搜索结果：ESMO gastrointestinal oncology

Most oncology trials define superiority according to dichotomized P value thresholds, which are frequently misinterpreted. Posterior probability, however, directly estimates the probability of the hypothesis at hand. Here, we reanalyze a large collection of modern phase III trials and benchmark posterior probability versus the standard trial interpretation based on statistical significance. Outcomes from 194,129 patients were manually reconstructed from the primary end points of 230 phase III, superiority-design oncology trials. Posterior probabilities of treatment effect were then calculated across multiple priors and several effect sizes of clinical relevance, including minimum clinically important difference (MCID) defined as hazard ratio (HR) < 0.8 per ASCO criteria or HR < 0.64 per European Society of Medical Oncology (ESMO) criteria. All trials interpreted as superior using P value thresholds had probabilities >90% for achieving at least marginal benefits (HR < 1). However, only 62% of positive trials (74/120) had >90% probabilities of achieving the ASCO MCID (HR < 0.8), even under an enthusiastic prior, including 70% of trials (57/82) leading to regulatory approval. Only 30% of positive trials (36/120) had >90% probability of achieving the ESMO MCID (HR < 0.64). Conversely, 24% of trials (26/110) interpreted as not superior had >90% probability of achieving marginal benefits (HR < 1), even under a skeptical prior. Bayesian models, although often in agreement with statistical significance thresholds, add considerable unique interpretative value for a subset of phase III oncology trials. Posterior probability may provide a solution for overcoming the discrepancies between refuting the null hypothesis and detecting clinically relevant effects.

Rectal cancer treatment in Nordic countries has traditionally differed, especially regarding neoadjuvant treatment. The aim of this review is to give an overview of the current rectal cancer guidelines in the Nordics and compare these to international guidelines. Oncologists and colorectal surgeons from the Nordic countries (Denmark, Finland, Norway, and Sweden) and the Netherlands were invited to participate in this narrative review. Two consensus meetings were held to agree on the content. All authors provided recommendations from their national guidelines. In addition, recommendations from the European Society of Medical Oncology (ESMO) and from the US National Comprehensive Cancer Network (NCCN) guidelines were extracted. Several differences between the included guidelines were identified. The radiological "sigmoid take-off" definition for the upper margin of the rectum has been adapted in Denmark and the Netherlands, whereas the other guidelines rely on distance from the anal verge on rigid sigmoidoscopy. Indications for direct surgery vary considerably, where the NCCN guidelines recommend more aggressive neoadjuvant treatment, primarily total neoadjuvant therapy (TNT), the Nordic and European guidelines open for direct surgery more often, and reserve especially TNT for high-risk cases. European countries more often recommend short-course radiotherapy, whereas NCCN maintains chemoradiotherapy as the mainstay. Whereas intentional and opportunistic organ preservation is an established part of the Dutch, NCCN, and ESMO guidelines, its use is mostly restricted to clinical trials in the Nordics. The Nordics and the Netherlands are restrictive in terms of adjuvant treatment, which is frequently recommended in ESMO and NCCN. Whereas neoadjuvant immunotherapy is recommended for mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) rectal cancer in NCCN, this use is off-label in Europe and not routinely recommended. Although all guidelines rely on the same evidence, there are considerable differences, especially in the indications and type of oncologic treatment, both in the neoadjuvant and in the adjuvant setting.

Outcomes of patients with gastrointestinal (GI) malignancies have improved substantially since the introduction of immunotherapy, with immune checkpoint inhibitors (ICIs) approved for specific subsets. Two biomarkers (mismatch repair/microsatellite instability status and programmed death-ligand 1 expression) are currently used to guide ICI indications. However, ICIs can be prescribed independently of any biomarker in other scenarios, such as for biliary tract cancer and hepatocarcinoma. Moreover, pharmacokinetics and pharmacodynamics modeling consistently demonstrates wide therapeutic windows, which suggest that a flat dose-response relationship for ICIs is probably excessive. Lastly, as clinical experience with immunotherapy expands, both acute and late toxicities are becoming increasingly relevant. Collectively, these factors create ambiguity regarding the indications of ICIs in GI oncology and raise concerns about increased toxicity and economic sustainability. In this review, we explore potential approaches to optimize immunotherapy for patients with GI cancer, encompassing patient selection, dose adjustment, and cost reduction. We highlight already implemented strategies to address these challenges and present evidence from local health care initiatives demonstrating the feasibility of weight-based dosing. However, we acknowledge important regulatory constraints that would entail the implementation of these changes, as they would require robust new clinical data and formal approval processes before being part of the clinical routine practice.

Signet-ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer, constituting 0.5-2.5% of all adenocarcinomas. It is characterized by signet ring cells as the dominant malignant cell type. Developing gastrointestinal (GI) second primary malignancies (SPMs) after SRCC is a rare event reported in the literature and insufficiently addressed. This study aimed to explore this gap and provide updated evidence about this rare cancer. Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Standardized incidence ratio (SIR) analyses with multiple outcome assessment were performed, applying a two-month latency exclusion period to evaluate the risk of GI SPMs in patients diagnosed with primary colorectal SRCC. The SIR was calculated as observed/expected (O/E), with excess absolute risk (EAR) per 10,000. Significance was achieved at 0.05 with a 95% confidence interval (CI). There was an increased risk for GI SPMs after SRCC in the 2-11 months interval (O/E=2.49, P<0.05, EAR=37.31), and over 10 years of follow-up (O/E=3.08, P<0.05, EAR=59.20). Small intestine SPMs in the 2-11 months interval had an O/E of 4.17 (P<0.05, 95% CI: 0.11-23.26, EAR=1.97), with an overall O/E of 9.62 (P<0.05, EAR=6.32). No events of GI SPMs were observed among young patients during follow-up (O/E=1.05, P>0.05, EAR=0.12). Young patients had lack of observed events for GI SPMs (O/E=0.00, EAR=-0.15), compared to middle-aged (O/E=7.66, P<0.05) and elderly patients (O/E=2.36, P<0.05). Patients received chemotherapy showed a slightly higher observed incidence of SPMs (O/E=2.39, P<0.05, EAR=49.29); however, this finding should be interpreted cautiously given known limitations of chemotherapy data within the SEER database. Patients diagnosed with colorectal SRCC are at a significantly increased risk of developing GI SPMs. Given the poor overall prognosis of colorectal SRCC, early surveillance protocols must be carefully contextualized at short intervals (6-12 months) for early detection of GI SPMs. However, a reduced intensity surveillance is recommended beyond 3-5 years to integrate prevention with long-term follow-up. Recommendations should be tailored according to patients' risk profiles with individualized patient focused programs.

The therapeutic landscape of colorectal cancer (CRC) has evolved with the identification of molecular subtypes, including mismatch repair-deficient/microsatellite instability-high, POLE mutations, RAS/BRAF alterations, and HER2 amplification, enabling use of precision therapies and immune checkpoint inhibitors for selected populations. However, most microsatellite-stable (MSS) tumors remain resistant due to tumor heterogeneity, adaptive resistance, and an immunosuppressive tumor microenvironment (TME). Advances in molecular profiling, spatial biology, and immune characterization have revealed vulnerabilities beyond canonical signaling, facilitating novel strategies such as antibody-drug conjugates (ADCs), bispecific antibodies, DNA damage response (DDR) targeting, TME-directed therapies, cellular therapies, and epigenetic modulation. HER2-directed ADCs, notably trastuzumab deruxtecan, have shown clinically meaningful activity in HER2-positive metastatic CRC, providing proof of concept for ADC-based therapy. Additional targets under investigation include CEACAM5, LGR5, EGFR, HER3, MET, B7-H3, and CDH17. Bispecific antibodies and co-stimulatory agonists are being developed to overcome antigen heterogeneity and pathway redundancy, with the EGFR-MET bispecific antibody amivantamab showing initial clinical efficacy. Moreover, next-generation immune checkpoint inhibitors and multitarget combinations aim to reinvigorate T-cell responses in MSS tumors. Early chimeric antigen receptor T-cell studies targeting CEA and GUCY2C demonstrate feasibility and manageable toxicity, although tumor-intrinsic and TME barriers persist. Emerging strategies increasingly focus on modulating the TME to enhance immune infiltration and effector function, targeting CCR8, TGF-&#x3b2;, adenosine, CSF1R, CXCR1/2, STING, and CD47. DDR and epigenetic therapies offer additional opportunities to sensitize resistant tumors. Integrated, multidimensional biomarker approaches and artificial intelligence-driven interpretation of tumor and TME features are expected to guide personalized therapy, anticipate resistance, and broaden the benefit of targeted and immune-based interventions in CRC.

Access to high-quality cancer care remains a major challenge across Latin America, particularly for patients with gastrointestinal (GI) malignancies. Despite major advances in cancer prevention, diagnosis, molecular testing, and treatment, substantial disparities persist in access to timely and appropriate care throughout the region. This narrative review examines the multidimensional nature of access in GI oncology, encompassing availability, accessibility, affordability, acceptability, and quality. We analyze the principal barriers affecting cancer care delivery in Latin America, including economic constraints, geographic disparities, fragmented health systems, sociocultural determinants, limited access to precision oncology, and regulatory challenges. We further explore how these barriers contribute to delayed diagnosis, advanced-stage presentation, treatment interruptions, reduced access to biomarker testing and innovative therapies, and ultimately poorer clinical outcomes. The review highlights evidence-informed strategies that have demonstrated potential to improve access, including National Cancer Control Plans (NCCPs), organized colorectal cancer screening programs, patient navigation initiatives, multidisciplinary care models, virtual tumor boards, teleoncology, digital health solutions, and artificial intelligence-enabled interventions. Particular attention is given to equity-focused approaches addressing the needs of women, rural populations, indigenous communities, migrants, and young adults affected by early-onset GI cancers. Improving access to GI cancer care requires coordinated action across policy, health system, institutional, and community levels. Strengthening governance through NCCPs, expanding precision oncology infrastructure, leveraging digital innovation, and implementing robust monitoring frameworks are critical to reducing disparities. Lessons learned from Latin America may provide valuable insights for other low- and middle-income settings seeking to translate scientific advances into equitable cancer outcomes.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment by harnessing the immune system to target tumors. The introduction of ipilimumab, an anti-CTLA-4 monoclonal antibody, marked a major milestone in immuno-oncology when it was approved by the U.S. Food and Drug Administration (FDA) in 2011 for advanced melanoma. By blocking CTLA-4, ipilimumab enhances T-cell activation and promotes antitumor immunity. Subsequent development and approval of anti-PD-1 and anti-PD-L1 antibodies, such as nivolumab and pembrolizumab, since 2014 have broadened the scope of ICI therapy to various malignancies, often demonstrating improved tolerability relative to CTLA-4 inhibition. While these agents have significantly improved clinical outcomes, they also disrupt immune homeostasis, leading to immune-related adverse events (irAEs), in which healthy tissues are attacked by the immune system. Among these, gastrointestinal irAEs - including hepatitis and colitis - are frequently observed and may require intensive management. These toxicities are immunologically mediated and differ substantially from adverse effects associated with conventional cytotoxic chemotherapy. As ICIs gain broader indications clinicians must be prepared to identify and manage irAEs promptly. This review provides an in-depth discussion of ICI-associated gastrointestinal toxicities, emphasizing their epidemiology, immunopathogenesis, diagnostic strategies, and therapeutic management, in line with the latest clinical guidelines from major oncological societies such as ASCO and ESMO.

Advances in cancer detection and treatment have resulted in a growing population of survivors. Many face long-term physical, psychological, and financial challenges that are unevenly distributed across socioeconomic, racial, and demographic groups. Clinical guidelines should provide recommendations to guide survivorship care and ensure equity. To provide an overview of recommendations from existing guidelines addressing follow-up care after cancer. International and German clinical guidelines were identified through a systematic search of MEDLINE, TRIP, GuidelineCentral, NICE, G-I-N and SIGN, complemented by manual searches of relevant registries (AWMF, Onkopedia, ESMO, IGHG). Guidelines were included if they contained at least one recommendation on follow-up or survivorship care. Screening was performed independently by two reviewers. Recommendations were coded using a predefined framework and synthesized using tables and interactive evidence-maps. 198 guidelines comprising 2270 recommendations were included. The most frequently represented categories were cross-sectional guidelines (i.e., not limited to a specific cancer type) (n&#x202f;=&#x202f;36), followed by gastrointestinal tumors (n&#x202f;=&#x202f;15) and myeloid proliferations (n&#x202f;=&#x202f;14); most targeted adults (n&#x202f;=&#x202f;150). Of all recommendations, 39% were evidence-based. Frequently addressed topics included previous treatment (n&#x202f;=&#x202f;342), long-term survivorship (>5 years) (n&#x202f;=&#x202f;705), screening for adverse events (n&#x202f;=&#x202f;263), timing of follow-up (n&#x202f;=&#x202f;338), and counselling and education (n&#x202f;=&#x202f;234). The extent to which recommendations explicitly addressed equity-related factors varied considerably: age was frequently considered (n&#x202f;=&#x202f;160), whereas socioeconomic status (n&#x202f;=&#x202f;18), race/ethnicity (n&#x202f;=&#x202f;5), and religion/culture (n&#x202f;=&#x202f;6) were rarely addressed. Survivorship care was addressed heterogeneously across guidelines, with long-term and equity aspects underrepresented. More consistent, evidence-based and equity-oriented guideline development is needed.

Comprehensive genomic profiling (CGP) is increasingly adopted in the management of patients affected by GI cancers. However, the applicability, performance, and clinical utility of CGP in the real-world setting are still undefined. We retrospectively evaluated CGP performance and clinical benefit in consecutive patients with GI tumor at the Veneto Institute of Oncology-IRCCS, Padua. We assessed CGP success and its advantage over routine diagnostics in detecting actionable molecular targets. A custom list of gain alterations was defined, including targets not classified as ESMO Scale for Clinical Actionability of molecular Targets tier IA at the time of analysis. Of the 1,450 samples, 140 (9.7%) were inadequate for CGP. Failure was mainly due to low quantity of extracted tumor DNA (P = .002). Of the 1,265 metastatic patients, GAs were detected in 355 (28.1%) cases, of whom 55 (15.5%) were treated with targeted therapy. Survival did not differ between patients with no GAs and those with GAs who were not treated accordingly (median overall survival 12.0 v 10.9 months), whereas it was significantly longer for those receiving treatment for actionable GAs (26.4 months). This advantage was confirmed in an exploratory, inverse probability of treatment-weighted analysis (adjusted hazard ratio, 0.72 [95% CI, 0.58 to 0.89]; P = .002). Among 283 (83.7%) untreated patients with complete follow-up, 41.6% did not receive targeted therapy due to lack of clinical trial or failure to meet inclusion criteria. Appropriate specimen selection and early molecular assessment at the time of advanced disease diagnosis are essential to detect clinically actionable molecular alterations and therapeutic opportunities in patients with GI cancers. Our results support CGP in comprehensive cancer centers.

Transarterial chemoembolization (TACE) is the standard of care for intermediate-stage unresectable hepatocellular carcinoma (HCC), but progression-free survival (PFS) with TACE alone remains limited. Recent randomized clinical trials have evaluated the addition of immune checkpoint inhibitors (ICIs) to TACE. We conducted a meta-analysis of randomized trials to assess the efficacy and safety of TACE plus ICIs versus TACE alone in unresectable HCC. A systematic search of PubMed, Embase, Cochrane Library, and American Society of Clinical Oncology and European Society for Medical Oncology databases was carried out through 15 December 2025 and last updated on 3 June 2026 to identify randomized clinical trials comparing TACE with or without ICIs in unresectable HCC. Outcomes included PFS, objective response rate (ORR), overall survival (OS), and safety. Random-effects meta-analyses were conducted using R software (version 4.5.2, R Foundation for Statistical Computing, Vienna, Austria). Six randomized clinical trials (EMERALD-1, EMERALD-3, Jia et al., LEAP-012, TALENTACE, and CARES-005) involving 2439 patients were included. Compared with TACE alone, combination therapy improved PFS [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.52-0.77, P < 0.01] and ORR (risk ratio 1.45, 95% CI 1.31-1.61, P < 0.001). OS benefit was borderline (HR 0.85, 95% CI 0.73-0.99, P = 0.04), although data remain immature. Combination therapy was associated with higher rates of any-grade and grade &#x2265;3 adverse events, serious adverse events, and treatment discontinuations. Adding ICIs to TACE improved PFS and response rates compared with TACE alone in unresectable HCC, at the cost of increased toxicity. OS benefit was borderline and should be interpreted with caution; longer follow-up is required.

Lurbinectedin in combination with irinotecan showed synergistic antitumor activity in preclinical studies. A phase I/II trial (NCT02611024) evaluated this combination in patients with advanced solid tumors. The phase II stage evaluated the antitumor activity of the recommended dose (RD) (lurbinectedin 2.0&#xa0;mg/m2 on Day (D)1 plus irinotecan 75&#xa0;mg/m2 on D1 and D8 q3wk with primary granulocyte colony-stimulating factor prophylaxis) in five tumor-specific cohorts. This pooled analysis describes the safety profile of this combination from 233 patients with different advanced solid tumors treated at the RD. Adverse events (AEs) and laboratory abnormalities were graded using NCI-CTCAE v.4. The most frequent AEs (any grade) related to treatment were fatigue (71% of patients/25% of cycles), diarrhea (62%/17%), nausea (59%/18%), vomiting (35%/7%) and decreased appetite (32%/6%); the most common grade&#x2009;&#x2265;&#x2009;3 AEs were fatigue (14%/2%), diarrhea (14%/2%) and febrile neutropenia (9%/1%). The most common grade&#x2009;&#x2265;&#x2009;3 laboratory abnormality regardless of relationship was neutropenia (53%). The rate of discontinuation due to treatment-related AEs was 3% (n&#x2009;=&#x2009;7 patients). There was one treatment-related death (0.4%) involving a 63-year-old male patient (0.4%) diagnosed with metastatic NEN who died due to grade 5 staphylococcal bacteremia. In conclusion, this pooled analysis shows a predictable and manageable safety profile for lurbinectedin in combination with irinotecan in patients with advanced solid tumors, with myelosuppression, fatigue and gastrointestinal disorders being the main toxicities observed.Trial code: ClinicalTrials.gov identifier: NCT02611024.

The optimal perioperative strategy for resectable pancreatic ductal adenocarcinoma (PDAC) remains undefined, and predictive biomarkers to guide treatment selection are lacking. The phase II nanoliposomal IrinoTecan with 5-fluorouracil, levofolinic acid and oxaliplatin in patients with Resectable pancreatic cancer (nITRO) trial showed the activity of perioperative NALIRIFOX in patients with resectable PDAC. Here, we report updated survival outcomes and translational analyses of this trial. Plasma levels of 25 cytokines were quantified via multiplex bead-based immunoassay. Germline whole-exome sequencing assessed variants in tumor suppression, DNA damage repair (DDR), and drug metabolism pathways. Five in silico tools re-evaluated variants of uncertain significance. Statistical correlations between circulating cytokines or germline pathogenic variants and clinical outcomes were determined. After a median follow-up of 50.2 months, the median overall survival (mOS) was 32 months in the intention-to-treat population and 48 months in patients who underwent resection. High baseline tumor necrosis factor-alpha (TNF-&#x3b1;) levels were consistently associated with reduced treatment response (P = 0.022), lower resection probability (P = 0.007), and shorter survival (P = 0.014). Germline pathogenic/predicted damaging variants in DDR or tumor suppressor genes (g.Deficient) were detected in 36.2% of patients and correlated with improved outcomes. Patients with combined g.Deficient/TNF-&#x3b1;-low status achieved the most favorable prognosis, with an mOS of 55 months and a 100% resection rate. DPYD c.496A>G predicted both severe gastrointestinal toxicity and chemotherapy dose reductions. Long-term results from the nITRO trial confirm the activity of perioperative NALIRIFOX in resectable PDAC. Inflammatory, genomic, and pharmacogenomic biomarkers strongly influenced treatment response, surgical eligibility, survival, and toxicity. Biomarker integration could enable more precise patient stratification and guide personalized perioperative strategies in PDAC.

Although trastuzumab-deruxtecan (T-DXd) has demonstrated significant efficacy in advanced breast cancer, treatment discontinuation due to adverse events occurs in &#x223c;20% of patients. Pharmacogenetic variants in uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) increase the toxicity risk for other antibody-drug conjugates using topoisomerase I inhibitors, but they remain unexplored for T-DXd. The PROCURE Project is a translational study involving 26 Spanish institutions, investigating the association of germline pharmacogenomic variants with T-DXd toxicity for patients with HER2-positive or HER2-low advanced breast cancer. UGT1A1&#x2217;28 genotypes were determined in blood samples, and pharmacogenomic analyses were performed using the clinical data and adverse events extracted from the medical records of the patients. Additionally, stratified Cox models were used to quantify the risk of treatment discontinuation in the different UGT1A1 genotypes. Between July 2022 and March 2024, a total of 292 patients with genetic and clinical information were enrolled in the study. At data cutoff, the median treatment duration with T-DXd was 12.0 months [95% confidence interval (CI) 10.5-14.1]. UGT1A1 genotype distribution among patients was 43.2% wild-type (&#x2217;1/&#x2217;1), 46.2% heterozygous (&#x2217;1/&#x2217;28), and 10.3% homozygous (&#x2217;28/&#x2217;28). No association was observed between UGT1A1 genotypes and the most common T-DXd adverse events. However, poor metabolizers (&#x2217;28/&#x2217;28) compared with extensive and intermediate metabolizers (&#x2217;1/&#x2217;1 and &#x2217;1/&#x2217;28, respectively) showed a trend toward higher incidence of neutropenia (13.3% versus <6%), as well as a higher incidence of grade &#x2265;3 gastrointestinal toxicity (diarrhea and vomiting). The incidence of drug-induced pneumonitis/interstitial lung disease (ILD) was 11.0% (32/292). No association was observed between UGT1A1 variants and the incidence of pneumonitis/ILD. Patients carrying UGT1A1&#x2217;28/&#x2217;28 genotype showed a longer treatment duration (HR 0.47, 95% CI 0.23-0.93, P = 0.03) compared with UGT1A1 wild-type patients. In the PROCURE Project, UGT1A1 variants, including the &#x2217;28/&#x2217;28 genotype, were not predictive of T-DXd-related adverse events in advanced breast cancer. The project highlights the need to identify alternative biomarkers to optimize toxicity risk stratification and guide personalized treatment strategies.

For the past decades, chemotherapy constituted the therapeutic foundation in advanced or metastatic pancreatic cancer. Despite significant advances in the molecular understanding, translation into tangible patient benefit has remained modest. Until recently, mutant KRAS, the dominant oncogenic driver, was considered undruggable, and only a small subgroup of patients potentially benefited from targeted therapies. With the emergence of KRAS inhibitors, most patients with pancreatic cancer in theory qualify for targeted therapeutics. Final results from the RASolute 302 trial showed clinically meaningful activity of RAS inhibition in patients with metastatic pancreatic cancer and paved the way for approval. Ongoing preclinical and coclinical studies have documented both intrinsic and acquired mechanisms of resistance to KRAS inhibition. Given the cellular plasticity seen in pancreatic cancer, the identification and anticipation of resistance mechanisms will be critical to exploit emerging therapeutic vulnerabilities through novel combination strategies. In view of the increasing number of trials and the growing body of evidence for targeted therapies, pancreatic cancer is entering a transitional phase in which precision oncology strategies must be redefined beyond rare molecular subgroups. In this review, we will briefly revisit targeted therapeutic approaches in pancreatic cancer to then discuss the clinical implications of genomic and transcriptomic heterogeneity in KRAS-mutant and KRAS wild-type disease. We will outline how our expanding biological insights into pancreatic cancer could inform combination and sequential therapeutic approaches.

The European Thoracic Oncology Platform (ETOP) International Breast Cancer Study Group (IBCSG) Partners Foundation initiated a series of workshops for experts to review current evidence and offer recommendations to guide future antibody-drug conjugate (ADC) research. Here, we summarise key findings from the third workshop, which included experts in various solid tumours, basic/translational research scientists and pharmaceutical industry representatives. Recent positive phase III trial data have further incorporated ADCs into the standard of care [e.g. lung: sacituzumab tirumotecan; breast: trastuzumab deruxtecan (T-DXd), sacituzumab govitecan, datopotamab deruxtecan; muscle-invasive bladder cancer: enfortumab vedotin; ovarian cancer: mirvetuximab soravastine; cervical cancer: tisotumab vedotin]. Thus, research priorities must be tailored according to tumour type, potentially focussing initially on settings where ADCs could replace chemotherapy. Many phase III ADC trials have been initiated based on positive phase I data and although these trials are larger than those conducted historically, prespecified criteria (e.g. patient numbers and magnitude of efficacy) should be met to justify proceeding directly to phase III. Importantly, although several ADCs have been successfully developed without mandatory biomarker selection, biomarker-driven ADC development enables rational patient selection, as illustrated by multiple ADCs (e.g. T-DXd, mirvetuximab soravtansine and telisotuzumab vedotin). The identification, development and validation of predictive biomarkers are therefore essential, particularly given several critical nuances, including the algorithms used to assess biomarker status and the type of specimen analysed, all of which may be influenced by temporal and spatial heterogeneity. Additional ADC research priorities include the optimisation of ADC constructs to enhance efficacy/tolerability and the identification of reliable ADC targets, including work to elucidate attributes of already-identified targets. Finally, considering the vast amount of ADC-related data being generated, artificial intelligence could be leveraged to analyse combined datasets and generate composite biomarkers, including tumour histology, optimal target expression thresholds, molecular alterations and activated pathways affecting payload activity and target function, to accelerate research.

The optimal therapeutic strategy for nonmetastatic pancreatic ductal adenocarcinoma (PDAC) remains controversial. This study sought to provide an overview of contemporary clinical management patterns across Europe. A survey was designed by a multidisciplinary team under the aegis of the European Organization of Research and Treatment of Cancer Gastrointestinal Tract Cancer Group, providing insights into initial diagnosis, surgery, and clinical management of patients with resectable, borderline resectable (BR), and locally advanced (LA) PDAC. Eighty-three practitioners from 16 European countries answered the survey. In cases of resectable PDAC, frontline surgery was the preferred option (74%) followed by neoadjuvant chemotherapy (22%). For BR PDAC, the preferred induction strategy was chemotherapy alone (70%). Radiotherapy (RT) was proposed to be added after chemotherapy in cases of poor response or persistence of vascular contact (37%). For LA PDAC, the panel's strategies were (i) induction chemotherapy followed by chemoradiotherapy (42%), (ii) chemotherapy alone (35%), and (iii) chemotherapy followed by stereotactic body radiotherapy (23%). In cases of very good response without remaining vascular contact or with a carbohydrate antigen 19-9 (CA19-9) normalization after induction chemotherapy, cancellation of the planned RT, leading to immediate surgical exploration, was proposed in 77% and 42%, respectively. This European survey highlights the significant heterogeneity in PDAC clinical practices and the frequent reconsideration and adaptation of the initially planned therapeutic strategies according to treatment response, a question not explored in clinical trials. This study demonstrates the urgent need to harmonize practices in Europe.

Liposomal irinotecan in combination with oxaliplatin, 5-fluorouracil, and leucovorin (NALIRIFOX) improved survival outcomes of patients with treatment-na&#xef;ve metastatic pancreatic adenocarcinoma (mPAC) compared with nab-paclitaxel + gemcitabine in the phase III NAPOLI-3 trial. However, no Japanese centre participated in NAPOLI-3. Therefore, this study aims to demonstrate the applicability of the efficacy and safety results of NALIRIFOX observed in the NAPOLI-3 trial to a Japanese population. In this ongoing, phase II study, patients with treatment-na&#xef;ve mPAC received NALIRIFOX across 15 Japanese centres. Eligible patients had &#x2265;1 measurable metastatic lesion, an Eastern Cooperative Oncology Group performance status of 0-1, and an initial mPAC diagnosis &#x2264;6 weeks before screening. The primary endpoint was objective response (OR) per independent central review (ICR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and quality of life (QoL). Forty-one Japanese patients received NALIRIFOX, and the median follow-up duration was 12.8 months. Seventeen (41.5%) patients had an OR and the DCR was 61.0% per ICR. Median OS was 9.9 months [95% confidence interval (CI) 7.4-12.9]; 6-month OS rate was 73.2%. Median PFS per ICR was 4.4 months (95% CI 2.3-7.2). Treatment-emergent adverse events (TEAEs) occurred in 97.6% of patients and the most frequent serious TEAEs were decreased appetite (22.0%) and decreased neutrophil count (17.1%). QoL global health status was maintained throughout the study. The efficacy and safety of NALIRIFOX for first-line treatment of mPAC in this Japanese population is consistent with results of NAPOLI-3.

Growing evidence supports the prognostic and predictive value of circulating tumor DNA (ctDNA) in gastrointestinal cancers. This study evaluated ctDNA as a prognostic biomarker for detecting molecular residual disease (MRD) and recurrence in patients with resected biliary tract cancer (BTC). We retrospectively analyzed real-world data from patients (N = 167) with stage I-III resectable BTC who underwent ctDNA analysis using a personalized, tumor-informed 16-plex multiplex PCR-coupled next-generation sequencing assay (SignateraTM; Natera, Inc., Austin, TX) between July 2020 and February 2024. Plasma samples (n = 751) were collected preoperatively, postsurgically (2-12 weeks; MRD window), and longitudinally (postdefinitive treatment surveillance). ctDNA results were compared with traditional biomarkers carbohydrate antigen 19-9 and carcinoembryonic antigen. The median follow-up was 21 months (range 2-97). ctDNA detection rates during MRD and postdefinitive treatment surveillance windows were 23% (19 of 82) and 38% (31 of 82), respectively. ctDNA positivity during MRD and postdefinitive treatment surveillance was significantly associated with inferior relapse-free survival (RFS) and overall survival (OS). ctDNA positivity was the most significant prognostic factor associated with RFS during the MRD window [hazard ratio (HR) 15.86, 95% CI 4.69-53.6, P < 0.001] and during postdefinitive treatment surveillance (HR 14.93, 95% CI 5.33-41.9, P < 0.001) by multivariate analysis. In contrast, carbohydrate antigen 19-9 and carcinoembryonic antigen were not significantly prognostic in either setting. Patients with ctDNA positivity during the MRD and postdefinitive treatment surveillance windows demonstrated significantly inferior RFS and OS, and ctDNA was more accurate than current clinical biomarkers. These findings highlight the value of ctDNA monitoring in improving prognostication in BTC, with the potential to enhance post-operative risk stratification and inform surveillance strategies through earlier detection of recurrence.

While immunotherapy plus chemotherapy is the current first-line standard for gastric or gastroesophageal junction adenocarcinoma (GC/GEJC), subgroup analyses in patients with peritoneal metastasis are limited and show inconsistent benefits across trials (e.g., ATTRACTION-4, CheckMate 649). This post-hoc analysis evaluated the efficacy of immunotherapy plus chemotherapy in patients with or without peritoneal metastases. This is an exploratory post-hoc analysis of the randomised, double-blind, phase 3 RATIONALE-305 trial. Treatment-na&#xef;ve patients aged &#x2265;18 years with advanced GC/GEJC were enrolled across 13 countries from December 13, 2018, to February 9, 2021. Patients were randomised (1:1) to tislelizumab (200 mg intravenous every 3 weeks) plus chemotherapy or placebo plus chemotherapy until disease progression or unacceptable toxicity. Patients with or without peritoneal metastasis at baseline were identified and reanalysed. Outcomes included overall survival (OS) and progression-free survival (PFS) in the intention-to-treat population, and safety in all patients who received at least one dose of study drug. RATIONALE-305 is registered with ClinicalTrials.gov, NCT03777657. Among the 997 randomised patients, 434 (43.5%) had peritoneal metastases at baseline. Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy irrespective of peritoneal metastasis status, with consistent benefits observed in patients with peritoneal metastases (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.64-0.96) and those without peritoneal metastases (HR, 0.79; 95% CI, 0.65-0.95). The OS benefits were greater in patients with a programmed death ligand-1 tumour area positivity score of &#x2265;5%, regardless of peritoneal metastasis status. Significant PFS benefit was also observed with tislelizumab plus chemotherapy in both patients with peritoneal metastasis (HR, 0.80; 95% CI, 0.64-0.98) and without peritoneal metastasis (HR, 0.77; 95% CI, 0.64-0.94). The safety profile was similar between treatment arms and consistent across subgroups. Tislelizumab plus chemotherapy significantly improved OS versus placebo plus chemotherapy in patients with GC/GEJC, irrespective of the presence of peritoneal metastases, with a comparable safety profile between treatment arms. Further dedicated prospective studies are warranted to validate these findings in this population. This study was supported by the Noncommunicable Chronic Diseases-National Science and Technology Major Project, National Natural Science Foundation of China, the Guangdong Basic and Applied Basic Research Foundation, Cancer Innovative Research Program of Sun Yat-sen University Cancer Center, Young Talents Program of Sun Yat-sen University Cancer Center, and Sanming Project of Medicine in Shenzhen.