Management of HER2 alterations in non-small cell lung cancer – The past, present, and future

Lung Cancer, Journal Year: 2023, Volume and Issue: 186, P. 107385 - 107385

Published: Sept. 28, 2023

Language: Английский

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Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: May 7, 2024

Recently, targeted therapy and immunotherapy have emerged as effective treatment options for non-small cell lung cancer (NSCLC). This progress has been facilitated by the rapid development of diagnostic therapeutic technologies continuous research new drugs, leading to a era in precision medicine NSCLC. is breakthrough patients with common mutations human epidermal growth factor receptor (EGFR) gene Consequently, use drugs significantly improved survival. Nevertheless, certain rare genetic are referred EGFR exon 20 insertion (ex20ins) mutations, which differ structure from conventional namely, 19 deletion (19-Del) 21 point mutations. Owing their distinct structural characteristics, harboring these ex20ins unresponsive traditional tyrosine kinase inhibitor (TKI) therapy. particular group did not fall within scope applicability. However, activating A763_Y764insFQEA mutation elicits more pronounced response than near far regions C-helix immediately following it should, therefore, be treated differently. Currently, there lack treatments The efficacy chemotherapy relatively favorable, whereas effectiveness remains ambiguous owing inadequate clinical data. In addition, first- second-generation limited. third-generation novel proven effective. Although EGFR-TKIs expected treat NSCLC, they face many challenges. main focus this review on emerging therapies that target NSCLC highlight major ongoing trials while also providing an overview associated challenges advancements area.

Language: Английский

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A Real-World Study of Patient Characteristics and Clinical Outcomes in EGFR Mutated Lung Cancer Treated with First-Line Osimertinib: Expanding the FLAURA Trial Results into Routine Clinical Practice

Cancers, Journal Year: 2024, Volume and Issue: 16(6), P. 1079 - 1079

Published: March 7, 2024

Osimertinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) that used for first-line therapy in EGFR mutated non-small cell lung cancer (NSCLC) based on results randomized FLAURA trial (ClinicalTrials.gov number NCT02296125). We performed retrospective analysis baseline characteristics and clinical outcomes 56 real-world patients treated with osimertinib. In total, 45% were determined to be FLAURA-eligible 55% FLAURA-ineligible published inclusion/exclusion criteria aforementioned trial. For outcomes, median osimertinib time treatment discontinuation (TTD) all was 16.9 months (95% CI: 12.6–35.1), whereas TTD 31.1 14.9–not reached) cohort 12.2 8.1–34.6 months) cohort. Re-biopsy at acquired resistance disclosed both on- off-target mechanisms. The most common therapies following included local followed by post-progression osimertinib, platinum-doublet chemotherapy or without combinatory targeted therapies. overall survival 32.0 15.7–not reached), not reached cohort, it 16.5 Our data support use real-word settings highlight need designing registration trials are more inclusive patient/disease seen routine practice. It yet if evolving combination strategies (either plus amivantamab lazertinib) will similarly translate from settings.

Language: Английский

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Patterns of HER2 expression and genomic correlates in lung cancer, with a focus on preanalytical variables impacting immunohistochemical staining results

Journal of Clinical Pathology, Journal Year: 2025, Volume and Issue: unknown, P. jcp - 210095

Published: March 12, 2025

Aims Fam-trastuzumab deruxtecan-nxki (T-DXd) was recently approved for advanced stage or metastatic solid tumours with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) 3+ staining. Data on HER2 IHC testing and knowledge of genomic correlates in lung cancer are scarce. This study analyses characteristics HER2-expressing addresses issues preanalytical variables specimens. Methods staining performed selected archival cytology surgical pathology specimens patients eligible T-DXd therapy. Patient tumour next-generation sequencing (NGS) data were correlated results. Results 166 thoracic samples had expression assessed: 46% 0, 28% 1+, 13% 2+ 3+. scores overall lower cell blocks as compared specimens; 79% cases paired a decrease their score from specimen to specimen. Of NGS available, only 14% (3/21) concomitant ERBB2 alterations. Among all specimens, point mutations noted 4% (4/110) amplification 3% (3/110). The majority (17/21, 81%) non- alterations, including: KRAS , TP53, STK11 mutations. Conclusions is seen small but clinically significant proportion associated variety co-occurring non-ERBB2 Preanalytical including fixation can significantly impact the assessment via immunohistochemistry.

Language: Английский

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Genomic and clinical characterization of HER2 exon 20 mutations in non-small cell lung cancer: insights from a multicenter study in South China

BMC Cancer, Journal Year: 2025, Volume and Issue: 25(1)

Published: April 22, 2025

The objective of this study was to investigate the clinical and genetic characteristics relevance HER2 exon 20 oncogenic variants in non-small cell lung cancer (NSCLC) patients. This prospective analyzed 51 NSCLC patients with mutations, identified via next-generation sequencing (NGS) tissue, blood, cerebrospinal fluid, or pleural effusion samples. Patients were grouped based on presence mutations (exon vs. non-exon 20) further divided whether they had received prior anti-tumor treatments (baseline non-baseline). Clinical data, treatment responses analyzed. Progression-free survival (PFS) overall (OS) evaluated using Kaplan-Meier methods compared log-rank tests. Gene ontology (GO) analysis performed uncover biological significance mutated genes. In a cohort 651 patients, (7.83%) harbored alterations, including (3.08%) mutations. median age HER2-altered subgroup 58.5 years. Adenocarcinoma most prevalent subtype (96.1%), presented at stage IV (72.5%). common metastatic sites lungs (68.6%), lymph nodes (52.9%), brain (43.1%). Among (39.3%) Exon more non-baseline group (55.0% 29.0%, P = 0.049) males (75.0%, 0.025). These associated higher rate metastasis lungs, (P < 0.001). demonstrated poorer outcomes 0.048). No significant differences observed age, smoking history, histological subtype, TNM diagnosis between groups. majority in-frame indel (92.0%), specific mutation being p.Y772_A775dup (70%). Ontology linked unregulated protein kinase activity anoikis. Our found that have risk drug resistance, leading worse than highlights urgent need for targeted therapies aimed insertions improve subgroup.

Language: Английский

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Biologics for novel driver altered non-small cell lung cancer: potential and pitfalls

Critical Reviews in Oncology/Hematology, Journal Year: 2025, Volume and Issue: unknown, P. 104748 - 104748

Published: May 1, 2025

Precision medicine has revolutionized clinical paradigm of lung cancer (LC) patients optimizing therapeutical options on the basis molecular fingerprinting tumor cells. The advent genomic era contributed to widespread diffusion sequencing technologies laying for approval an increasing number clinically relevant predictive biomarkers in settings. In rapidly evolving scenario biomarkers, mandatory testing genes demonstrated a statistically significant benefit LC elected tests, but emerging are under investigation raise bar management patients. To date, promising IHC-based emerged as potentially integrative tools panel approved biomarkers. On this basis, genomic, transcriptomic and proteomic data gaining ground toward "3D" biology" supporting need multidimensional analysis cells stratify Here we sought overview most investigated trials be integrated into diagnostic NSCLC

Language: Английский

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Anti-angiogenic therapy or immunotherapy? A real-world study of patients with advanced non-small cell lung cancer with EGFR/HER2 exon 20 insertion mutations

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: March 19, 2024

Background For patients with EGFR/HER2 exon20 insertions, platinum-containing double-drug chemotherapy is still the standard treatment method. First-generation TKIs have almost no therapeutic activity against EGFR exon 20 insertions. The efficacy of second-and third-generation controversial. Immunotherapy research scarce, and there an urgent need for more evidence new options this group patients. Methods We reviewed advanced NSCLC insertion mutations treated in Shanghai Chest Hospital Pulmonary from 2015 to 2022 assessed receiving chemotherapy, anti-angiogenic therapy immunotherapy, including objective response rate (ORR) disease control (DCR), compared progression-free survival (PFS) overall (OS). Results Of 126 included study, 51 had EGFR20ins 7 5 HER2-20ins mutations. In first-line treatment, bevacizumab + (Beva+Chemo), ICI+chemotherapy (ICI+Chemo), alone (Chemo), ORR: 40% vs 33.3% 15% (p=0.0168); DCR: 84% 80.9% 67.5% (p=0.1817); median PFS: 8.3 7.0 4.6 months (p=0.0032), ICI+Chemo has a trend benefiting on OS. Stratified analysis showed that was effective mutation 10.3 vs. 6.3m (P=0.013); Beva+Chemo mutation, 6.6 4.3m (p=0.030). second-line significant advantage PFS targeted therapy, PFS:10.8 4.0 (P=0.016). Conclusion prolongs PFS, after progression, combined seems better than Furmonertinib-based PFS. may be choice.

Language: Английский

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First-in-human phase I study of BEBT-109 in previously treated EGFR exon 20 insertion-mutated advanced non-small cell lung cancer

Med, Journal Year: 2024, Volume and Issue: 5(5), P. 445 - 458.e3

Published: March 22, 2024

Language: Английский

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The current landscape, advancements, and prospects in the treatment of patients with EGFR exon 20 insertion mutations warrant scientific elucidation

Frontiers in Oncology, Journal Year: 2024, Volume and Issue: 14

Published: June 11, 2024

Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most prevalent mutation in non-small cell lung cancer (NSCLC), following 19del and L858R mutations. The unique nature of EGFR ex20ins poses challenges for effectiveness first- second-generation tyrosine kinase inhibitors (TKIs). As a result, chemotherapy remains primary more effective treatment approach. However, with advancements time technology, numerous experimental studies have revealed potential novel drugs therapies to stronger inhibitory effects on In this comprehensive review, we provide an overview current landscape, recent advancements, prospects patients advanced NSCLC characterized by

Language: Английский

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Current status of molecular diagnostics for lung cancer

Exploration of Targeted Anti-tumor Therapy, Journal Year: 2024, Volume and Issue: 5(3), P. 742 - 765

Published: June 27, 2024

The management of lung cancer (LC) requires the analysis a diverse spectrum molecular targets, including kinase activating mutations in EGFR, ERBB2 (HER2), BRAF and MET oncogenes, KRAS G12C substitutions, ALK, ROS1, RET NTRK1-3 gene fusions. Administration immune checkpoint inhibitors (ICIs) is based on immunohistochemical (IHC) PD-L1 expression determination tumor mutation burden (TMB). Clinical characteristics patients, particularly age, gender smoking history, significantly influence probability finding above targets: for example, LC young patients characterized by high frequency rearrangements, while heavy smokers often have and/or TMB. Proper selection first-line therapy influences overall treatment outcomes, therefore, majority these tests need to be completed within no more than 10 working days. Activating events MAPK signaling pathway are mutually exclusive, hence, fast single-gene testing remains an option some laboratories. RNA next-generation sequencing (NGS) capable detecting entire repertoire druggable alterations, therefore it gradually becoming dominating technology diagnosis.

Language: Английский

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