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.
Oz Levinkron,1,* Thubeena Manickavasagar,2,* Sanjay Popat,2 Richard Scawn1,21Opthalmology Unit, Chelsea & Westminster NHS Trust, London, UK; 2Lung Medical Oncology Unit, The Royal Marsden, London, UK*These authors contributed equally to this workCorrespondence: Sanjay Popat, Lung Medical Oncology Unit, The Royal Marsden Hospital, Fulham Road, London, SW3 6JJ, UK, Email Sanjay.popat@rmh.nhs.ukAbstract: 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.Keywords: unilateral icterus, unilateral scleral icterus, unilateral jaundice, choroidal metastases
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.
RET fusion is one of the key driver oncogenes in lung cancer. Selective RET inhibitors have become the standard of care for these patients. However, acquired resistance remains inevitable Among the mechanisms of on-target resistance, solvent front mutations in the RET kinase domain are the most common. In contrast, kinase domain insertion mutations are rarely reported as a mechanism of resistance. This article reports a case of a patient with advanced lung adenocarcinoma. Initial genetic testing at diagnosis revealed a CCDC6-RET fusion. The patient achieved partial response after treatment with pralsetinib, but subsequently developed disease progression. After resistance developed, next-generation sequencing (NGS) was performed. The results showed that the original RET fusion persisted. Additionally, a newly acquired insertion mutation (p.L730_G731insL) was detected in the RET kinase domain. Based on this resistance mechanism, the patient discontinued pralsetinib. Treatment was switched to another selective RET inhibitor, selpercatinib. Follow-up imaging evaluation showed that the pulmonary lesions achieved a partial response (PR).This suggests that selpercatinib has therapeutic activity against the tumor carrying this RET insertion mutation. However, the patient received concurrent brain radiotherapy and radiofrequency ablation of liver lesions; therefore, the response in intracranial and hepatic sites cannot be solely attributed to selpercatinib. The observation is hypothesis-generating rather than proof of sensitivity. This case provides a reference for precision treatment strategies after resistance to RET inhibitors.
Trastuzumab deruxtecan, zongertinib and sevabertinib have been approved in the United States for the treatment of patients with advanced metastatic HER2 mutated non-small-cell lung cancer (NSCLC). Unfortunately, tumor progression is inevitable in many cases. In this case report, we share our experience with a patient with HER2 mutated NSCLC who responded to the combination of trastuzumab deruxtecan and zongertinib after progressing on each agent when given alone, highlighting the potential for such combinations.
Introduction:MET amplification is a critical oncogenic driver and a major mechanism of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). Currently, next-generation sequencing (NGS)-based assays are increasingly used in clinical practice. However, they lack a unified standard for defining MET amplification across multiple NGS platforms with a potential actionable threshold. Methods:This was a multiple-site joint study to optimize the cut-off value for MET amplification using tumor tissue and NGS analysis. In the training cohort, five NGS panels were used to detect MET gene copy number (GCN), and fluorescence in situ hybridization (FISH) was used as a reference. Receiver operating characteristic (ROC) curve analysis was used to identify the optimal cutoff with 100% specificity and 66.7% sensitivity. The results were validated in an independent cohort to explore the correlation between MET amplification and efficacy of MET inhibitors in patients with NSCLC. Results:In the training cohort (n=21), the optimal MET GCN cut-off was determined to be 6.55, yielding an area under the curve of 0.9, corresponding to an accuracy of 85.7%. MET polysomy, identified using FISH (n=2), was also detected using NGS. All five NGS panels demonstrated good concordance with FISH, with accuracies ranging from 75.0% to 85.7%. In the validation cohort (n=29), NGS analysis demonstrated a good performance, with an accuracy rate of 79.3%. Patients with MET GCN ≥ 6.55 had a significantly longer median progression free survival than those with MET GCN < 6.55 (hazard ratio = 0.42; p = 0.03). Conclusion:In this study, an exploratory cut-off of 6.55 for MET GCN by NGS was associated with MET amplification and longer progression-free survival in patients receiving targeted therapy. However, given the retrospective design and limited sample size, these findings should be regarded as exploratory and require validation in larger, prospective cohorts before broader clinical application.
Purpose:Chemotherapy is the main therapy for non-targetable advanced non-small cell lung cancer (NSCLC). Nevertheless, few biomarkers are currently available for predicting clinical outcomes and monitoring treatment response. Patients and Methods:The blood samples of 42 patients with non-targetable advanced NSCLC who received chemotherapy were collected before chemotherapy and after chemotherapy. The circulating immune cells and subpopulation Treg were investigated using flow cytometry, and human immune checkpoint biomarker levels were analysed by multiplex bead-based assay. Results:After selecting the effective biomarkers for survival analysis, high pre-chemotherapy sCD25 (≥499.52 pg/mL; 4.52 vs 14.98 months, p = 0.030) and post-chemotherapy (≥515.23 pg/mL; 3.90 vs 21.25 months, p = 0.004) were associated with poorer median progression-free survival (PFS). An increase in pre-chemotherapy neutrophil to lymphocyte ratio (NLR) (ratio ≥ 6.9; 5.15 vs 21.54 months, p = 0.008) and post-chemotherapy NLR (ratio ≥ 3.1; 10-month OS 50.35% vs 83.57%, p = 0.014) was correlated with shorter overall survival (OS). Moreover, increased pre-chemotherapy %NKT cells (≥6.8%) were linked to improved clinical benefit rate (CBR) (2.72 vs 3.97 months, p = 0.013), while higher post-chemotherapy %NK cells (≥23.1%) were associated with rapid overall response rate (ORR) at 4 months (82.05% vs 25%, p = 0.035). Conclusion:Our findings suggest that sCD25 and NLR show potential as indicators of PFS and OS, respectively. Additionally, pre-chemotherapy %NKT and post-chemotherapy %NK cells may provide insight into monitoring chemotherapy response. This pilot study identified potential candidate biomarkers for further investigation to confirm their clinical utility.
Putthapoom Lumjiaktase,1 Nanthisa Kemawichanurat,1 Kanthon Santiwiwas,1 Thatchathum Kuttiyod,2 Songporn Oranratnachai,3 Narumol Trachu,4 Nanamon Monnamo,4 Khantong Khiewngam,5 Kantapat Simmalee,1 Thanyanan Reungwetwattana5,6 1Clinical Immunology Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand; 2Ratchasuda Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand; 3Oncology Unit, Sriphat Medical Center, Faculty of Medicine, Chiangmai University, Chiangmai, Thailand; 4Research Center, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand; 5Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 6Faculty of Medicine Ramathibodi Hospital, Ramathibodi Lung Cancer Consortium (RLC), Mahidol University, Bangkok, ThailandCorrespondence: Kantapat Simmalee, Clinical Immunology Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Tungpayathai, Rajathewee, Bangkok, 10400, Thailand, Tel +66959520109, Email Kantapat.sim@hotmail.com Thanyanan Reungwetwattana, Division of Medical Oncology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Road, Tungpayathai, Rajathewee, Bangkok, 10400, Thailand, Tel +66898565656, Email thanyanan.reu@mahidol.ac.thPurpose: Chemotherapy is the main therapy for non-targetable advanced non-small cell lung cancer (NSCLC). Nevertheless, few biomarkers are currently available for predicting clinical outcomes and monitoring treatment response.Patients and Methods: The blood samples of 42 patients with non-targetable advanced NSCLC who received chemotherapy were collected before chemotherapy and after chemotherapy. The circulating immune cells and subpopulation Treg were investigated using flow cytometry, and human immune checkpoint biomarker levels were analysed by multiplex bead-based assay.Results: After selecting the effective biomarkers for survival analysis, high pre-chemotherapy sCD25 (≥ 499.52 pg/mL; 4.52 vs 14.98 months, p = 0.030) and post-chemotherapy (≥ 515.23 pg/mL; 3.90 vs 21.25 months, p = 0.004) were associated with poorer median progression-free survival (PFS). An increase in pre-chemotherapy neutrophil to lymphocyte ratio (NLR) (ratio ≥ 6.9; 5.15 vs 21.54 months, p = 0.008) and post-chemotherapy NLR (ratio ≥ 3.1; 10-month OS 50.35% vs 83.57%, p = 0.014) was correlated with shorter overall survival (OS). Moreover, increased pre-chemotherapy %NKT cells (≥ 6.8%) were linked to improved clinical benefit rate (CBR) (2.72 vs 3.97 months, p = 0.013), while higher post-chemotherapy %NK cells (≥ 23.1%) were associated with rapid overall response rate (ORR) at 4 months (82.05% vs 25%, p = 0.035).Conclusion: Our findings suggest that sCD25 and NLR show potential as indicators of PFS and OS, respectively. Additionally, pre-chemotherapy %NKT and post-chemotherapy %NK cells may provide insight into monitoring chemotherapy response. This pilot study identified potential candidate biomarkers for further investigation to confirm their clinical utility.Keywords: non-targetable advanced NSCLC, immunological biomarkers, chemotherapy, survival outcomes, clinical response
Purpose:Approximately 38% of Chinese patients with non-small cell lung cancer (NSCLC) exhibit a mutation in the epidermal growth factor receptor (EGFR) gene. Afatinib, which targets the EGFR, is approved for first-line treatment in advanced EGFR mutation-positive NSCLC worldwide. The aim of this prospective, observational and non-interventional real-world study was to examine the effectiveness and safety of first line afatinib in Chinese patients, newly diagnosed with EGFR mutation-positive NSCLC. Patients and Methods:Patients were enrolled at 10 sites in China from May 2020 to December 2021 and followed-up from May 2020 to December 2023. Adult patients (aged ≥18 years) were treated with oral afatinib 30 mg or 40 mg once daily. The primary outcome was time on treatment (TOT). Secondary outcomes were overall survival (OS), overall response rate (ORR) and safety. Results:A total of 72 patients were enrolled and treated with afatinib. Most were male (54.2%), Chinese (98.6%), never smokers (63.9%), and had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1 (98.6%) and patients had a mean (SD) age of 62.2 (9.6) years. Median TOT overall was 14.4 months and was prolonged in younger (aged <65 years) vs older (aged ≥65 years) age groups, common vs uncommon baseline EGFR mutations, and higher afatinib starting dose (40 mg vs 30 mg). Median OS was not reached; the median follow-up time of the study was 25.1 months. ORR was 62.7% overall and was higher in common vs uncommon baseline EGFR mutations, higher afatinib starting dose, and with vs without brain metastases. The two most common treatment-emergent adverse events were diarrhea and rash. No new safety concerns were found. Conclusion:This study provides real-world evidence of the effectiveness and safety of afatinib as first-line therapy for Chinese patients with EGFR mutation-positive advanced NSCLC.
Background:Claudin 3 (CLDN3) is a transmembrane protein which forms tight junctions (TJs) together with other claudins, occludin, and junctional adhesion molecules. Because of its membranous localization CLDN3 is a potential therapeutic target. Altered CLDN3 has been proposed as a prognostic feature in lung cancer and other tumors. Material and Methods:To better understand the prevalence of expression and its impact on the prognosis of different lung cancer subtypes, we investigated CLDN3 expression by immunohistochemistry in a set of tissue microarrays containing 858 resected lung cancers. Results:CLDN3 positivity was markedly more frequent and more intense in pulmonary adenocarcinoma (AC, 95.9% positive) than in squamous cell carcinoma (SCC, 53.3%; p<0.0001). Among 444 ACs, CLDN3 staining was strong in 64.2%, moderate in 25.0%, weak in 6.8% and negative in 4.1%. In 214 SCCs, CLDN3 staining was strong in 6.1%, moderate in 11.7%, weak in 35.5% and negative in 46.7%. Reduced CLDN3 staining was significantly linked to advanced pT stage in both AC and SCC (p<0.0001 each). The fraction of strongly positive cases decreased markedly from pT1 (AC: 67.6%; SCC: 11.1%) to pT4 (47.2%/1.8%). Low CLDN3 expression was also linked to nodal metastasis (p=0.0339) and R+ status (p = 0.0068) in SCCs. Absent or reduced CLDN3 staining was significantly associated with shortened overall survival in pulmonary ACs (p=0.0235) and SCCs (p=0.0330). Conclusion:It is concluded that CLDN3 expression is common in lung cancer, that its level of expression is higher in AC than in SCC, and that a reduced expression level is associated with unfavorable outcome in both SCC and AC. Once anti-CLDN3 targeted drugs should prove to be safe and efficient, NSCLC may represent a major application for such treatments.
Alectinib is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) that has been widely used as first-line (1L) treatment of advanced ALK+ non-small cell lung cancer (NSCLC) ever since its approved indication on November 17, 2017, based on the ALEX trial and its perceived well-tolerability. Lorlatinib, a third-generation ALK TKI, achieved 1L indication on March 3, 2021, but is generally associated with adverse events including weight gain in up to 44% of patients from the recent update of the CROWN study; hence its use as 1L treatment has lagged behind alectinib. Recently, alectinib has also been reported to cause significant weight gain. Incretin receptor agonists such as glucagon-like peptide-1 receptor (GLP-1) agonists semaglutide have been approved to treat obesity (body mass index [BMI] ≥ 30). Here, we report a patient's case who had gained significant weight during still on-going 12-year treatment with alectinib and achieved weight loss through semaglutide but discontinued several months after starting semaglutide due to acute gallstone pancreatitis requiring emergency cholecystectomy. We believe this is the first case report on the efficacy and potential adverse events of GLP-1 agonist in treating the weight gain induced by alectinib.
Background and Purpose:Immune checkpoint inhibitors (ICIs) have improved outcomes in non-small cell lung cancer (NSCLC), yet durable benefit is limited to a subset of patients. Reliable predictive biomarkers are therefore essential. We reviewed genomic, proteomic, and metabolomic studies to evaluate how multi-omics integration advances prediction of ICI efficacy in NSCLC. Methods:A systematic search of PubMed, ClinicalTrials.gov, and Google Scholar was conducted on April 11, 2024, covering studies published from 2016 through January 2025, to identify omics-based biomarkers of ICI response in NSCLC. In total, 33 genomic, 9 proteomic, and 9 metabolomic studies met inclusion criteria. Each was evaluated using a standardized evidence rubric (0-14) assessing effect robustness, validation, cohort size, and clinical endpoint relevance. Results:Genomic predictors of poor response included EGFR and ALK/RET/ROS1 fusions, as well as KRAS co-mutations with STK11, KEAP1, or SMARCA4, all linked to immune-cold phenotypes with low tumor mutational burden (TMB) and poor T-cell infiltration. In contrast, KRAS/TP53 co-mutations, NOTCH family alterations, and BRAF V600E aligned with immune-hot signatures characterized by interferon signaling, PD-L1 upregulation, and cytotoxic T-cell infiltration. Proteomic studies consistently identified chemokines CXCL9 and CXCL10, apoptotic regulators (CASP8, FASLG), and checkpoint proteins (soluble PD-1, PD-L1, LAG-3) as predictive, while acute-phase proteins (SAA1/2, S100A8/9) correlated with resistance. Multi-analyte platforms such as PROphet demonstrated promising risk-stratification potential. Metabolomic profiling linked ICI benefit to higher baseline tryptophan, histidine, and short-chain fatty acids, while resistance was associated with increased 3-hydroxyanthranilic acid, pyruvate, and lipid metabolites indicating immunosuppressive IDO pathway activity. Conclusion:Multi-omics approaches converge on pathways governing antigenicity, interferon signaling, and immune-metabolic crosstalk. Although promising, most biomarkers require prospective validation in large, uniformly treated cohorts. Integrative strategies-particularly when combined with AI-driven analytics-hold potential to refine patient stratification and guide clinical use of ICIs in NSCLC.
Background:Pulmonary nodular lymphoid hyperplasia is a rare benign lymphoproliferative disorder. Patients are commonly asymptomatic. Its radiological presentation is characterized by peripheral single nodular lesion, multiple nodules or mass-like consolidation. Therefore, it can mimic other more frequent pulmonary diseases, such as lung cancer and pulmonary lymphoma. The diagnosis is often late, relying on histopathological findings. Case Presentation:We report a case of a 66-year-old woman who presented with cough and upper respiratory tract symptoms. Chest CT revealed a mass in the right lower lobe, mediastinal and hilar enlarged lymph nodes and multifocal ground-glass and part solid nodules. PET-CT findings were concerning for primary lung malignancy. She underwent transbronchial needle aspiration biopsy of the enlarged lymph nodes and pulmonary mass. The results were negative for malignancy, but immunophenotyping by flow cytometry was concerning for a lymphoproliferative disorder. For this reason, a percutaneous CT-guided transthoracic core needle biopsy of the mass was performed. Immunophenotypic features of lymphoma were not identified. Overall findings were suggestive of nodular lymphoid hyperplasia. The follow-up chest CT showed near complete resolution of the mass with a residual ground-glass lesion and stability of the enlarged lymph nodes, ground-glass and part solid nodules. Conclusion:Pulmonary nodular lymphoid hyperplasia is an uncommon lung disorder, usually detected incidentally on chest imaging. Its radiological features can mimic lung cancer and other more prevalent pulmonary diseases. Therefore, a multidisciplinary approach, including histopathological confirmation is essential for an accurate diagnosis. Although rare, it should be considered in the differential diagnosis of pulmonary malignancies.
Splice site mutations around or within exon 14 of MET (METex14+) are rare, but are one of the common actionable driver mutations in elderly patients with non-small cell lung cancer (NSCLC). Globally, only two MET tyrosine kinase inhibitors (TKIs), both Type Ib (capmatinib and tepotinib), have been approved in a single Phase 2 trial. In China, three additional Type Ib MET TKIs (savolitinib, gumarontinib, and vebreltinib), in addition to capmatinib, and tepotinib, have been approved. Here, we report the timeline for MET TKIs approval in China. We summarized the Chinese METex14+ NSCLC demographic and molecular characteristics and reviewed pivotal phase 2 data (clinical efficacy and adverse events). All five MET TKIs seem to have similar efficacy and adverse events with vebreltinib reported numerically the highest BIRC-ORR. Notably, the gumarontinib (GLORY) trial conducted in both China and Japan also led to the approval of gumarontinib in Japan for METex14+ NSCLC. On June 30, 2025, vebreltinib has been approved for NSCLC with MET amplification while combination of savoltinib and osimertinib has been approved for EGFR+ post EGFR TKINSCLC with MET amplification post EGFR TKI based on the SACHI trial (NCT05015608). We discuss the current unmet clinical need (need to develop Type II MET TKI to overcome acquired resistance MET mutations at D1228 and Y1230) and future optimal treatment approaches.
Background:Despite the approval to date of 3 generations of ALK tyrosine kinase inhibitors (TKIs) and the clinical development of a 4th-generation ALK TKI, neladalkib (NVL-655), patients still eventually progress on sequential treatment of various generations of ALK TKIs. Patients with advanced ALK+ NSCLC can survive many years with sequential use of various generations of ALK TKIs but will eventually exhaust all approved available ALK TKIs. Further options for these patients besides clinical trial could include the repurposing of approved multi-targeted TKIs for other oncologic indications. Gilteritinib, a multi-targeted FLT3 (and AXL, ALK, ROS1) TKI, is approved as monotherapy at 120 mg once daily for FLT3+ refractory/relapsed acute myelogenous leukemia (AML). Case Description:Patient is currently an 82-year-old African-American female never-smoker who was diagnosed with stage 4 NSCLC at age 62. Almost 7.5 years after initial diagnosis and after disease progression on multiple chemotherapy regimens, her tumor was found to harbor an EML4-ALK v1 fusion. Since then, she has been treated with multiple ALK TKIs including crizotinib, alectinib, brigatinib, and lorlatinib sequentially (from age 75 to 80) but requiring dose reduction and interruption of lorlatinib due to neurocognitive toxicity from previous stereotactic brain radiation and resection and eventual discontinuation of lorlatinib. Repeat plasma genotyping after discontinuation of lorlatinib revelaed EML4-ALK v1 without known off-targeted resistances. With written consent from patient and family, she was started on gilteritinib 80 mg once daily with a quick dose increase to 120 mg and achieved stable disease with rapid clearance of ALK fusion from plasma, stability of the CNS metastasis, as well as a decrease in CEA and size of the left upper lesion. Patient is alive today and doing well without CNS effects while on full-dose gilteritinib. Conclusion:This is the first patient case report with >24 months on-going follow-up demonstrating that gilteritinib could be repurposed as a potent and tolerable ALK inhibitor based on previously reported pre-clinical activity and with potential CNS activity. A Phase 2 trial of gilteritnib in alectinib- or lorlatinib-refractory ALK+ NSCLC is being planned (NCT07140016).
The heterogeneous nature of cell populations in human tumors is a major contributor to tumor evolution, including and perhaps most importantly in response to treatment. Here, we review current knowledge on tumor heterogeneity and cell state plasticity in small cell lung cancer (SCLC), a fast growing and highly metastatic form of lung cancer which develops rapid resistance to therapy. There is a pressing need to expand treatment options for patients with SCLC, which requires a better understanding of the mechanisms by which this disease is able to rapidly grow and evolve in response to therapy. Our current understanding points to epigenetic rather than genetic factors in defining major aspects of inter- and intra-tumoral heterogeneity in SCLC. SCLC is overall considered to be a neuroendocrine (NE) cancer type but SCLC tumors harbor a wide diversity of cancer cell states, including both NE and non-neuroendocrine (non-NE) states, defined by their mutually exclusive expression of a set of transcription factors such as ASCL1, NEUROD1, and POU2F3. The immune microenvironments of SCLC tumors also contain a great deal of heterogeneity. Here, we discuss the different SCLC cell states associated with their defining transcription factors, as well as the epigenetic mechanisms regulating the ability of SCLC cells to switch from one state to another. We further discuss how the composition of SCLC tumors and the surrounding immune cells may affect the response to chemotherapy and immunotherapy. Being able to control plasticity and heterogeneity in SCLC may in the future offer unique opportunities to improve treatment efficacy in this recalcitrant cancer.
The identification of molecular driver mutations in non-small cell lung cancer (NSCLC) has changed the therapeutic landscape for this disease. Over the last 20 years, a growing number of driver mutations have been identified in addition to new targeted therapies that have resulted in significant improvement in survival for a subset of patients. There is ongoing research to identify additional molecular targets and therapeutic strategies to improve outcomes in a greater percentage of patients with lung cancer. This review aims to highlight new therapeutic strategies targeting known driver mutations and data regarding emerging molecular targets for the treatment of NSCLC.
Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare form of EGFR mutation. Unlike the classical mutations such as exon 19 deletion and exon 21 p.L858R point mutation, EGFR-KDD is a special type of large genomic rearrangement (LGR) that results in the duplication of the tyrosine kinase domain at the protein level, leading to the formation of an intramolecular dimer and activation of the EGFR signaling pathway. Case reports and in vitro experiments have shown that EGFR-KDD patients can benefit from EGFR TKI treatment. Similar to classical EGFR mutations, EGFR-KDD inevitably develops resistance during EGFR TKI treatment, leading to disease progression. Due to the rarity of EGFR-KDD, the acquired resistance mechanisms are not yet fully understood, but known mechanisms include EGFR amplification and T790M mutation. In this study, we report a 71-year-old female EGFR-KDD patient who showed a positive response to afatinib treatment initially, but developed resistance upon tumor progression. Subsequent next-generation sequencing (NGS) on the re-biopsy revealed TP53 exon c.688_764 deletion and MET exon 15-20 duplication, suggesting that MET bypass activation might be the acquired resistance mechanisms. Additionally, we conducted a literature review on EGFR-KDD and examined case reports of EGFR-KDD patients treated with EGFR TKIs to summarize the treatment outcomes and resistance mechanisms. We hope to provide more treatment information for patients with rare gene mutations in lung cancer.
Background:Brigatinib and alectinib are next-generation anaplastic lymphoma kinase inhibitors (ALKis) showing efficacy against naïve and post-crizotinib-treated advanced ALK+ non-small-cell lung cancers (NSCLCs). Real-world data on alectinib efficacy after brigatinib failure are lacking. Methods:Alectinib efficacy was retrospectively assessed in patients previously treated with brigatinib during an early-access program (EAP) from 1 August 2016 to 21 January 2019. The primary endpoint was alectinib median progression-free survival (mPFS) according to local investigators. Results:Among the 183 patients included in the brigatinib EAP, 92 (50.3%) received ≥1 agent(s) post-brigatinib; 30 (16.4%) received alectinib, 19 (10.4%) immediately post-brigatinib; 11 (6%) after ≥1 other treatment line(s). With median follow-up at 25.5 (95% CI: 10.6-30.5) months, mPFS on brigatinib for the study population (n = 30) was 13.6 (95% CI: 6.3-17.7) months. For patients given alectinib immediately post-brigatinib, mPFS and median overall survival (mOS) were 4.8 (95% CI: 2.0-12.5) and 27 (95% CI: 12.5-not reached (NR)) months, respectively. In this subgroup, brigatinib was discontinued for toxicity or progression for 5/19 (26%) or 14/19 (74%) patients, with mPFS lasting 12.5 (95% CI: 3.3-17.9 and 3.4 (95% CI: 0.9-9.2) months, respectively. For patients receiving ≥1 agent(s) between brigatinib and alectinib, with median follow-up at 13.3 (95% CI: 2.3-31.5) months, mPFS and mOS were 5.0 (95% CI: 0.5-18.8) and 19 (95% CI: 2.3-NR) months, respectively. Conclusion:According to the results of this retrospective real-world study, alectinib post-brigatinib showed limited overall activity but remains an option for patients with advanced ALK+ NSCLCs, especially when brigatinib was discontinued because of toxicity.
