Recent advances in molecular pathology, driven by integrated and comprehensive diagnostic approaches, have significantly advanced precision oncology. By leveraging multiomics technologies, molecular pathology enables the simultaneous assessment of genomic alterations, transcriptomic profiles, proteomic activity, and metabolic states integrated with conventional pathological evaluation to better explain tumour biology and behaviour. Large-scale international consortia, including The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumour Analysis Consortium (CPTAC) have systematically demonstrated the value of harmonised multiomics analyses in defining tumour subtypes, uncovering functional dependencies, and generating clinically actionable insights. Evidence from coordinated precision oncology initiatives, such as the National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) trial further indicates that treatment strategies guided by molecular pathology profiling are associated with improved clinical outcomes, including progression-free survival in molecularly selected patient populations. Consequently, molecularly stratified treatment approaches are increasingly required in routine clinical practice to enable targeted therapies for selected tumour entities. Integration of molecular data with functional and clinical outcomes has further facilitated the detection of emerging mechanisms of therapeutic resistance and heterogeneous treatment responses. Importantly, studies have shown that reliance on genomic analysis alone is insufficient to achieve optimal targeted therapy, underscoring the need for multi-layered molecular interrogation. This review highlights the biological and clinical relevance of multiomics integration, emphasising its critical role in comprehensive morpho-molecular tumour assessment and functional analyses while providing clinicians with a practical framework for interpreting integrated molecular diagnostics and addressing the methodological and translational challenges that must be overcome to enable broader implementation of precision oncology in routine practice.

The paradigm of molecular diagnostics has long been shifted to multi-gene panel testing from standard single-gene testing. Despite the known utilities and advantages identified in comprehensive genomic profiling, there remains challenges to implement panel testing in healthcare setting. Forty-two advanced stage solid tumor cases were enrolled and examined with next-generation sequencing (NGS). All the patients had at least one variant detected and 31 out of 42 patients (31/42, 73.8% of cohort) harboured at least 1 clinically significant variant (tier I and tier II). Tumor mutational burden (TMB) was computed using the NGS data. Majority of the cases had intermediate TMB. The presentation of data emphasized the importance of providing upfront panel testing for effective treatment plan. However, the lack of harmonization in the results reporting in electronic medical record system, and the lack of national healthcare funding to support testing cost and therapeutic drugs are the main barrier to progress.

Gastrointestinal stromal tumours (GISTs) are the clearest solid-tumour model of precision oncology because diagnosis, prognosis, and treatment are strongly shaped by molecular genotype. The discovery of activating mutations in KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) transformed management by enabling genotype-directed use of tyrosine kinase inhibitors (TKIs) across localized and advanced disease. This review summarizes how molecular classification informs contemporary GIST care, from diagnostic work-up and risk stratification to neoadjuvant, adjuvant, and metastatic treatment planning. KIT exon 11 mutations generally predict sensitivity to standard-dose imatinib, whereas KIT exon 9 tumours may benefit from dose escalation. PDGFRA D842V confers primary resistance to imatinib but sensitivity to avapritinib, illustrating the clinical value of mutation-specific therapy. We also review KIT/PDGFRA-wild-type GISTs, including succinate dehydrogenase (SDH)-deficient, neurofibromin 1 (NF1)-associated, B-Raf proto-oncogene (BRAF)-mutant, and neurotrophic tyrosine receptor kinase (NTRK)-rearranged subtypes, where extended molecular testing is increasingly important. Surgery remains central in localized disease, but operative timing, extent of resection, and use of neoadjuvant therapy should be individualized according to tumour site, rupture risk, technical feasibility, and genotype. In advanced disease, sequential use of imatinib, sunitinib, regorafenib, ripretinib, and selected mutation-specific agents reflects evolving resistance biology and the need for ongoing molecular interpretation. Emerging tools such as broader genomic profiling and liquid biopsy may further refine treatment selection. GIST therefore demonstrates that precision oncology is most effective when molecular diagnostics, surgery, systemic therapy, and multidisciplinary decision-making are integrated across the full disease course.

Objectives: To describe epidermal growth factor receptor (EGFR) mutation (EGFRm) testing practices and treatment patterns in EGFRm-positive patients with advanced/metastatic non-small cell lung cancer (NSCLC) and evaluate clinical outcomes. Methods: Data were drawn from a cross-sectional, retrospective chart review of adult patients with advanced/metastatic NSCLC in Argentina, Belgium, Brazil, India, the Netherlands, Russia, Singapore, Switzerland, and Türkiye between June–September 2021. Eligible patients had an initial advanced/metastatic stage NSCLC diagnosis, and positive first EGFRm test between April 2017–March 2018. Data were reported from NSCLC diagnosis to end of follow-up (June-2020) or death. Index was the receipt date of EGFRm result. Analyses were descriptive. Results: Overall, 208 physicians reported data on 947 patients. Mean (standard deviation) age at diagnosis was 60.3 (10.9) years and 79.4% had an ECOG 0–1. EGFRm was identified by single-gene (64.0%) and multi-gene (36.0%) panel testing. Median (interquartile range) turnaround time was 14 (10–22) days. Prior to and following index, 26.9% and 68.6% of patients, respectively, were administered EGFR-tyrosine kinase inhibitors (EGFR-TKI) as first-line (1 L) treatment. Disease progression occurred in 60.4% and 70.1% pre-index and post-index, respectively. Among those receiving 1 L EGFR-TKI, partial response was reported in 56.5% of patients pre-index and in 65.0% post-index. The median overall survival on post-index 1 L EGFR-TKI was not reached. Conclusion: EGFRm status was mostly determined by single-gene testing, and around one-quarter of patients were prescribed pre-index 1 L EGFR-TKI. Further research into outcomes for EGFRm-positive patients not receiving 1 L EGFR-TKI, and pre-index vs post-index treatment would be valuable.

Background: Glypican-3 (GPC3), a cell surface glycoprotein, regulates cell growth and exhibits increased expression in hepatocellular carcinoma (HCC) and squamous non-small cell lung cancer (SQ-NSCLC). This study developed an artificial intelligence (AI) algorithm for predicting GPC3 expression to accelerate clinical trial enrollment, comparing it with manual immunohistochemistry (IHC) scoring. Methods: Using 167 NSCLC and 133 HCC formalin-fixed paraffin-embedded tumor blocks, GPC3 expression was quantified via IHC assays. Machine learning (ML) models were trained on digitized NSCLC whole slide images to identify GPC3-positive tumor areas, applying data-driven cutoffs for classification. Association between GPC3 and programmed cell death-ligand 1 (PD-L1) IHC expression in NSCLC sample was explored. Results: GPC3 expression peaked in HCC (63.9%), followed by SQ-NSCLC (52.6%) and adeno-NSCLC (lung adenocarcinoma) (10.0%). No significant correlation was found between GPC3 and PD-L1 expression in SQ-NSCLC. AI-based screening surpassed clinical pathologists by 10% in precision, achieving 100% recall at a 1% cutoff. ML model quantification aligned well with pathologist consensus. Profiling GPC3 expression emphasized its prevalence in HCC and SQ-NSCLC. Conclusion: Our AI platform standardizes, scales, and reproducibly characterizes GPC3 in NSCLC, supporting patient selection in clinical studies.

While traditionally informed by tumor tissue origin and histopathology, advancements in next-generation sequencing (NGS) technology have catalyzed tumor-agnostic approaches which prioritize molecular alterations for personalized treatment. Here, we demonstrate the clinical utility of molecularly guided tumor-agnostic precision medicine in an Asian cohort, leveraging an Asian-centric NGS panel tailored to address the unique genetic landscape of the region. 1,167 formalin-fixed paraffin-embedded tissue samples from 1,150 Asian cancer patients across >70 centers in 7 countries underwent real-world NGS testing using an Asian-centric pan-cancer hybrid-capture NGS panel (UNITED), profiling 572 cancer-related genes and 91 RNA fusion partners. Biomarkers were classified as actionable if therapeutic indications were FDA-approved, guideline-recommended, or supported by robust phase III clinical trials. The cohort encompassed 23 cancer types, with lung (17.7%), colorectal (12.8%), prostate (11.1%), and breast (8.6%) cancers accounting for 50.1% of the clinical volume. Actionable biomarkers were identified in 62.2% of samples, with KRAS, EGFR, and PIK3CA among the most frequently mutated genes. The likelihood of identifying ≥1 actionable mutation was highest in CNS tumors (83.6%), followed by lung cancer (81.2%), breast cancer (79%), and others. Among 27,552 somatic variants detected, 1,291 (4.7%) were potentially targetable by regulatory-approved therapies. Notably, ≥1 tumor-agnostic biomarker (including TMB-H, dMMR/MSI-H, NTRK/RET fusions, and BRAF V600E) was identified in every cancer type, detected in 98 samples (8.4%). This includes in 16.9% of lung tumors, 12.2% of tumors of unknown primary origin, 11.8% of endometrial tumors, and others. As expected, TMB was significantly associated with MSI (p<0.0001). ERBB2 amplification, a potential surrogate marker for HER2 overexpression, was identified in 42 samples (3.6%) and was most frequently detected in breast tumors (15%), followed by endometrial tumors (11.8%), ovarian tumors (8.9%), and others. Homologous recombination deficiency (HRD) was observed in 407 samples (34.9%) and were present in about half of the tumors of the breast (50%), colon (49%), urothelium (47.1%), endometrium (47.1%) and lung (44%). Notably, HRD-positive tumors exhibited significantly higher TMB compared to HRD-negative tumors (median TMB 5.58 vs. 5.15, p=0.0001). Leveraging an Asian-centric NGS panel, actionable molecular alterations were detected in 62.2% of Asian cancer patients. The high prevalence of actionable biomarkers, coupled with the detection of regulatory-approved tumor-agnostic markers, underscores the significance of comprehensive NGS testing in facilitating tumor-agnostic precision medicine in an Asian setting, thereby improving treatment strategies and patient outcomes. Jing Yi Lee, Aya E. Helali, Zi Yi Wan, Donald Y. Poon, Jens Samol, Tsz Him So, Su Pin Choo, Ravindran Kanesvaran, Cheng-Vai Hui, Joseph S. Au, Timothy Yip, Ross Soo, Michelle Pek, Ruifen Weng, Bin Tean Teh, Min-Han Tan, Jonathan Poh, Jason Y. Chan. Clinical actionability of an Asian pan-cancer tissue-based next generation sequencing (NGS) assay [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 720.

TPS6123 Background: Induction chemotherapy (IC) and chemoradiotherapy (CRT) is the current standard of care (SOC) for locoregionally advanced NPC (LA-NPC). However, CRT alone or CRT and adjuvant chemotherapy (AC) are also first-line SOC options. Plasma Epstein-Barr virus (EBV) DNA is an archetypal biomarker for endemic NPC, and has been assessed for pre-and on-treatment clinical stratification. RIBBON-UM is a phase 2, multi-arm umbrella trial investigating pre- and on-treatment plasma EBV DNA assessment to individualise treatment of patients with LA-NPC. Methods: Patients who are newly-diagnosed, biopsy-proven NPC of TNM-stage III-IVA by AJCC/UICC 8 th ed and have DETECTABLE EBV DNA pre-treatment are eligible. RIBBON-UM incorporates a 2-tier stratification by TN-status and EBV DNA levels – (1) First, patients will be stratified into low- (LR) and high-risk (HR) based on pre-treatment EBV DNA cut-off 4000 copies/mL AND/OR T4N+ or N2-3 disease; (2) Second, for the HR patients who are assigned to IC (gemcitabine-cisplatin), patients will be further stratified into HR and very-high risk (VHR) depending on their EBV DNA clearance post-3 cycles of IC. RIBBON-UM consists of 3 treatment arms (NCT05517135): Arm I will enroll LR patients (T3N0-1, T4N0 AND EBV DNA <4000 copies/mL) to upfront CRT (cisplatin/carboplatin) ± AC (cisplatin and 5-fluorouracil or capecitabine based on physician’s discretion). HR patients (T4N+ OR N2-3 OR EBV DNA ≥4,000 copies/mL) will receive upfront IC, and if UNDETECTABLE EBV DNA post-IC, they will be assigned to Arm II – CRT ± AC. For patients with a DETECTABLE EBV DNA post-IC (VHR), these patients are assigned to Arm III – a single-arm, phase 2 trial investigating experimental AC (NCT06093061), embedded within the RIBBON-UM protocol. Currently, VHR patients enrolled into Arm III will receive CRT + 1-y combined tislelizumab (200 mg IV 3-weekly) and metronomic capecitabine at 650 mg/m 2 bidaily (RIBBON-LA-01, NCT06093061) or 1-y metronomic capecitabine (if they decline). Statistical plan of RIBBON-UM consists of 2 analyses: (1) we will evaluate if our risk-stratification strategy by TN-status and pre- and on-treatment EBV DNA levels improves 2-y disease-free survival (DFS) rate of patients with LA-NPC from 65% (historical) to 75% for the modular platform trial; (2) we hypothesise that AC intensification (Arm III) will improve 2-y DFS of the VHR cohort from 60% (historical) to 75%. 133 and 62 patients are required to test these hypotheses at 5% 1-sided significance level with 80% power, respectively. The risk-stratified treatment individualisation and AC intensification strategies will be deemed successful if 96 of 133 (from Arms I-III) and 44 of 62 patients (Arm III) remain disease-free at 2 y. From Nov 2022 to Jan 2025, we have enrolled 93 and 51 patients into RIBBON-UM and RIBBON-LA-01, respectively. We expect enrolment to RIBBON-UM to complete by Jun 2025. Clinical trial information: NCT05517135 , NCT06093061 .

INTRODUCTION:HER2-directed treatments for HER2-overexpressing (HER2-OE; immunohistochemistry [IHC] 3+/2+) NSCLC are needed. METHODS:DESTINY-Lung03 is an open-label, multi-arm, phase 1b study. Part 1 evaluated trastuzumab deruxtecan (T-DXd, 4.4 or 5.4 mg/kg) plus durvalumab (1120 mg) and cisplatin (60 or 75 mg/m2; Arm 1A)/carboplatin (area under the plasma concentration-time curve [AUC] 4 or 5; Arm 1B) or T-DXd 5.4 mg/kg monotherapy (Arm 1D) in pretreated metastatic HER2-OE NSCLC. Primary end points: dose-limiting toxicities (DLTs) and adverse events (AEs: Arms 1A and 1B). Secondary end points: safety (Arm 1D) and efficacy (all arms). RESULTS:At data cutoff (April 1, 2024), 11, 24, and 36 patients received treatment in Arms 1A, 1B, and 1D, respectively. DLTs reported in Arm 1A: febrile neutropenia (n = 1; grade [G] 5; 4.4 mg/kg/1120 mg/60 mg/m2 doses); decreased platelet count (n = 2; G4 and G5; 5.4 mg/kg/1120 mg/75 mg/m2 doses). DLTs reported in Arm 1B: febrile neutropenia (n = 1; G3; 4.4 mg/kg/1120 mg/AUC 5 doses; n = 1; G4; 4.4 mg/kg/1120 mg/AUC 4 doses); decreased platelet count (n = 1; G4; 5.4 mg/kg/1120 mg/AUC 5 doses). Drug-related serious AEs occurred in 63.6%, 37.5%, and 16.7% of Arms 1A, 1B, and 1D, respectively. Confirmed objective response rate (95% confidence interval) per investigator: 37.5% (18.8-59.4; Arm 1B) and 44.4% (27.9-61.9; Arm 1D). CONCLUSIONS:Data confirm the activity of T-DXd monotherapy in pretreated HER2-OE NSCLC but do not support T-DXd plus durvalumab and platinum chemotherapy use in this population. CLINICAL TRIALS: GOV IDENTIFIER:NCT04686305.

Early detection of lung cancer is crucial for improving survival rates because it allows for potentially curative treatments; however, most lung cancer cases in Singapore are diagnosed at advanced stages. This review article provides an overview of current practices in the management of early-stage non-small-cell lung cancer (stages I-IIIA) in Singapore (i.e., screening, diagnosis, treatment, and follow-up) while identifying and addressing the associated challenges. Implementing a locally adapted, subsidized national screening program with awareness campaigns can facilitate lung cancer screening uptake. Improving the accessibility and affordability of diagnostic tests and treatments, establishing clear referral pathways and diagnostic workup, adopting multidisciplinary teams, and utilizing cost-effective treatments are critical to timely and effective management of early-stage lung cancers. Establishment of local guidelines for follow-up care, integrating digital technologies and artificial intelligence, and expanding patient assistance programs for follow-up procedures are vital to improving long-term outcomes. Overall, improving the management of early-stage lung cancer necessitates collaboration among healthcare professionals, medical societies, policymakers, patient advocacy groups, and the general public.

Epstein-Barr Virus associated smooth muscle tumour (EBV-SMT) is a rare tumour with an estimated prevalence of <2 cases per million. It develops in patients who are immunocompromised and in whom the risk of EBV reactivation causing tumorigenesis is high. Examples of immunocompromised states include patients infected with human immunodeficiency virus (HIV), patients on iatrogenic immunosuppression following transplantation and patients with primary/congenital immunodeficiency. Although the association between EBV and development of EBV-SMT is well established, the underlying pathophysiology for this association is unclear. We present a case of a patient with HIV related EBV-SMT who has been on treatment with sirolimus for >5 years with disease continuing to remain controlled, clearly demonstrating the durable activity of sirolimus in the management of EBV-SMT. We scrutinized the literature pertaining to novel therapeutics which have been used for the management of EBV-SMTs and set it into context with other EBV associated neoplasms. To our knowledge, this is the first case report of a patient treated with sirolimus and we recommend that mTOR inhibition with sirolimus be considered as a first therapeutic option together with HAART in patients with HIV associated EBV-SMTs.

•No targeted treatments are currently approved for patients with EGFR-mutant non–small-cell lung cancer (NSCLC) and MET-mediated resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs).•This case series describes real-world outcomes with tepotinib, a selective MET-TKI, in combination with EGFR-TKIs in patients with EGFR-mutant, MET-altered NSCLC and resistance to EGFR-TKIs.•Among the 25 patients included, tepotinib was given in combination with a range of EGFR-TKIs (osimertinib, n = 18; gefitinib, n = 5; dacomitinib, n = 1; afatinib, n = 1) as second (n = 8), third (n = 9), or fourth-or-later (n = 8) line therapy.•Tepotinib plus EGFR-TKIs demonstrated clinical benefit per physician's assessment in 23/25 patients, with a partial response in 15/25 patients.•Tepotinib plus EGFR-TKIs showed favorable tolerability that was consistent with previous observations, with edema reported as the most common tepotinib-related adverse event (14/25 patients).•This case series, including patients with several prior treatment lines, suggest tepotinib plus an EGFR-TKI as a potential chemotherapy-sparing, oral targeted treatment option for patients with EGFR‑mutated, MET-altered NSCLC after progression on EGFR‑TKIs.

PURPOSE:To evaluate the performance of a circulating tumor DNA (ctDNA) and circulating tumor RNA (ctRNA) liquid biopsy, LiquidHALLMARK (LHM), compared with tissue next-generation sequencing (NGS) and Guardant360 CDx (G360 ctDNA) liquid biopsy for biomarker detection in metastatic nonsquamous non-small cell lung cancer. PATIENTS AND METHODS:This multicenter, prospective study (ClinicalTrials.gov identifier: NCT04703153) enrolled patients across the United States and Singapore. Patients were tested with tissue NGS, LHM, and G360 ctDNA. The primary objective was noninferiority of LHM ctDNA to tissue NGS and G360 ctDNA. Secondary analyses included turnaround time (TAT), overall response rate (ORR), and progression-free survival (PFS), with exploratory analysis of the clinical utility of ctRNA. RESULTS:LHM ctDNA (48.2%) detected 11.4% fewer biomarker-positive patients than tissue NGS (59.6%) and did not meet noninferiority criteria. Compared with tissue NGS, LHM ctDNA and G360 ctDNA were concordant in 72.1% and 66.1% of patients, establishing noninferiority of LHM ctDNA to G360 ctDNA (P = .002). TAT was shorter for LHM ctDNA than for tissue NGS (mean 9.7 v 21.7 days; P < .001). ORR/PFS was similar in patients receiving targeted therapy based on all three assays. Addition of ctRNA increased the diagnostic yield of tissue NGS-confirmed gene rearrangements by 28.6% relative to LHM ctDNA and all actionable biomarkers by 15.6% relative to G360 ctDNA. LHM ctDNA and ctRNA (51/68) detected 8.8% more biomarker-positive patients than G360 ctDNA (45/68), demonstrating superiority of LHM ctDNA and ctRNA (P = .001). CONCLUSION:LHM ctDNA is noninferior to G360 ctDNA, but not tissue NGS. Treatment outcomes based on liquid biopsy are comparable with those based on tissue NGS. Incorporation of ctRNA into LHM ctDNA improves the diagnostic yield of actionable, tissue NGS-confirmed gene rearrangements.

Advancements in next-generation sequencing have facilitated tumour-agnostic approaches for cancer therapy. Here, we demonstrate the clinical utility of molecularly guided tumour-agnostic precision medicine in an Asian cohort, leveraging an Asian-centric DNA/RNA comprehensive genomic profiling (CGP) panel. A total of 1166 tissue samples encompassing 29 cancer types underwent real-world CGP testing. Actionable biomarkers were identified in 62.3% of samples, including 1291 (4.7%) somatic variants potentially targetable by regulatory-approved therapies. At least one tumour-agnostic biomarker, including high tumour mutation burden (TMB-high), microsatellite instability (MSI-high), NTRK/RET fusions, and BRAF V600E was identified in 98 samples across 26 cancer types (8.4%). ERBB2 amplification was identified in 42 samples (3.6%) and was most frequently detected in breast (15.0%), followed by endometrial (11.8%) and ovarian tumours (8.9%). Homologous recombination deficiency (HRD) was observed in 407 samples (34.9%). The high prevalence of actionable biomarkers underscores the significance of CGP in facilitating precision medicine in an Asian setting.

Background Vascular endothelial growth factor (VEGF) is overexpressed in nasopharyngeal carcinoma and suppresses the anti-tumour immune response. Previous studies have shown that adding anti-VEGF treatment to PD-1 inhibition treatment strategies improves tumour response. We aimed to compare the efficacy of pembrolizumab, a PD-1 inhibitor, with or without bevacizumab, a VEGF inhibitor, in nasopharyngeal carcinoma. Methods In this randomised, open-label, phase 2 trial done at two hospitals (National University Cancer Institute and Tan Tock Seng Hospital) in Singapore, patients with platinum-resistant recurrent or metastatic nasophayngeal carcinoma were eligible if they were aged 21 years or older and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Patients were assigned (1:1; using random permuted blocks with varying sizes of 4 and 6) to receive either intravenous pembrolizumab (200 mg) every 21 days or a combination of pembrolizumab with intravenous bevacizumab (75 mg/kg) administered 1 week prior to each dose, until radiographic disease progression, unacceptable toxicity, completion of 32 cycles, or withdrawal of consent. The study was open label, therefore no masking of treatment assignment was implemented. The primary endpoint was objective response rate, assessed using RECIST (version 1.1) by independent radiologists and analysed in the intention-to-treat population (ie, all randomly assigned patients). This trial is registered with ClinicalTrials.gov, NCT03813394, and enrolment has closed. Findings Between May 13, 2019, and Dec 6, 2023, we assessed 60 individuals for eligibility, 12 were excluded, and 48 were randomly allocated to pembrolizumab alone (n=24) or a combination of bevacizumab and pembrolizumab (n=24). The median age was 56 years (IQR 48-65), and 40 (83%) of 48 patients were male and eight (17%) were female. The median follow-up was 283 months (IQR 151-559). The objective response rate was significantly higher in the bevacizumab and pembrolizumab group (583% [95% CI 366-779] than in the pembrolizumab group (125% [27-324]; unadjusted RR 467 [95% CI 154-1418]; p=00010). Grade 3 treatment-related adverse events occurred in two (8%) of 24 patients in the pembrolizumab group and in seven (29%) of 24 patients in the bevacizumab and pembrolizumab group; the most common severe or grade 3-4 treatment-related adverse events were thrombosis or bleeding (four [17%] of 24 patients in the bevacizumab and pembrolizumab group vs none of 24 patients in the pembrolizumab group), and others were transaminitis (none vs 1 [4%]), colitis (1 [4%] vs none]), cytopenias (none vs 1 [4%]), dermatological toxicities (1 [4%] vs none]), hypertension (1 [4%] vs none]), and proteinuria (1 [4%] vs none]). There were no grade 4 treatment-related adverse events or treatment-related deaths in either group. Interpretation Pembrolizumab in combination with bevacizumab was more efficacious than pembrolizumab monotherapy, with manageable toxicities in platinum-resistant nasopharyngeal carcinoma. If validated in a phase 3 trial, the combination therapy could be a new standard of care in this population of patients. Copyright (c) 2025 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

BACKGROUND:While the development in multimodal therapies has helped improve treatment outcomes for patients with locally advanced gastric adenocarcinoma (LAGC), there still exist disparities in opinion with an optimal treatment plan. This consensus hopes to provide clinicians with structured guidelines to aid in the decision-making for treatment options for LAGC. METHODS:The consensus statement was initiated by establishing a taskforce in collaboration with the Asia Pacific Gastroesophageal Cancer Congress (APGCC) and a multidisciplinary expert panel was selected. Clinical questions on LAGC where perceived variance in practice or opinion may exist were formulated. Studies involving patients with Stage 2 or 3 gastric or Siewert 3 junctional cancers with treatment arms of perioperative chemotherapy, neoadjuvant chemotherapy, adjuvant chemotherapy, immunotherapy and surgery were included. A total of two rounds of voting were performed. Consensus was determined to be reached when a single answer or a combination of either "strongly agree/agree" or "strongly disagree/disagree" responses exceeded 75%. RESULTS:A total of thirteen clinical questions were developed. They were identified through five main categories: Distal LAGC, Proximal LAGC, Deficient mismatch repair tumors, Chemotherapy and Immunotherapy, and Elderly/Unfit patients. After two rounds of voting by our multidisciplinary expert panel, eleven out of a total thirteen clinical questions had reached consensus. No consensus was reached for two clinical questions. CONCLUSION:The APGCC consensus statement aims to guide clinicians in the treatment options for LAGC and Siewert 3 junctional cancer and has clarified some of the roles of perioperative chemotherapy and immunotherapy.

3062 Background: Genomic profiling of metastatic NSCLC to inform targeted therapy selection is endorsed by numerous guidelines. While tissue biopsy is the mainstay of molecular profiling, liquid biopsy offers a practical real-world approach to non-invasively identify guideline-recommended biomarkers. LIQUIK was a prospective, multicenter, observational cohort study to evaluate the performance of a combined ctDNA and ctRNA liquid biopsy assay, LiquidHALLMARK (LHM ctDNA and ctRNA) in comparison to the ctDNA-only liquid biopsy Guardant360 (G360 ctDNA) and tissue next-generation sequencing (NGS) for biomarker detection in metastatic NSCLC. Diagnostic performance of the primary cohort has been previously presented. Here, we report clinical outcomes after 1-year follow-up of the cohort. Methods: LIQUIK (NCT04703153) enrolled 151 non-squamous NSCLC patients across the USA and Singapore from Apr 2021 to Dec 2022. Enrolled patients were genotyped using tissue NGS, LHM ctDNA and ctRNA, and G360 ctDNA for 9 biomarkers ( EGFR , ALK , RET , ROS1 , BRAF , KRAS , MET , ERBB2 , NTRK1 / 2 / 3 ). Patients were treated according to their physician’s choice of first-line therapy following biomarker testing. Tumor assessments were performed at baseline and within 6 months (mo) of treatment initiation. Overall response rate (ORR), progression-free survival (PFS), and the clinical utility of ctRNA were investigated. Results: Among the 151 patients, 129 were subsequently treated in the first-line setting (49.6% on targeted therapy, 41.1% on chemotherapy, and 30.2% on immunotherapy), with 27 on combination therapy. Of the 64 patients on targeted therapy, 47 had matched biomarker findings from tissue NGS, 47 from LHM ctDNA and ctRNA, and 43 from G360 ctDNA. ORRs of patients on targeted therapy and chemo/immunotherapy were 40.4% and 16.1% respectively. Among patients treated with targeted therapy, ORR was similar between patients with biomarker-matched findings from tissue NGS (45.2%), LHM ctDNA and ctRNA (40.5%), and G360 ctDNA (36.8%). PFS of patients on targeted therapy (median 23.6 mo) was significantly longer than those not on targeted therapy (median 3.8 mo; HR = 0.26; p < 0.001). Median PFS was similar between patients with biomarker-matched findings from tissue NGS (23.6 mo), LHM ctDNA and ctRNA (18.6 mo), and G360 ctRNA (20.1 mo). Overall, incorporation of ctRNA into LHM identified 2 additional biomarker-positive patients. Both ctRNA-exclusive biomarkers were confirmed by tissue NGS, and both patients were treated with biomarker-matched targeted therapy. While one patient was lost to follow-up, the second patient had a partial response to treatment. Conclusions: Treatment outcomes based on liquid and tissue biopsies are comparable. The inclusion of ctRNA in liquid biopsy increases its diagnostic yield of actionable biomarkers. Clinical trial information: NCT04703153 .

BACKGROUND:There is an unmet need for precise biomarkers for early non-invasive breast cancer detection. Here, we aimed to identify blood-based DNA methylation biomarkers that are associated with breast cancer.METHODS:DNA methylation profiling was performed for 524 Asian Chinese individuals, comprising 256 breast cancer patients and 268 age-matched healthy controls, using the Infinium MethylationEPIC array. Feature selection was applied to 649,688 CpG sites in the training set. Predictive models were built by training three machine learning models, with performance evaluated on an independent test set. Enrichment analysis to identify transcription factors binding to regions associated with the selected CpG sites and pathway analysis for genes located nearby were conducted.RESULTS:A methylation profile comprising 51 CpGs was identified that effectively distinguishes breast cancer patients from healthy controls achieving an AUC of 0.823 on an independent test set. Notably, it outperformed all four previously reported breast cancer-associated methylation profiles. Enrichment analysis revealed enrichment of genomic loci associated with the binding of immune modulating AP-1 transcription factors, while pathway analysis of nearby genes showed an overrepresentation of immune-related pathways.CONCLUSION:This study has identified a breast cancer-associated methylation profile that is immune-related to potential for early cancer detection.

BACKGROUND:Epstein-Barr virus-specific cytotoxic T lymphocyte (EBV-CTL) is an autologous adoptive T-cell immunotherapy generated from the blood of individuals and manufactured without genetic modification. In a previous phase II trial of locally recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients, first-line gemcitabine and carboplatin (GC) and EBV-CTL combination demonstrated objective antitumor EBV-CTL activity and a favorable safety profile. The present study explored whether this combined first-line chemo-immunotherapy strategy would produce superior clinical efficacy and better quality of life compared with conventional chemotherapy treatment. PATIENTS AND METHODS:This multicenter, randomized, phase III trial evaluated the efficacy and safety of GC followed by EBV-CTL versus GC alone as first-line treatment of R/M NPC patients. Thirty clinical sites in Singapore, Malaysia, Taiwan, Thailand, and the USA were included. Subjects were randomized to first-line GC (four cycles) and EBV-CTL (six cycles) or GC (six cycles) in a 1 : 1 ratio. The primary outcome was overall survival (OS) and secondary outcomes included progression-free survival, objective response rate, clinical benefit rate, quality of life, and safety. CLINICALTRIALS:gov identifier: NCT02578641. RESULTS:A total of 330 subjects with NPC were enrolled. Most subjects in both treatment arms received four or more cycles of chemotherapy and most subjects in the GC + EBV-CTL group received two or more infusions of EBV-CTL. The central Good Manufacturing Practices (GMP) facility produced sufficient EBV-CTL for 94% of GC + EBV-CTL subjects. The median OS was 25.0 months in the GC + EBV-CTL group and 24.9 months in the GC group (hazard ratio = 1.19; 95% confidence interval 0.91-1.56; P = 0.194). Only one subject experienced a grade 2 serious adverse event related to EBV-CTL. CONCLUSIONS:GC + EBV-CTL in subjects with R/M NPC demonstrated a favorable safety profile but no overall improvement in OS versus chemotherapy. This is the largest adoptive T-cell therapy trial reported in solid tumors to date.