Lung Cancer: Targets and Therapy最新文献

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 4^th-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.

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.

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.