Cancer treatment is evolving from organ-based classification toward biomarker-driven precision medicine, culminating in the development of tumor-agnostic therapies approved based on molecular characteristics, irrespective of tumor origin. Since the US Food and Drug Administration's landmark 2017 approval of pembrolizumab for microsatellite instability-high tumors, nine tumor-agnostic drugs have been approved, offering unprecedented treatment options for patients with rare cancers and actionable genomic alterations. However, this scientific breakthrough has revealed profound global implementation challenges. We reviewed the current landscape of tumor-agnostic drug approvals, regulatory pathways, and implementation experiences across multiple regions, including Europe, Asia-Pacific, Latin America, Africa, and the Middle East. Barriers to access were examined across regulatory, reimbursement, infrastructure, and workforce domains to inform a conceptual framework for implementation. Access remains inconsistent even in high-resource settings, with fewer than 50% of eligible patients receiving matched therapies. In Europe, centralized regulatory approval through the European Medicines Agency contrasts sharply with fragmented national reimbursement decisions, creating delays in access. Asia-Pacific nations demonstrate rapid growth in tumor-agnostic approvals and drug development capacity, although significant urban-rural disparities persist. Latin America, Africa, and areas in the Middle East face fundamental barriers, including limited testing infrastructure, workforce shortages, and competing health care priorities. To address these challenges, we propose a four-pillar framework for equitable implementation: comprehensive biomarker testing capability, innovative clinical trial designs with decision-support systems, harmonized regulatory approval and reimbursement mechanisms, and investment in genomically competent workforce development. International initiatives including Project Orbis and cross-border trial consortia demonstrate promising models for regulatory convergence. Realizing the transformative potential of tumor-agnostic therapies requires coordinated global strategies that bridge the divide between genomic innovation and geographic accessibility, ensuring all patients benefit regardless of socioeconomic status or location.

PURPOSEThere is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs.METHODSUsing the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) a two-round international multistakeholder Delphi survey (N = 109 in Round 1 [October 2024]; N = 96 in Round 2 [December 2024]); and (4) an independently chaired virtual consensus meeting (N = 31; January 2025) where multidisciplinary, international experts reviewed and voted to finalize items for inclusion.RESULTSConsensus was reached on six recommendations emphasizing three core PRO tolerability concepts: overall side effect impact, symptomatic adverse events, and overall health-related quality of life. The integration of PROs to inform final dose recommendations in dose escalation and optimization trials should be considered, regardless of trial design. The recommendations highlight the importance of PRO data analysis over time and across dose levels, defining PRO research objectives as descriptive or statistically powered, and assessing PRO-related end points to guide end point selection for subsequent studies.CONCLUSIONThis foundational guidance outlines key PRO research objectives in DFOTs. By facilitating the systematic integration of PROs, this guidance supports the utilization of patient-centered evidence for the tolerability and efficacy assessment of therapies to inform dose escalation, optimization, and regulatory evaluation-ultimately contributing to the development of safer, more effective therapies.

The historical development of plasma Epstein–Barr virus DNA for informing clinical decisions for patients with nasopharyngeal carcinoma has culminated in the EP-STAR trial. The circulating tumour DNA clearance patterns observed during neoadjuvant chemotherapy could be used to guide adjuvant therapy, improve outcomes and possibly reflect differences in tumour biology. Herein we discuss why this study constitutes a full-circle moment and provides valuable insights for advancing circulating tumour DNA-based applications in precision oncology.

Purpose:BRAFV600E-mutated metastatic colorectal cancers (mCRCs) are associated with poorer prognosis. We present a case, in which noninvasive therapeutic monitoring was performed on a patient with BRAF-mutant mCRC, aiming to track disease progression and elucidate the mechanisms of response and resistance towards anti-BRAF therapy. Methods:A 40-year-old man diagnosed with metastatic BRAFV600E mutant sigmoid adenocarcinoma received multiple lines of treatment, including first-line chemotherapy + bevacizumab and targeted therapy of cetuximab, encorafenib ± binimetinib. Noninvasive therapeutic monitoring was performed on ctDNA using our in-house designed droplet digital PCR assay and fragmentomics. We also performed serial and paired analyses of tissue, liquid biopsy, and in vitro studies at different multiple timepoints. Results:ctDNA and fragmentomics biomarkers were concordant with, and even preceded traditional serological and radiological biomarkers in predicting disease progression. Molecular analyses and drug testing also revealed mutations that are either potentially targetable or account for resistance, which guided the subsequent treatment regimen. Conclusion:This case demonstrates the potential application of ctDNA and fragmentomics biomarkers, molecular analyses, and drug testing in noninvasive therapeutic monitoring of BRAFV600E mutant mCRC. These illustrate the potential application of such noninvasive therapeutic monitoring in larger scale cohorts of patients.

To investigate change in diffusion weighted imaging (DWI) between pre-treatment (pre-) and after induction chemotherapy (post-IC) for long-term outcome prediction in advanced nasopharyngeal carcinoma (adNPC). Mean apparent diffusion coefficients (ADCs) of two DWIs (ADCpre and ADCpost−IC) and changes in ADC between two scans (ΔADC

Abstract Anti-PD1 therapy in nasopharyngeal carcinoma (NPC) demonstrates limited efficacy, with only 19.3% of patients achieving one-year progression-free survival. Identifying predictive biomarkers is crucial for enhancing therapeutic outcomes. Endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in MHC Class I peptide processing, has been implicated in immune evasion mechanisms. We analyzed a cohort of 10 patients with recurrent/metastatic NPC treated with anti-PD-1 therapy. Tumor epithelial and microenvironment regions were separately obtained using laser-capture microdissection (LCM) from FFPE samples, and gene expression was profiled using an in-house RNA-Seq technique optimized for low-input RNA, generating 26 libraries. Immunohistochemistry (IHC) was performed to assess ERAP2 expression in this cohort and on NPC tissue microarray (n=153) comprising primary, recurrent, and metastatic tumors for validation. Functional studies were conducted using the C666-1, NPC43 and C17 cell lines engineered to overexpress ERAP2 via lentiviral transduction. Co-culture with HLA-matched PBMCs and nivolumab was performed. Mass spectrometry was performed to evaluate changes in the immunopeptidome of ERAP2-overexpressing cells. ERAP2 was among the most highly upregulated genes in non-responders compared to responders (p<0.05, log2​ fold change = 2.8). IHC (n=153) showed moderate to high ERAP2 expression in 53.8% of primary, 51.5% of recurrent, and 53.3% of metastatic tumors. In a proliferation assay, ERAP2-overexpressing C666-1 cells showed no change in cell index when co-cultured with HLA-matched PBMCs and nivolumab (Δ = 0.2), while mock-transfected cells showed a significant reduction (Δ = -15.4, p<0.05). Mass spectrometry-based immunopeptidome analysis did not show any obvious change in MHC-I peptide size distribution in C666-1 cells despite ERAP2 overexpression. In contrast, NPC43 cells exhibited a notable shift, with NPC43 ERAP2-overexpressing cells predominantly generating 9mer peptides (48.2% vs 9.6%), compared to 11mer peptides (14.1% vs 56.8%) in mock transfected cells. These results provide evidence that ERAP2 overexpression is associated with anti-PD1 resistance in NPC, potentially through mechanisms of impaired T-cell-mediated cytotoxicity and altered peptide presentation. Our current work includes examining the effects of altered antigen presentation on cytotoxicity, as well as the potential of ERAP2 as a predictive biomarker and therapeutic target. Citation Format: Luvita Suryani, Yi Ren, Dawn Sijin Nin, Joseph W Foley, Yaw Chyn Lim, Chee Seng Tan, Kevin J Cullen, Han Chong Toh, Kwok Wai Lo, Brigette BY Ma, Robert B West, Boon Cher Goh, Lih Wen Deng, Joshua K Tay. ERAP2 overexpression and anti-PD-1 resistance in nasopharyngeal carcinoma [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B080.

Nasopharyngeal carcinoma (NPC) is a major disease burden in endemic regions, where Epstein–Barr virus (EBV) infection has a key aetiological role in this malignancy. Both plasma EBV DNA and serum antibodies targeting EBV antigens have been validated independently in large-scale prospective trials as effective biomarkers for early detection of NPC. Plasma EBV DNA analysis by PCR could identify patients with early-stage, asymptomatic NPC. Emergent studies have shown that fragmentomics analysis of plasma EBV DNA can further enhance the specificity of NPC detection at the time of testing and better predict the future risk of NPC. Initial antibody-based NPC screening approaches were based on the detection of immunoglobulin A antibodies targeting EBV viral capsid antigen or Epstein–Barr nuclear antigen 1, which resulted in a subsequent reduction in NPC-specific mortality in a population screening trial. Subsequently, the detection of anti-BNLF2b antibodies alone has been reported to achieve higher sensitivity and specificity relative to the dual antibody approach. Cost-effectiveness analyses support the implementation of NPC screening in endemic regions using either EBV DNA or antibodies. Ongoing research initiatives are focusing on developing prophylactic and therapeutic vaccines as preventive measures against EBV-associated diseases, including NPC. In this Review, we discuss these advances as well as their relevance for the implementation of prevention strategies such as population-wide NPC screening and vaccination in endemic areas of NPC prevalence. We also highlight valuable insights from plasma EBV DNA studies that might facilitate optimization of liquid biopsy-based screening strategies for other types of cancer. Epstein–Barr virus (EBV) infection has a key aetiological role in endemic nasopharyngeal carcinoma (NPC). The authors of this Review discuss advances in NPC screening, which leverage the detection of either plasma EBV DNA or serum antibodies targeting EBV antigens, as well as in prevention, which relies on prophylactic and therapeutic vaccines for NPC.

Fragmentomics analysis of plasma autosomal DNA has shown promise in cancer diagnostics. Here we evaluated the clinical utility of plasma Epstein-Barr virus (EBV) DNA fragmentomics analysis for nasopharyngeal carcinoma (NPC) screening. Among our prospective cohort of approximately 20,000 subjects that underwent two rounds of screening, we analyzed the first-round blood samples of subjects who tested positive for EBV DNA via polymerase chain reaction (PCR) (n = 558). We found that those who subsequently developed NPC in the second round exhibited a distinctive mononucleosomal size pattern, an NPC-associated end motif (specifically, a depletion of CC-motif) and aberrations in methylation identified through fragmentomics-based methylation analysis (FRAGMA). Subjects with these aberrant fragmentomics features and higher quantity of EBV DNA had a relative risk of 87.1 times greater for developing NPC in the second round compared to subjects tested negative for EBV DNA on PCR. These results demonstrate plasma DNA fragmentomics could predict future cancer risk.

Purpose: MAK683, a first-in-class and highly selective allosteric inhibitor of the embryonic ectoderm development subunit of polycomb repressive complex 2, has shown sustained antitumor activity in tumor xenograft models. This first-in-human phase 1/2 study evaluated the safety, pharmacokinetics (PK), and clinical activity of single- agent MAK683 in advanced malignancies. Methods: MAK683 was administered fasted once daily or twice daily continuously in 28-day treatment cycles. Safety assessments included the nature of dose-limiting toxicities (DLTs) and the incidence and severity of adverse events (AEs) and serious AEs. The PK profile of MAK683 was assessed in sequential blood samples of cycles 1-6, and pharmacodynamic profiles were measured by H3K27me3 changes from baseline. Results: Overall, 139 patients (clear cell carcinoma of the ovary [CCCO], 9 [6.5%]; castration-resistant prostate cancer [CRPC], 22 [15.8 %]; diffuse large B-cell lymphoma [DLBCL], 31 [22.3%]; epithelioid sarcoma [ES], 17 [12.2 %]; gastric cancer [GC], 37 [26.6 %]; nasopharyngeal carcinoma [NPC], 17 [12.2 %]; SWI/SNF-mutated sarcoma, 6 [4.3 %]) received MAK683. Median duration of exposure was 57 days (range: 4-1006). Fifteen patients experienced 22 DLTs including thrombocytopenia (4.9 %) and febrile neutropenia (3.3 %). MAK683- related AEs were reported in 98 patients (70.5 %); 43 patients had grade 3/4 drug-related AEs, including neu- tropenia, thrombocytopenia, and anemia. MAK683 was quickly absorbed, with peak plasma concentrations ranging from 0.975 to 4.08 h. Median progression-free survival was 1.9 months (90 % confidence interval [CI]: 1.8-2.3), and overall response rate was 5.8 % (90% CI: 2.52-11.03 %). Clinical activity was observed in patients with advanced DLBCL and ES. Conclusion: Overall, MAK683 treatment was well tolerated, and clinical activity was observed in patients with advanced DLBCL and ES. Clinical Trial Information: NCT02900651.

Epstein-Barr virus (EBV)+ve nasopharyngeal carcinoma (NPC) is prevalent in Southern China where patients with recurrent/ metastatic disease can be treated with chemotherapy and/or immune-checkpoint inhibitors. Claudin 1 (CLDN1) is a member of the tight junction (TJ) family of proteins that is overexpressed in some cancers with their non-junctional (NJ) epitopes exposed at the epithelium. This study investigated CLDN1 as a novel therapeutic target in NPC and evaluated the preclinical activity of ALE.C04 - a first-in-class, highly specific monoclonal antibody targeting NJ-CLDN1, in NPC models. Expression of NJ-CLDN1 was assessed in three EBV+ve NPC cell lines (C666-1, NPC43 and C17C), four patient-derived- xenografts (PDXs) and NPC biopsies (n=44). The anti-proliferative effect of ALE.C04 was evaluated in NJ-CLDN1+ve NPC cell lines by clonogenic and invasion assay, co-cultured with or without human-derived natural killer (NK) cells. Results are validated in PDX models (C15, C17). ALE.C04 was administrated either as a single agent or in combination with chemotherapy or bevacizumab. NJ-CLDN1 were overexpressed in two NPC cell line (NPC43 and C17C), three PDXs (C15, C17 and X2117) and biopsies (80%). Interestingly, NJ-CLDN1 was not detected in PDX Xeno-666 and its derived cell line, C666-1. A non-significant correlation trend was found between h-score with overall survival. Treatment with ALE.C04 suppressed colony formation of NJ-CLDN1+ve cell lines, with more significant effect observed in C17C. Effect of ALE.C04 as a single agent is modest on the growth of NJ-CLDN1+ve positive cell lines and C17 PDX model. Whilst in combinatorial approach, ALE.C04 showed synergism with gemcitabine as tumor growth was suppressed in C17 PDX. In contrast, ALE.C04 monotherapy significantly suppressed growth in C15 PDX, resulting in substantial changes in gene expression profile (via RNA-Sequencing) compared to the control group. The results of the in vitro coculture assay and in vivo combination with gemcitabine and bevacizumab will be presented. The results generated to date provide a proof-of-concept of targeting NJ-CLDN1 signaling in NPC using ALE.C04, especially in combination with chemotherapy or anti-vascular agent. ALE.C04 is now being evaluated in patients with NPC and other head and neck cancers in a phase 1 clinical trial (NCT06054477). Kar Wei Chin, Connie Wun Chun Hui, Chi-Hang Wong, Grace T. Y. Chung, Winky Lai, Alberto Toso, Luigi Manenti, Li Lili, Chi Man Tsang, Qian Tao, Edwin Pun Hui, Anthony T. C Chan, Kwok Wai Lo, Brigette B. Y. Ma. Evaluation of a novel target Claudin1 in preclinical models of nasopharyngeal carcinoma [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 7338.

Serine/threonine kinase 3 (STK3) is recognized as a key regulator in Hippo pathway and a tumor-suppressing gene in various cancer types. However, its non-canonical role has been gradually revealed in cancer development. Our objective is to elucidate the upregulation pattern and molecular mechanisms of STK3 in advancing gastric cancer (GC) progression. The regulation of YAP1 on STK3 was assessed through a combination of bulk and single-cell RNA-sequencing, Western blot, ChIP-qPCR, gene knockout mouse models, and functional rescue assays. The oncogenic roles of STK3 were confirmed through subcutaneous xenograft formation models and functional assays including spheroid formation and organoid growth. The phosphorylated target of STK3 was revealed by co-immunoprecipitation and in vitro kinase assays. STK3-targeted drugs were screened out by molecular docking and cellular thermal shift assay (CETSA). Reduction of YAP1 significantly impaired STK3 expression at both mRNA and protein levels, and deletion of STK3 partially attenuated the oncogenic activity of YAP1. Notably, MNNG-induced tumors in Yap1−/−Taz−/− mice exhibited decreased STK3 expression. Knockdown of STK3 led to reduced expression of stemness markers and xenograft growth, while sensitizing GC organoids and xenografts to 5-fluorouracil treatment. Mechanistically, the direct interaction between STK3 and GSK-3β promoted GSK-3β phosphorylation and β-catenin nuclear accumulation, and thus the activation of Wnt signaling. Furthermore, aminopterin demonstrates as a promising STK3-targeted small molecule with remarkable effectiveness in inhibiting GC cell malignance and xenograft growth. STK3 was identified as a transcriptional target of YAP1, leading to enhanced DNA repair ability and stemness acquisition during GC progression by activating Wnt/β-catenin activity through GSK-3β degradation. Moreover, STK3-targeted therapy offered a novel approach to concur acquired chemo-resistance in GC patients.

Propelled by a growing understanding of nasopharyngeal carcinoma pathogenesis through elucidation of its genomic and immune landscape, therapy has progressed from radiotherapy alone to combined chemotherapy and immunotherapy. This Clinical Outlook focuses on recent milestones and future directions for patients with nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE:Quantification of deep invasion of the primary tumor is a predictor of outcome in oral cancer, but its predictive value in nasopharyngeal carcinoma (NPC) is unknown. This study aimed to investigate deep invasion of the primary NPC by using volumetric measurements on MRI for the prediction of outcome. MATERIALS AND METHODS:Retrospective review was conducted of 822 MRIs from patients with newly diagnosed nonmetastatic NPC with volumetric analysis of the primary tumor to obtain total primary tumor volume (PTV), deep invasion volume (DIV), and ratio of deep to the total primary tumor volume (DIVr). Optimal predictors were identified by the multivariable Cox regression and c-index correlating with disease-free survival (DFS), distant metastases-free survival (DMFS), and overall survival (OS). RESULTS:High DIVr, DIV, and PTV significantly correlated with poor DFS, DMFS, and OS (all P < .01); DIVr being the optimal measurement (hazard ratio = 3.234 for DFS, 3.409 for DMFS, and 3.184 for OS). Compared with the eighth edition American Joint Committee on Cancer (AJCC) T-category, DIVr showed modest improvement in c-indexes for predicting DFS (0.602 versus 0.620, P = .03) and DMFS (0.597 versus 0.626, P < .01), but not OS (P = .15). The use of a DIVr-based T-category had similar survival prognostication to the eighth edition AJCC T-category although there was improved prediction in DMFS. CONCLUSIONS:DIVr is a better predictor of outcome in NPC than PTV or DIV, with slightly superior performance to the eighth edition AJCC T-category especially for DMFS.

The burden of colorectal cancer (CRC) is high in the Asia-Pacific region, and several countries in this region have among the highest and/or fastest growing rates of CRC in the world. A significant proportion of patients will present with or develop metastatic CRC (mCRC), and BRAFV600E-mutant mCRC represents a particularly aggressive phenotype that is less responsive to standard chemotherapies. In light of recent therapeutic advances, an Asia-Pacific expert consensus panel was convened to develop evidence-based recommendations for the diagnosis, treatment, and management of patients with BRAFV600E-mutant mCRC. The expert panel comprised nine medical oncologists from Australia, Hong Kong, Singapore, and Taiwan (the authors), who met to review current literature and develop eight consensus statements that describe the optimal management of BRAFV600E-mutant mCRC in the Asia-Pacific region. As agreed by the expert panel, the consensus statements recommend molecular testing at diagnosis to guide individualized treatment decisions, propose optimal treatment pathways according to microsatellite stability status, advocate for more frequent monitoring of BRAFV600E-mutant mCRC, and discuss local treatment strategies for oligometastatic disease. Together, these expert consensus statements are intended to optimize treatment and improve outcomes for patients with BRAFV600E-mutant mCRC in the Asia-Pacific region.

Introduction: The assessment and management of oligometastatic colorectal cancer has evolved over the last two decades. We aimed to examine trends in the presentation, management and outcomes of patients presenting with liver-only disease, given recent changed standards for baseline imaging, and evolving definitions of resectability. Patients with lung-only disease can provide a contemporaneous control group. Methods: Prospectively maintained data from the multi-site Treatment of Recurrent and Advanced Colorectal Cancer Registry were reviewed over three consecutive periods; 2009-2013, 2014-2018, and 2019-2023. Survival outcomes were determined by Kaplan-Meier method. Results: Of 4613 patients with metastatic colorectal cancer, median age was 66 years (interquartile range 56-76), and 2356 (51 %) patients had a single metastatic site. Compared to the earlier periods, patients diagnosed in 2019-2023, were younger, had better ECOG scores and were more likely to have three or more metastatic sites. The proportion of patients with liver-only metastases decreased over the three consecutive periods, from 32.0 % (n = 462), to 27.0 % (n = 498) to 25.9 % (n = 33), p < 0.001, however the proportion of liveronly metastases patients undergoing resection increased from 41.5 to 59.3 %, p < 0.001. The incidence and resection rate of lung-only metastases was unchanged over time. Conclusion: The increasing number of metastatic sites and reduced number of patients with liver-only metastases is potentially explained by the increased use of FDG-PET imaging at baseline. The increased proportion of patients with liver-only disease undergoing resection may be explained by advancement in surgical techniques, improvements in systemic therapies and the evolving definition of resectable disease. Synopsis: The pattern and treatment of metastatic colorectal cancer has evolved over the last two decades. This study examines the trends in presentation management and outcomes of patients with metastatic colorectal cancer using a multi-site database.