Many real-world patients with advanced biliary tract cancer (BTC) are excluded by TOPAZ-1 criteria; this study assessed cisplatin and gemcitabine plus durvalumab (CGD) efficacy and safety in these patients. Data from 1358 patients with advanced BTC treated with first-line CGD across 55 international centers were retrospectively analyzed. Patients were classified as TOPAZ-1-in (meeting all inclusion criteria) or TOPAZ-1-out (meeting ≥ 1 exclusion criterion). Primary endpoints were overall survival (OS) and progression-free survival (PFS); secondary endpoints included objective response rate (ORR), disease control rate (DCR), and safety. Furthermore, OS and PFS of the TOPAZ-1-out cohort were compared with reconstructed survival data from the phase III trial. 912 (67.1%) patients were classified as TOPAZ-1-in, and 446 (32.9%) as TOPAZ-1-out. After a median follow-up of 14.5 months (95% CI: 13.7-36.5), OS was 16.1 months in TOPAZ-1-in and 12.5 months in TOPAZ-1-out (HR 0.69, 95% CI: 14.6-16.5, p = 0.0001); PFS was 8.2 versus 6.5 months (HR 0.73, 95% CI: 7.1-8.1, p < 0.0001). Median OS in the TOPAZ-1-out cohort (12.5 months) was nearly identical to the phase III trial experimental arm (12.9 months; HR 1.15, p = 0.13); for PFS the HR was 1.12 (95% CI 0.93-1.42; p = 0.09). Among TOPAZ-1-out patients, active infection, elevated bilirubin, and ECOG PS > 1 were linked to poorer OS, while no detrimental impact emerged for ALT/AST abnormalities, corticosteroid use, renal or hematologic parameters, or prior surgery within 6 months, suggesting treatment effectiveness was broadly maintained across clinical subgroups. Furthermore, TOPAZ-1-out patients experienced no significant increase in adverse events compared with the TOPAZ-1-in group. Real-world data suggest CGD may be effective in TOPAZ-1-out patients, with no evident increase in toxicity, supporting the potential expanded use of the regimen in clinical practice.

Abstract Rectal cancer, a common subtype of colorectal cancer, is rising worldwide due to lifestyle factors and aging population. Patients with locally advanced rectal cancer (LARC) are commonly treated with neoadjuvant chemoradiotherapy and surgery; however, recurrence rates remain high, ranging from 25% to 40%, depending on disease stage. Among the hallmarks of cancer, metabolic dysregulation and immune suppression play a critical role in tumor recurrence. Valproic acid (VPA), a histone deacetylase inhibitor, has shown potential in modulating these processes. The V-shoRT-R3 clinical trial (NCT01898104) have investigated the combination of VPA with short-course radiotherapy (SCRT) and capecitabine in LARC patients, aiming to enhance therapeutic efficacy by targeting some cancer hallmarks. To assess the biological effects of VPA within the V-shoRT-R3 trial, a multi-omic approach was employed. Peripheral blood samples were collected at baseline and after 10 days of VPA treatment, and analyzed by cytokine profiling (48-plex Bio-Plex assay) and metabolomics (1H-NMR and LC-MS). Gene expression was profiled (770-plex Nanostring panel) on matched biopsy and surgical specimens. Validation studies are ongoing using spatial transcriptomics and immunohistochemistry in an expanded patient’s cohort. Preliminary data from 48 patients suggest that adding VPA to SCRT and capecitabine improves clinical outcomes. Specifically, the VPA-based regimen was associated with a significant increase in relapse-free survival compared to standard treatment. At a median follow up of 70,14 months (IQR 63-77) 3 pts in SCRT arm relapsed, with a RFS rate of 83% (cv scrt), 71% SCRT 66% CSCRT 40% V SCRT respectively. Cytokine analysis revealed a significant downregulation of IL1β, LIF, CSF1, and CSF2, following VPA treatment, suggesting suppression of the myeloid compartment. Metabolomic analysis revealed altered amino acid and energy metabolism, with enrichment in immune-related pathways. Notably, VPA induces increased tryptophan and decreased kynurenine levels suggesting a reduction of indoleamine 2,3-dioxygenase (IDO) activity confirmed also by its reduced expression indicating a shift away from immunosuppressive metabolism. Moreover, gene expression analysis revealed activation of NK cell, IL10, and cytotoxicity signatures in VPA-treated patients, indicating marked immune modulation. VPA promotes immune activation and metabolic reprogramming, improving outcomes in LARC. Multi-omics analyses and ongoing validations will define VPA-driven mechanisms to inform for more personalized therapeutic strategies. Citation Format: Maria Serena Roca, Elena Di Gennaro, Federica Iannelli, Alfonso De Stefano, Carmen Romano, Francesca Collina, Cristina Testa, Rossella De Cecio, Palmina Bagnara, Susan Costantini, Roberto De Gregorio, Sean Houghton, Shauna Lee Houlihan, Dario Righelli, Andrea Sboner, Alicia Alonso, Antonio Avallone, Alfredo Budillon. Valproic acid enhances immune reprogramming in locally advanced rectal cancer: Insights from the VshoRTR3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2453.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. Over the last decade, the therapeutic landscape of advanced HCC has substantially evolved following the introduction of immune checkpoint inhibitor-based combinations, including anti-programmed death ligand 1 (PD-L1) plus anti-vascular endothelial growth factor (VEGF) agents and dual immune checkpoint blockade strategies targeting programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Nevertheless, the optimal timing and integration of locoregional therapies following systemic treatment remain poorly defined, particularly in patients achieving major radiological responses. In this setting, multidisciplinary evaluation is essential to guide individualized therapeutic strategies. CASE SUMMARY: Herein we present the case of a 68-year-old male with advanced HCC. First-line systemic treatment with atezolizumab plus bevacizumab was administered for six cycles, resulting in a major radiological and biochemical response. Following multidisciplinary discussion, selective transarterial embolization (TAE) was performed as consolidative locoregional treatment. At the last follow-up evaluation at 42 months, the patient remained alive with no evidence of disease recurrence. CONCLUSION: Our case highlights the potential role of a multidisciplinary therapeutic strategy in selected patients with advanced HCC. The integration of systemic immunotherapy-based treatment with consolidative locoregional therapy may enable successful downstaging and durable disease control, suggesting a possible role of leftward treatment stage migration in advanced unresectable HCC.

INTRODUCTION:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, requiring a multidisciplinary approach for effective management. The MDT Project aimed to define and pilot a structured care model for HCC management in Italy, supported by the implementation of integrated care pathways (ICPs), to standardize organizational processes and ensure the organizational requirements needed for appropriate patient management. METHODS:A multi-phase approach included a narrative review, semi-structured interviews with national experts, and the development of an optimal care model operationalized through a maturity model with 15 organizational elements. A total of 13 hospitals, selected to reflect national heterogeneity, participated in a pilot phase involving tailored action plans and hospital-specific ICPs. In total, ten hospitals proceeded to ICP implementation, and eight achieved certification by an external accreditation body. An expert consensus meeting subsequently validated the care model, key performance indicator (KPI) panel, and assessment tools. Organizational changes were assessed pre- and post intervention through the maturity model evaluation and a survey capturing clinicians' perceptions. RESULTS:Organizational improvements were observed primarily in areas directly targeted by the action plans, including the formalization of care-flow processes, multidisciplinary team structuring, case management, and coordination processes. More limited progress was seen in information systems and KPI monitoring, which require structural investments. Clinicians perceived the certification process as helpful in consolidating procedural standardization and documentation quality. CONCLUSIONS:The MDT Project piloted an organizational model for HCC management in Italy, focusing on care-pathway governance, multidisciplinary coordination, and center readiness. These findings represent an initial step toward broader implementation; future phases should incorporate clinical outcomes and patient-reported measures to evaluate the model's long-term impact.

PurposeTo assess the cross-software reproducibility of Computed Tomography (CT) radiomic features extracted using three widely adopted platforms (Siemens syngo.via Frontier, 3D Slicer/PyRadiomics, and mint Lesion) and to identify a subset of highly robust features suitable for multi-platform and multi-center radiomics applications.MethodsA retrospective cohort of 97 lesions (primary colorectal cancer, colorectal liver metastases, and hepatocellular carcinoma) who underwent contrast-enhanced Computed Tomography (CT) in the portal venous phase was analyzed. Semi-automatic 3D lesion segmentations were exported for radiomic extraction across the three platforms. Shared radiomic features among tools were harmonized and z-score normalized. Cross-platform similarity was assessed using distribution distance metrics, hierarchical clustering, and the Adjusted Rand Index (ARI). A novel Composite Robustness Index (CI) integrating Pearson correlation, Kolmogorov–Smirnov statistics, and mean fold-difference was developed to quantify feature-level reproducibility.ResultsFirst-order intensity features and key GLCM descriptors (e.g., Correlation, Joint Average, Sum Entropy) demonstrated the highest cross-software stability, with nearly superimposable distributions and strong concordance in clustering structure. Siemens syngo.via Frontier and 3D Slicer/PyRadiomics showed the highest agreement (mean ARI >0.85), while mint Lesion™—which lacks higher-order texture families—showed moderate deviations (mean ARI ≈ 0.70–0.75). High-order features, particularly GLDM and GLRLM metrics, exhibited substantial variability across platforms. The CI ranking enabled identification of a reproducible set of “highly reproducible features, ” including glcm_Correlation, firstorder_Mean, firstorder_RMS, firstorder_90Percentile, and shape axis-length descriptors.ConclusionDespite intrinsic software differences, a consistent subset of radiomic features remains reproducible across heterogeneous extraction tools. The combined use of distribution analysis, hierarchical clustering, and the Composite Robustness Index offers a rigorous framework for evaluating cross-platform reliability. These findings support the feasibility of multi-tool radiomics and provide a validated feature set for harmonized quantitative imaging pipelines.

Surgery after response to first-line chemoimmunotherapy may offer a potential curative option for patients with locally advanced biliary tract cancer (BTC) initially considered unresectable. However, robust real-world evidence in this setting remains limited. We retrospectively analyzed patients with locally advanced BTC treated with first-line cisplatin, gemcitabine, and durvalumab (CGD) across 55 centers in 12 countries. Endpoints included overall survival (OS), progression-free survival (PFS), disease-free survival (DFS) among resected patients, objective response rate (ORR), and the prognostic impact of surgery. A multivariable logistic regression model was developed to predict surgical conversion using baseline clinical and laboratory variables. Among 1358 screened patients, 219 had locally advanced disease and were included in the analysis. Median follow-up was 14.5 months. ORR was 34.6%, with median PFS and OS of 10.0 and 20.7 months, respectively. Twenty-four patients (10.9%) underwent surgical resection after systemic therapy. Median OS was 22.5 months in resected patients versus 19.9 months in those who did not undergo surgery. Median DFS after resection was 15.8 months. Pathological lymph node involvement was independently associated with shorter DFS. Larger baseline tumor size correlated with higher odds of radiological response but not with OS. An exploratory elastic-net model retained four baseline variables and showed moderate discriminative ability for surgical conversion, with an apparent AUC of 0.72 and an optimism-corrected AUC of 0.65. First-line CGD enabled secondary resection in approximately 11% of patients with locally advanced BTC. A simple baseline model may support patient selection for conversion surgery, although prospective validation is needed.

BACKGROUND:Postoperative circulating tumor DNA (ctDNA) is an emerging biomarker for molecular residual disease (MRD) detection in early-stage colorectal cancer (CRC). However, its prognostic value in patients with resected metastatic disease has not been comprehensively assessed. This study aimed to evaluate the association between postoperative ctDNA detection and survival outcomes, including after completion of adjuvant chemotherapy (post-ACT), in patients with metastatic CRC (mCRC) treated with curative intent. METHODS:A systematic search of PubMed/MEDLINE, Scopus, and Embase was conducted up to March 17, 2025. Eligible studies included adults with mCRC undergoing curative intent treatment, reporting hazard ratios (HRs) for time-to-event outcomes according to postoperative ctDNA status. Random-effects meta-analyses were performed to pool HRs for recurrence-free survival (RFS) and overall survival (OS). Risk of bias was assessed using the QUIPS tool. The study followed PRISMA guidelines and was registered in PROSPERO (CRD42024528320). RESULTS:Sixteen studies (N = 1048) were included. Postoperative ctDNA positivity was detected in 409 patients (39.0%) and was associated with significantly worse RFS (16 studies; HR = 4.45, 95% CI, 3.44-5.75; P < 0.0001) and shorter OS (9 studies; HR = 6.23; 95% CI, 3.15-12.33, P = 0.0003). Notably, post-ACT ctDNA positivity (N = 96, 41.4%) remained associated with recurrence (5 studies; HR, 6.08; 95% CI, 4.04-9.16; P < 0.001). CONCLUSIONS:Postoperative ctDNA positivity in mCRC treated with curative intent is strongly associated with increased risk of recurrence and mortality. These findings support its role as a consistent prognostic biomarker and highlight the need for biomarker-guided clinical trials in this setting.

The integration of molecular diagnostics into surgical oncology is redefining the management of colorectal cancer (CRC). Microsatellite instability (MSI) testing and mismatch repair (MMR) analysis have moved from purely prognostic tools to key determinants of therapeutic strategy. In MSI-high (MSI-H) and MMR-deficient (dMMR) tumours, immune checkpoint inhibitors have shown unprecedented pathological response rates, leading to a paradigm shift in non-metastatic CRC. Recently published trials suggest that immunotherapy may alter the timing and extent of resection, while raising new questions about patient selection, surgical planning, and long-term oncological safety. Conversely, microsatellite-stable (MSS) disease remains a therapeutic frontier, with ongoing studies exploring combined immunotherapy regimens. This evolving landscape demands that surgeons develop a deeper understanding of tumour biology and participate actively in translational research. The future of CRC surgery will rely not only on technical excellence but on the ability to integrate molecular knowledge into precise, multidisciplinary treatment algorithms.

Background: Biliary tract cancers (BTCs) are aggressive malignancies with limited treatment options. The addition of durvalumab or pembrolizumab to cisplatin–gemcitabine improves overall survival (OS), but validated biomarkers of benefit remain limited. Immune-mediated adverse events (imAEs) have been proposed as treatment-emergent clinical correlates of immune activation. Methods: We retrospectively analyzed an international cohort of patients with locally advanced or metastatic BTC treated with first-line cisplatin–gemcitabine plus durvalumab. Primary endpoints were OS and progression-free survival (PFS). The principal exposure was the occurrence of any imAE. A post hoc complete-case Cox model was adjusted for age, sex, primary tumor site, prior surgery, ECOG performance status, disease stage, albumin, bilirubin, and neutrophil-to-lymphocyte ratio (NLR); analyses of individual AEs were exploratory. Exact AE onset dates were not consistently available, precluding a reliable formal time-dependent exposure analysis. Results: A total of 1358 patients were included; all received durvalumab, and 276 (20.3%) developed at least one imAE. In the fully baseline-adjusted model, any imAE remained associated with a lower risk of death (adjusted HR 0.72, 95% CI 0.57–0.92; p = 0.008) and progression or death (adjusted HR 0.63, 95% CI 0.52–0.77; p < 0.001). In exploratory baseline-adjusted analyses of individual imAEs, other imAEs remained associated with OS (HR 0.39, 95% CI 0.24–0.62; p < 0.001) and PFS (HR 0.56, 95% CI 0.40–0.77; p < 0.001), while hypothyroidism remained associated with PFS only (HR 0.65, 95% CI 0.43–0.97; p = 0.034); rash and hyperthyroidism were not independently associated after full baseline adjustment. In AE-focused exploratory models, decreased appetite and hyponatremia were associated with worse outcomes, neutropenia with better outcomes, and ALT elevation with worse PFS. Baseline corticosteroid use was uncommon (n = 21), and all steroid analyses are vulnerable to confounding by indication and exposure-timing bias. Conclusions: Treatment-emergent imAEs may represent potential prognostic markers or clinical correlates of benefit, but they are not validated surrogate endpoints. Prospective studies with precise AE-onset capture are required.

BackgroundHepatocellular carcinoma (HCC) is the most common primary liver malignancy, characterized by aggressive biological behavior and a high propensity for extrahepatic spread. The most common sites of metastasis are the lungs, regional lymph nodes, bones, adrenal glands, and peritoneum. In contrast, the paranasal sinuses are an unusual site for metastatic HCC, and involvement of the sphenoid sinus represents an even rarer event.Case descriptionWe report the case of a 67-year-old male patient who presented with transient diplopia, left eyelid ptosis, and refractory epistaxis as the initial clinical manifestations of a previously undetected HCC. Histopathological evaluation of the sinus mass and subsequent imaging confirmed a metastatic lesion from a silent primary liver tumor. The patient was managed using a multidisciplinary approach, undergoing radiation therapy to the sphenoid sinus for pain control and endovascular embolization of the sphenopalatine arteries for refractory epistaxis. In March 2026, a contrast-enhanced computed tomography (CT) scan revealed new osteolytic lesions, consistent with bone metastases, involving the proximal third of the left clavicle and the T9 vertebral body. The patient subsequently received further palliative radiotherapy to the left clavicle and T7-T9, and initiated first-line systemic therapy with atezolizumab plus bevacizumab, completing four cycles. Due to disease progression at multiple skeletal sites and in the sphenoid region, as revealed by a CT scan in June 2026, second-line treatment with lenvatinib was initiated and is ongoing at the latest follow-up.ConclusionsDespite its rarity, the differential diagnosis of a paranasal sinus lesion should include the possibility of metastasis from HCC, particularly in patients with underlying chronic liver disease. Histopathological confirmation and a multidisciplinary approach are critical for optimizing therapeutic planning in this challenging clinical scenario.

BACKGROUND:Currently, data concerning the prognostic impact of metastatic sites in biliary tract cancers (BTC) are limited. OBJECTIVE:The aim of the present study is to evaluate the prognostic impact of metastatic sites in patients with BTC treated with cisplatin-gemcitabine-durvalumab (CGD). PATIENTS AND METHODS:The study population comprised a large worldwide cohort of patients treated with CGD. The primary objectives were overall survival (OS) and progression-free survival (PFS) based on the location and number of metastatic sites. RESULTS:A total of 666 patients with locally advanced (111) or metastatic (555) BTC treated with CGD were included in the study. None of the metastatic sites were shown to have a prognostic impact on OS at multivariate analysis. Patients with one to two metastatic sites had longer OS (hazard ratio [HR] 0.59; p = 0.005) and PFS (HR 0.73; p = 0.03) compared with those with three to five metastatic sites in the univariate analysis but not in the multivariate analysis. No statistically significant differences were observed in OS or PFS across different metastatic sites limited to a single organ. Patients with progressive disease (PD) on first-line CGD with a change in metastatic sites from baseline showed no statistically significant differences in OS2 (defined as the time from PD on first-line therapy to death for any cause) compared with those without a change in metastatic sites (HR 0.88; p = 0.60). CONCLUSIONS:Our study did not show statistically significant differences in outcomes associated with location and number of metastatic sites in a large population of patients with BTC treated with CGD.

BACKGROUND:Blood-based circulating tumour DNA (ctDNA) assays have emerged as a promising tool for minimally invasive colorectal cancer (CRC) screening. However, their diagnostic accuracy in asymptomatic, average-risk populations remains uncertain. This systematic review and meta-analysis aimed to synthesise current evidence on the performance of ctDNA-based blood tests for detecting advanced colorectal neoplasia (ACN), defined as the composite of invasive CRC and advanced precancerous lesions (APL). METHODS:A comprehensive search of PubMed, EMBASE, and the Cochrane Library was conducted through July 2025. Studies evaluating ctDNA-based blood assays against colonoscopy and histopathology in asymptomatic, average-risk adults were included. Pooled estimates were calculated using a bivariate random-effects model following Cochrane DTA guidance. RESULTS:Three population-based prospective studies were included (n = 36,381). For invasive CRC, pooled sensitivity was 0.72 (95% CI 0.49-0.88) and specificity 0.91 (95% CI 0.89-0.92), with an area under the curve (AUC) of 0.92. Sensitivity increased progressively from stage I (0.53) to stage IV (0.89). For APL, pooled sensitivity was 0.13 (95% CI 0.12-0.14) and specificity 0.90 (95% CI 0.88-0.91). When CRC and APL were considered together (ACN), overall sensitivity was 0.16 (95% CI 0.14-0.18) with specificity 0.91 (95% CI 0.89-0.92). CONCLUSIONS:ctDNA-based blood testing demonstrates high specificity and clinically relevant accuracy for invasive CRC, but limited detection of precancerous lesions. These findings consolidate current evidence by defining the complementary role of ctDNA in population screening. As a non-invasive, patient-centred approach, ctDNA testing could increase participation and access in CRC prevention, but large-scale studies are needed to confirm its clinical and economic viability.

Background Despite significant advances in the diagnosis and treatment of metastatic colorectal cancer (mCRC), five-year survival rates remain poor. Patients with left-sided, wild-type RAS and BRAF mCRC have shown clear benefits from anti-EGFR-based regimens. Following an induction phase, maintenance treatment with the combination of 5-fluorouracil and folinic acid (5FU/FA) with anti-EGFR monoclonal antibodies (cetuximab and panitumumab) is currently recommended. However, persistent skin toxicity and the emergence of resistance to anti-EGFR therapies pose significant challenges to both treatment adherence and efficacy. Consequently, the optimal strategy for post-induction treatment remains unclear. Findings from the phase II IMPROVE trial suggest that adopting an intermittent treatment approach after a four-month induction period may prolong the effectiveness of anti-EGFR therapy by delaying tumor progression and reducing skin toxicity. Therefore, this strategy has the potential to enhance patients' quality of life without compromising overall survival. Methods and design: IMPROVE-2 is a multicenter, open-label, academic, randomized non-inferiority phase-3 study designed to enroll 500 treatment-naive patients with unresectable left-sided RAS/BRAF wild-type mCRC across 49 Italian centers. Upon enrollment, patients will be randomized in a 1:1 ratio to receive one of the two treatment strategies following induction therapy with eight cycles of panitumumab plus FOLFIRI. In the absence of disease progression, patients will either continue treatment until progression or follow an intermittent regimen with treatment-free intervals until progression during therapy. The primary endpoint is time to treatment failure (TTF). Secondary endpoints include objective response rate, disease control rate, depth of response, progression-free survival, overall survival, toxicity, and quality of life. Correlative studies will explore prognostic and predictive biomarkers through next-generation sequencing of liquid biopsies and serum metabolomic profiling. Discussion IMPROVE-2 study aims to optimize anti-EGFR therapy in combination with chemotherapy in untreated left-side RAS/BRAF wild-type unresectable mCRC patients, through an intermittent approach, easily implementable in healthcare systems. Correlative studies could add new insights into the dynamic evolution of tumors in response to therapy, paving the way for better refining anti-EGFR therapy. This study is ongoing, with enrollment started in June 2024. Trial registration: EudraCT number 2023-509551-14-00; ClinicalTrials.gov identifier NCT06509126, registration date 2024-07-10

The Chromobox (CBX) family comprises key epigenetic regulators involved in transcriptional repression through chromatin modifications. Dysregulation of polycomb CBX proteins has been linked to epigenetic gene silencing and cancer progression. However, the specific roles and prognostic value of CBX family members in colorectal cancer (CC) remain unclear. In this study, we show that CBX genes are significantly dysregulated in CC tissues and cell models compared to normal colorectal tissue. Among them, CBX4 and CBX8 emerged as the most upregulated isoforms in tumors. Functional analyses revealed that CBX4 overexpression enhances CC cell proliferation, while its silencing reduces tumor growth. Similarly, pharmacological inhibition of CBX4 in patient-derived tumor organoids led to decreased proliferation, supporting its pro-tumorigenic role. Immunofluorescence analysis further revealed alterations in NF-κB signaling upon CBX4 inhibition, along with reduced mRNA levels of pathway components including NF-κB, TNF, IL-1, and c-Myc. These findings point to a potential interplay between CBX4 and inflammation-related pathways in CC. Overall, our study highlights the oncogenic role of CBX4 in colorectal cancer and supports its potential as a novel therapeutic target and early biomarker for disease progression.

BACKGROUND & AIMS:At the TOPAZ-1 (NCT03875235) primary analysis, durvalumab plus gemcitabine and cisplatin (GemCis) significantly improved overall survival (OS) in advanced biliary tract cancer (aBTC). We report updated exploratory analyses of OS and safety, extended long-term survivors (eLTS), and subsequent anticancer therapy use. METHODS:Participants with aBTC received durvalumab+GemCis or placebo+GemCis every 3 weeks (≤8 cycles), then durvalumab or placebo monotherapy every 4 weeks until progressive disease or other discontinuation criteria were met. OS and serious adverse events were assessed in the full analysis and safety analysis sets, respectively. eLTS outcomes were assessed (full analysis set participants alive ≥30 months after randomisation). RESULTS:A total of 685 participants were randomised: durvalumab+GemCis (n = 341); placebo+GemCis (n = 344). After a median 41.3 (95% CI 39.3-44.1) months' follow-up in all participants, median OS (95% CI) for durvalumab+GemCis vs. placebo+GemCis was 12.9 (11.6-14.1) vs. 11.3 (10.1-12.5) months (hazard ratio, 0.74 [95% CI 0.63-0.87]); 36-month OS rate was 14.6% vs. 6.9%, respectively. In participants who achieved disease control (566/685; 82.6%), the 36-month OS rate was higher for durvalumab+GemCis (17.0%) vs. placebo+GemCis (7.6%). Overall, 12.8% were eLTS, with more eLTS in the durvalumab+GemCis (17.0%) vs. placebo+GemCis (8.7%) arms; eLTS included all clinically relevant subgroups. Durvalumab+GemCis improved OS regardless of subsequent anticancer therapy use. In eLTS, serious adverse events were comparable between arms and less frequent than in the full safety analysis set. CONCLUSIONS:Survival benefit and manageable safety continued with durvalumab+GemCis vs. placebo+GemCis approximately 3 years after the last participant was randomised. All clinically relevant subgroups were represented in eLTS, supporting standard-of-care status for durvalumab+GemCis in aBTC. IMPACT AND IMPLICATIONS:Durvalumab plus gemcitabine and cisplatin (GemCis) was approved for use in advanced biliary tract cancer (aBTC) after the primary analysis of the randomised, double-blind, phase III TOPAZ-1 study demonstrated that it significantly improved overall survival (OS) vs. placebo plus GemCis. This update, with analyses of OS and safety, extended long-term survivors, and subsequent anticancer therapy use, took place at a median follow-up of 41.3 months, which, to our knowledge, represents the longest follow-up to date in participants with aBTC. Survival benefit and manageable safety continued with durvalumab plus GemCis, all clinically relevant subgroups were represented in extended long-term survivors, and OS benefit with durvalumab plus GemCis was consistent regardless of subsequent anticancer therapy use. These long-term follow-up results support the standard-of-care status for durvalumab plus GemCis in aBTC, and enable physicians, patients and caregivers to make informed treatment decisions. CLINICAL TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03875235; https://clinicaltrials.gov/study/NCT03875235.

Standard of care first-line systemic treatment for advanced biliary tract cancer includes chemo-immunotherapy with gemcitabine, cisplatin, and durvalumab, followed by maintenance durvalumab monotherapy. The present work aims to investigate the differences in baseline clinical and molecular characteristics between patients with early progression during chemo-immunotherapy and those who reach durvalumab maintenance therapy. The study population included patients with unresectable, locally advanced, or metastatic BTC who received treatment at 38 clinical Institutions in 12 countries from July 2021 to December 2023. The primary objective of the study was to investigate whether baseline clinical and molecular characteristics differed between patients with early progression during chemo-immunotherapy versus those reaching durvalumab maintenance therapy. Four hundred forty-eight patients were included in this study. Two hundred twenty-seven patients (50.7%) received maintenance with durvalumab monotherapy, whereas 221 (49.3%) did not receive maintenance therapy due to PD during first-line chemo-immunotherapy before completing 8 cycles. Results show that patients who received maintenance were more likely to be older (≥70 years), have an ECOG = 0, locally advanced disease, and a neutrophil-to-lymphocyte ratio (NLR) <3. A higher proportion of patients with BAP1 mutations received maintenance, while TP53 mutations were more common in those who progressed early. According to the present analysis, a substantial proportion of patients (50.7%) with advanced BTC who were treated with chemotherapy plus durvalumab proceeded to receive maintenance therapy with durvalumab monotherapy, with a median treatment duration of 4.4 cycles. Patients ≥70 years, with ECOG PS 0, with locally advanced disease, and with NLR <3 had a higher likelihood of receiving maintenance therapy.