, the threshold was reached for 9 out of 11 parameters (81.8%) requested by the procedure. This study confirmed the importance of close collaboration between oncologists and palliative care teams in responding properly to cancer patients' needs. The introduction of a procedure with indicators allowed punctual assessment of a team's performance.

Prognostic impact of FGFR2/3 alterations in patients with biliary tract cancers receiving systemic chemotherapy: the BITCOIN study.

AIM: FGFR2 rearrangements have been identified as a novel therapeutic target of biliary tract cancer (BTC). However, reliable prevalence estimates of this molecular alteration and its prognostic role have not been fully elucidated. METHODS: A retrospective mono-institutional series of 286 patients affected by locally advanced or metastatic BTC (183 intrahepatic cholangiocarcinomas, 67 extrahepatic cholangiocarcinomas, 36 gallbladder carcinomas) was profiled by means of targeted DNA/RNA next-generation sequencing, immunohistochemistry and fluorescence in situ hybridisation for FGFR2/3, ERBB2, NTRK alterations, IDH1/2 and BRAF mutations and DNA mismatch repair complex proteins alterations/microsatellite instability. RESULTS: FGFR2 rearrangements, amplifications and point mutations were detected in 15 (5.2%), 1 and 3 cases, respectively. FGFR3 alterations were observed in 5 (1.7%) cases. IDH1/2 were mutated in 35/223 cases (15.7%). A total of 9/258 (3.5%) and 6/260 (2.3%) BTCs had ERBB2 and BRAF gene alterations, respectively. Two cases (2/242; 0.8%) had NTRK1 amplifications but no rearrangement was found. A deficit of mismatch repair protein expression was identified in 9/237 cases (3.8%). At multivariate analysis, age, ECOG performance status, number of metastatic sites, tumour stage, FGFR2/3 alterations and IDH1/2 mutations were prognostic factors of overall survival. CONCLUSIONS: These data provide a strong proof - challenged with a robust and detailed multivariate model - that FGFR2/3 aberrations (including FGFR2 rearrangements) and IDH1/2 mutations can be prognostic for better survival in patients with BTC . The recognition and the measurement of their prognostic impact could be of primary importance for the correct interpretation of currently available data and in the design of new therapeutic trials.

Advances in pharmacotherapy for cholangiocarcinoma: from conventional therapies to targeted drugs.

INTRODUCTION: Cholangiocarcinomas (CCA) are rare, highly invasive tumors often diagnosed at an advanced disease stage with an associated poor prognosis. Surgery represents the only chance for curative-intent treatment, but recurrence rates remain high. Neoadjuvant or adjuvant chemotherapy are options for patients with resectable CCA to increase recurrence-free survival and overall survival, while palliative chemotherapy represents the treatment for unresectable disease. Global efforts are currently focused on the development of novel more effective therapies. AREAS COVERED: A review was conducted in August 2021 using the PubMed database with the following keywords: 'cholangiocarcinoma,' 'chemotherapy,' and 'therapy.' Manuscripts reporting on first- and second-line chemotherapy, neoadjuvant and adjuvant treatment regimens, and targeted therapies currently being tested or employed in the management of CCA were examined. EXPERT OPINION: The prognosis of CCA is negatively affected by several factors including a lack of reliable biomarkers leading to delayed diagnoses, high inter- and intra-tumoral heterogeneity, and few effective chemotherapy regimens. In pursuit of more effective therapies, ongoing trials are testing both conventional and targeted drugs.

Identification of Regorafenib Prognostic Index (REP Index) via Recursive Partitioning Analysis in Patients with Advanced Hepatocellular Carcinoma Receiving Systemic Treatment: A Real-World Multi-Institutional Experience.

BACKGROUND: The results of the pivotal RESORCE trial led to the approval of the tyrosine kinase inhibitor regorafenib as second-line treatment in advanced hepatocellular carcinoma (HCC) after sorafenib failure. Data about prognostic factors in a second-line HCC setting are scarce. OBJECTIVE: The aim of the present study was to investigate prognostic factors in a cohort of patients with advanced HCC treated with regorafenib after progressing on sorafenib. METHODS: We retrieved the data of 259 patients affected by advanced HCC treated with regorafenib as second-line treatment from four different Italian institutions and one South Korean institution and performed a recursive partitioning analysis to build a score system. RESULTS: At the first-step univariate analysis for overall survival (OS), alkaline phosphatase (ALP) was the most significant parameter and was chosen as the first node in our tree model. In the subpopulation of patients presenting with ALP ≤122 U/L (n=155) at baseline, the most statistically significant split was by progression-free survival (PFS) on previous sorafenib treatment, between patients with a PFS ≥ 6 months (n = 59) and patients with a PFS < 6 months (n = 96). In the subpopulation of patients with ALP ≤ 122 U/L and PFS to sorafenib ≥ 6 months, the final split was determined between patients with hepatitis B virus (HBV)-related liver disease (n = 22) and patients with no HBV-related liver disease (n = 37). In the subpopulation of patients presenting ALP >122 U/L (n = 104) at baseline, the most statistically significant split was by aspartate aminotransferase (AST) value, between patients with AST ≤ 56 U/L (n = 48) and patients with AST > 56 U/L (n = 56). We built the Regorafenib Prognostic Index (REP index) stratifying the population into "low-risk," "medium-risk," and "high-risk" groups. The difference in median OS between the three risk groups was statistically significant, being 20.8 months (95% confidence interval [CI] 10.0-46.3) in the "low-risk" group, 8.4 months (95% CI 7.2-1435.8) in the "medium-risk" group, and 5.5 months (95% CI 3.5-13.2) in the "high risk" group. The median PFS was 7.7 months (95% CI 3.7-19.3), 2.5 months (95% CI 2.1-28.8), and 2.4 months (95% CI 1.6-9.1) for the "low-risk," "medium-risk," and "high-risk" groups, respectively. CONCLUSION: The REP index is an independent prognostic factor for OS and PFS in patients with advanced HCC treated with regorafenib.

Real-Life Clinical Data of Cabozantinib for Unresectable Hepatocellular Carcinoma.

INTRODUCTION: Cabozantinib has been approved by the European Medicine Agency (EMA) for hepatocellular carcinoma (HCC) previously treated with sorafenib. Cabozantinib is also being tested in combination with immune checkpoint inhibitors in the frontline setting. Real-life clinical data of cabozantinib for HCC are still lacking. Moreover, the prognostic factors for HCC treated with cabozantinib have not been investigated. METHODS: We evaluated clinical data and outcome of HCC patients who received cabozantinib in the legal context of named patient use in Italy. RESULTS: Ninety-six patients from 15 centres received cabozantinib. All patients had preserved liver function (Child-Pugh A), mostly with an advanced HCC (77.1%) in a third-line setting (75.0%). The prevalence of performance status (PS) > 0, macrovascular invasion (MVI), extrahepatic spread, and alpha-fetoprotein (AFP) >400 ng/mL was 50.0, 30.2, 67.7, and 44.8%, respectively. Median overall survival (OS) and progression-free survival were 12.1 (95% confidence interval 9.4-14.8) and 5.1 (3.3-6.9) months, respectively. Most common treatment-related adverse events (AEs) were fatigue (67.7%), diarrhoea (54.2%), anorexia (45.8%), HFSR (43.8%), weight loss (24.0%), and hypertension (24.0%). Most common treatment-related Grade 3-4 AEs were fatigue (6.3%), HFSR (6.3%), and increased aminotransferases (6.3%). MVI, ECOG-PS > 0, and AFP >400 ng/mL predicted a worse OS. Discontinuation for intolerance and no new extrahepatic lesions at the progression were associated with better outcomes. CONCLUSIONS: In a real-life Western scenario (mostly in a third-line setting), cabozantinib efficacy and safety data were comparable with those reported in its registration trial. Data regarding the prognostic factors might help in patient selection and design of clinical trials.

Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases.

PURPOSE: More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD). PATIENTS AND METHODS: We analyzed a cohort of 112 patients with mCRC who had undergone metastatic resection with curative intent as part of the PREDATOR clinical trial. The study evaluated the prognostic value of ctDNA, correlating MRD status postsurgery with clinical outcomes by using a personalized and tumor-informed ctDNA assay (bespoke multiple PCR, next-generation sequencing assay). Postresection, systemic therapy was given to 39.2% of the patients at the discretion of the treating physician. RESULTS: Postsurgical, MRD positivity was observed in 54.4% (61 of 112) of patients, of which 96.7% (59 of 61) progressed at the time of data cutoff (hazard ratio [HR]: 5.8; 95% CI, 3.5 to 9.7; P < .001). MRD-positive status was also associated with an inferior overall survival: HR: 16.0; 95% CI, 3.9 to 68.0; P < .001. At the time of analyses, 96% (49 of 51) of patients were alive in the MRD-negative arm compared with 52.4% (32 of 61) in the MRD-positive arm. Patients who did not receive systemic therapy and were MRD-negative in the combined ctDNA analysis at two time points had an overall survival of 100%. In the multivariate analysis, ctDNA-based MRD status was the most significant prognostic factor associated with disease-free survival (HR: 5.78; 95% CI, 3.34 to 10.0; P < .001). CONCLUSION: This study confirms that in mCRC undergoing resection of metastases, postoperative MRD analysis is a strong prognostic biomarker. It holds promises for being implemented in clinical decision making, informing clinical trial design, and further translational research.

Role of the prognostic nutritional index in predicting survival in advanced hepatocellular carcinoma treated with regorafenib.

AIM: A link has been established between malnutrition, immunological status, and hepatocellular carcinoma (HCC). The prognostic nutritional index (PNI) has been recognized as a prognostic indicator in early-stage HCC and in patients treated with first-line therapy. However, to date, the role of the PNI in HCC patients treated with regorafenib has not been reported. METHODS: We undertook a multicentric analysis on a cohort of 284 patients affected by advanced HCC treated with regorafenib. The PNI was calculated as follows: 10 × serum albumin concentration (g/dl) + 0.005 × peripheral lymphocyte count (number/mm3 ). Univariate and multivariate analyses were used to investigate the association between PNI and survival outcomes. RESULTS: A PNI cut-off value of 44.45 was calculated by a receiver operating characteristic analysis. The median overall survival was 12.8 and 7.8 months for patients with high (>44.45) and low (≤44.45) PNI, respectively (hazard ratio, 0.58; 95% confidence interval, 0.43-0.77; p = 0.0002). In the univariate and multivariate analyses, low PNI value and increased serum bilirubin level emerged as independent prognostic factors for overall survival. No differences were found between high and low PNI in terms of progression-free survival (p = 0.14). CONCLUSION: If validated, the PNI could represent an easy-to-use prognostic tool able to guide the clinical decision-making process in HCC patients treated with regorafenib.

Sequential Treatment of Sorafenib-Regorafenib Versus Sorafenib-Physician's Choice: A Propensity Score-Matched Analysis.

BACKGROUND: Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients. OBJECTIVE: We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib-regorafenib compared with sorafenib and physician's choice in a real-life setting. PATIENTS AND METHODS: A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S-R) and the arm treated with sorafenib and physician's choice (S-P). Survival analysis was conducted on the matched population. RESULTS: After the application of propensity score matching, we analysed 99 patients in the arm treated with S-R and 99 patients in the arm treated with S-P. For the S-R group, the median overall survival was 22.2 months (95% CI 17.1-27.4), compared to 17.9 months (95% CI 15.1-50.0) for the S-P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S-R (p = 0.0382) compared to patients treated with S-P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread. CONCLUSION: This study provides additional proof of the superiority of the S-R treatment over the S-P treatment approach in advanced HCC patients from a real-life setting.