LUNG CANCER-TARGETS and THERAPY

Ross A Soo,1,* Anand Sachithanandan,2,* Kristin A Higgins,3,* June Hong Ahn,4,* MV Chandrakanth,5,* Gerardo Cornelio,6,* Achmad Faisal,7,* George Karimundackal,8,* Que K Do,9,* Jiraporn Setakornnukul,10,* Jeng-Sen Tseng,11,12,* Yasuhiro Tsutani,13,* Nan Wu14,*1Department of Haematology-Oncology, National University Hospital, Singapore, Singapore; 2Department of Clinical Medicine and Surgery (DCMS), Sunway Medical Centre, Kuala Lumpur, Malaysia; 3Department of Radiation Oncology, City of Hope Cancer Center, Atlanta, Georgia, USA; 4Division of Pulmonology and Allergy, Department of Internal Medicine, College of Medicine, Yeungnam University Medical Center, Daegu, Republic of Korea; 5Department of Medical Oncology, Narayana Hospital, Kolkata, West Bengal, India; 6Department of Medical Oncology, St Luke’s Medical Center, Quezon City, Philippines; 7Division of Cardiothoracic and Vascular Surgery, Department of Surgery, Fatmawati Hospital, Jakarta, Indonesia; 8Department of Surgical Oncology, Nanavati Max Super Specialty Hospital, Mumbai, Maharashtra, India; 9Department of Oncology, Thong Nhat Hospital, Ho Chi Minh, Vietnam; 10Department of Radiation Oncology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand; 11Lung Cancer Comprehensive Care and Research Center, Taichung Veterans General Hospital, Taichung, Taiwan; 12Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan; 13Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Sakai, Osaka, Japan; 14Department of Thoracic Oncology, Peking University Cancer Hospital, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ross A Soo, Department of Haematology-Oncology, National University Hospital, Singapore, Email ross_soo@nuhs.edu.sgAbstract: Lung cancer remains the most common malignancy in Asia and is characterised by a substantial proportion of cases occurring in never-smokers, a feature that distinguishes the region from many Western populations. Only 20– 25% of patients with newly diagnosed non‑small cell lung cancer (NSCLC) present with resectable disease. As precision oncology expands into earlier stages, understanding how global standards can be adapted to Asian healthcare systems is increasingly important. This expert consensus report summarises evidence-informed opinions and voting outcomes from 13 lung cancer specialists across 11 countries to identify regional priorities, practical implementation needs, and management strategies for early and locally advanced NSCLC. Experts supported annual low‑dose CT (LDCT) screening for high‑risk individuals, with adaptation of criteria to better capture Asia’s substantial burden of never‑smokers and individuals with strong family history. Early diagnostic pathways emphasised rapid tissue acquisition and timely biomarker testing specifically EGFR, ALK, and PD‑L1 at initial diagnosis for both resectable and unresectable disease. Across resectable stage II–III disease, evidence from multiple Phase III trials consistently demonstrates that integrating immunotherapy with neoadjuvant or perioperative chemotherapy improves pathological response and event‑free survival, while maintaining surgical feasibility. Differences between regimens relate largely to timing, agent selection, and biomarker effects, and practical adoption in Asia varies according to diagnostic capacity and local resource availability. For unresectable stage III NSCLC, concurrent chemoradiotherapy followed by consolidation durvalumab remains standard, while recent data from the LAURA trial support consolidation osimertinib after CRT for EGFR-mutated disease, with a marked progression-free survival benefit (HR 0.16). Shared regional gaps include limited screening uptake, variable reimbursement for molecular testing and targeted therapies, and uneven access to multidisciplinary care. Collectively, the available evidence suggests that earlier biomarker testing, structured nodule management pathways, and broader access to perioperative and consolidation therapies can meaningfully improve outcomes in Asian populations. Strengthening MDT integration and harmonising diagnostic and therapeutic workflows across settings remain essential next steps.Keywords: resectable NSCLC, EGFRm, SBRT

Chih-Hsi Scott Kuo,1,2,&ast; Shigeki Umemura,3,&ast; Chin-Chou Wang,4 Shingo Matsumoto,3 How-Wen Ko,1,2 Fu-Tsai Chung,1,2 Ping-Chih Hsu,1,2 Hiroki Izumi,3 Yuji Shibata,3 Hibiki Udagawa,3 Kiyotaka Yoh,3 Yuri Murata,3 Koichi Goto,3 Cheng-Ta Yang1,21Division of Thoracic Oncology, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan; 2Thoracic Oncology Unit, Chang Gung Memorial Hospital Cancer Center, Taipei, Taiwan; 3Department of Thoracic Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan; 4Division of Pulmonary & Critical Care Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan&ast;These authors equally contributed to this workCorrespondence: Cheng-Ta Yang, Division of Thoracic Oncology, Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taiwan, Email yang1946@cgmh.org.twBackground: Targeted therapy improves survival of oncogene-driven NSCLC. We evaluate the clinical outcome of advanced NSCLC with oncogenic drivers in LC-SCRUM-Asia Taiwanese and Japanese cohort using tiered groups of disease-driven oncogene.Methods: Fourteen genes were reported from NGS and grouped into four tiers based on lines of approved targeted therapies in Taiwan and Japan (Tier 1: ≥ two lines; Tier 2: one line; Tier 3: not targetable; Tier 4: potentially targetable; not yet approved). Overall survival (OS) of the four-tier gene groups was analyzed in Taiwanese cohort and validated in the 8619 Japanese patients using a two-stage approach.Results: Three-hundred-fifty-nine patients were enrolled in Taiwanese cohort, of which 249 (69.4%) patients had a reported genomic alteration. Patients with a history of smoking (HR 0.46 [95% CI, 0.23– 0.92]; p=0.031) and squamous cell carcinoma (HR 0.31 [95% CI, 0.12– 0.78]; p=0.014) had a lower incidence of genomic alterations. The top five genomic alterations were EGFR (44.6%), KRAS (7.2%), ALK (3.9%), MET (3.1%) and ERBB2 (2.5%) mutations. The four-tier gene groups were significantly associated with different OS in Taiwanese patients (Log rank test p < 0.001). The adjusted OS was the longest and the shortest in patients with Tier 1 (34.5 months) and Tier 4 (16.6 months) gene groups, respectively. In Japanese cohort, a similar trend between the four-tier gene groups and OS was observed (Log rank test p < 0.001) where the Tier 1 and the Tier 4 gene groups also demonstrated the longest (42.6 months) and the shortest OS (18.9 months), respectively.Conclusion: The available lines of targeted therapy impact survival in patients of advanced oncogene-driven NSCLC.Keywords: NSCLC, targeted therapy, disease-driven oncogene, tiered group

Introduction:Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality worldwide, and the identification of novel prognostic biomarkers associated with tumor immunity is urgently needed. Junctional adhesion molecule-like (JAML), a member of the junctional adhesion molecule family, participates in leukocyte adhesion, migration, and T-cell activation. Although JAML has been implicated in immune regulation and tumor progression in other cancers, its expression pattern, prognostic significance, and association with the immune microenvironment in NSCLC remain unclear. This study aimed to investigate the clinical and immunological significance of JAML in NSCLC. Methods:Transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were analyzed to evaluate JAML expression patterns in NSCLC subtypes. The prognostic value of JAML was assessed using Kaplan-Meier survival analysis and Cox regression models. The association between JAML expression and immune cell infiltration was investigated using TIMER2.0, CIBERSORT, and TISIDB analyses. Functional enrichment analyses were performed to explore potential biological pathways associated with JAML expression. In addition, JAML expression was validated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) in paired NSCLC and adjacent normal tissues. Results:JAML expression was significantly decreased in NSCLC tissues compared with normal tissues (P < 0.005), with the lowest expression observed in lung squamous cell carcinoma (LUSC) and reduced expression in lung adenocarcinoma (LUAD). Survival analysis demonstrated that patients with high JAML expression had significantly improved overall survival compared with those with low expression (univariate HR = 0.68, 95% CI: 0.54-0.86, P = 0.001; multivariate HR = 0.76, 95% CI: 0.57-1.00, P = 0.049). Immune infiltration analysis revealed that JAML expression was significantly associated with multiple immune cell populations, including CD8+ T cells (r = 0.42, P < 0.001), suggesting a close relationship between JAML expression and the tumor immune microenvironment. qRT-PCR validation confirmed that JAML expression was approximately 2.3-fold higher in adjacent normal tissues than in NSCLC tissues (P < 0.05). Conclusion:JAML is downregulated in NSCLC and its high expression is associated with favorable overall survival and distinct immune infiltration patterns. These findings indicate that JAML may serve as a potential prognostic biomarker and provide insights into the relationship between JAML expression and the tumor immune microenvironment in NSCLC.

Unilateral scleral icterus is an extremely rare clinical finding and is not typically associated with systemic hyperbilirubinemia. We report the case of a 28-year-old man with biopsy-proven transdifferentiated neuroendocrine lung carcinoma arising from EGFR-mutant non-small cell lung cancer (NSCLC), who presented with painless, localized yellow discoloration of the temporal sclera of the right eye without systemic features of jaundice. Ophthalmic examination revealed reduced visual acuity in the affected eye and an elevated temporal chorio-retinal mass. B-scan ultrasonography demonstrated a dome-shaped lesion measuring 6 mm in thickness with moderate internal reflectivity. Laboratory investigations, including serum bilirubin and liver enzymes, were normal, and systemic imaging showed no hepatic or biliary pathology. The patient was diagnosed with choroidal metastasis and treated with urgent external beam radiotherapy followed by systemic chemotherapy. The unilateral scleral icterus was attributed to localized xanthochromic changes related to the choroidal metastasis. This case highlights unilateral scleral icterus as a rare ocular sign of choroidal metastasis. To our knowledge, this is the first reported case in which choroidal metastasis-specifically from transdifferentiated neuroendocrine lung carcinoma-presented with unilateral scleral yellowing. Previously published cases of unilateral scleral icterus have been associated with subconjunctival or suprachoroidal hemorrhage, prior ocular surgery, localized facial malignancy, or treatment-related vascular changes rather than metastatic infiltration. This report expands the differential diagnosis of unilateral scleral discoloration and underscores the importance of prompt ophthalmologic evaluation in oncology patients with new ocular findings, even in the absence of visual symptoms or biochemical evidence of jaundice. It also emphasizes the value of multidisciplinary collaboration between ophthalmology and oncology in recognizing atypical manifestations of advanced malignancy.

Sunvozertinib has emerged as one of the most promising tyrosine kinase inhibitors (TKIs) for previously treated non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) exon 20 insertion (exon20ins) mutations, a molecular subset with limited sensitivity to conventional EGFR TKIs and a persistent unmet need especially in the second-line setting. Regulatory approvals have occurred at different doses-300 mg daily in China based on WU-KONG6 and 200mg daily in the United States based on WU-KONG1B-raising an important question regarding optimal dose selection in clinical practice. In this editorial, we outline the preclinical and clinical evidence supporting sunvozertinib's approval, compare the efficacy and tolerability at 200mg versus 300mg, and discuss other emerging TKIs in this evolving treatment landscape. Finally, we highlight a critical paradox: despite FDA approval, sunvozertinib remains largely inaccessible to patients in the United States.