Explore the vast range of titles available.

Final overall survival (OS) and time on treatment analysis of patients with mutation-positive non-small-cell lung cancer (NSCLC) who received sequential afatinib and osimertinib. Patients (n = 203) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months before data entry. Primary outcome was time on treatment; OS analysis was exploratory. Median time on treatment with afatinib and osimertinib was 27.7 months (90% CI: 26.7–29.9). Median OS was 37.6 months (90% CI: 35.5–41.3); median OS was 41.6 and 44.8 months in Del19-positive patients and Asian patients, respectively. In real-world clinical practice, sequential afatinib and osimertinib was associated with encouraging outcomes in patients with mutation-positive NSCLC, especially in Del19-positive patients and Asian patients. NCT03370770 ( )

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferential options for advanced non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. Osimertinib is a potent irreversible third-generation EGFR-TKI targeting EGFR mutations but has little effect on wild-type EGFR. In view of its remarkable efficacy and manageable safety, osimertinib was recommended as the standard first-line treatment for advanced or metastatic NSCLC patients with EGFR mutations. However, as the other EGFR-TKIs, osimertinib will inevitably develop acquired resistance, which limits its efficacy on the treatment of EGFR-mutated NSCLC patients. The etiology of triggering osimertinib resistance is complex including EGFR-dependent and EGFR-independent pathways, and different therapeutic strategies for the NSCLC patients with osimertinib resistance have been developed. Herein, we comprehensively summarized the resistance mechanisms of osimertinib and discuss in detail the potential therapeutic strategies for EGFR-mutated NSCLC patients suffering osimertinib resistance for the sake of the improvement of survival and further achievement of precise medicine.

The number of druggable tumor-specific molecular aberrations has grown substantially in the past decade, with a significant survival benefit obtained from biomarker matching therapies in several cancer types. Molecular pathology has therefore become fundamental not only to inform on tumor diagnosis and prognosis but also to drive therapeutic decisions in daily practice. The introduction of next-generation sequencing technologies and the rising number of large-scale tumor molecular profiling programs across institutions worldwide have revolutionized the field of precision oncology. As comprehensive genomic analyses become increasingly available in both clinical and research settings, healthcare professionals are faced with the complex tasks of result interpretation and translation. This review summarizes the current and upcoming approaches to implement precision cancer medicine, highlighting the challenges and potential solutions to facilitate the interpretation and to maximize the clinical utility of molecular profiling results. We describe novel molecular characterization strategies beyond tumor DNA sequencing, such as transcriptomics, immunophenotyping, epigenetic profiling, and single-cell analyses. We also review current and potential applications of liquid biopsies to evaluate blood-based biomarkers, such as circulating tumor cells and circulating nucleic acids. Last, lessons learned from the existing limitations of genotype-derived therapies provide insights into ways to expand precision medicine beyond genomics.

In 556 patients with previously untreated lung cancer bearing EGFR mutations, osimertinib and the first-generation EGFR inhibitors erlotinib and gefitinib had similar response rates, but osimertinib resulted in longer progression-free survival and had somewhat less toxicity.

Background/Aim: Despite recent advances in EGFR-tyrosine kinase inhibitor (TKI) drugs for glioblastoma multiforme (GBM), intrinsic EGFR alterations in GBM have resulted in drug resistance and unsatisfactory clinical development of EGFR-TKIs. Determining the unknown mechanisms underlying EGFR-TKI drug resistance is an urgent, but unmet, medical need for GBM. Although several m6A RNA methylation regulators, such as reader YTHDF1/2, were recently predicted to be related to GBM recurrence, none was associated with resistance to the 3rd generation EGFR-TKI osimertinib. Materials and Methods: Osimertinib-resistant GBM cells (U87OSR) were established to ascertain the correlation between m6A expression and osimertinib resistance, prior to systemic analyses on m6A writers, erasers, and readers. YTHDF3-silencing was employed to reveal changes in IC50, cellular migration, cancer stemness, and p21-guided senescence in U87OSR cells. Signaling pathways and an in vivo xenograft model of U87OSR cells were investigated to delineate the influence of osimertinib-resistance and elevated YTHDF3 expression. Results: YTHDF3 played a crucial role in inducing cellular proliferation, migration, and stemness in U87OSR GBM cells. Importantly, silencing of YTHDF3 markedly reduced the activation of certain signaling pathways, including EGFR- or ITGA7- AKT, and ERK in U87OSR cells. Our study also revealed the oncogenic function of YTHDF3 in inducing senescence escape via p21 down-regulation. In contrast, silencing of YTHDF3 resulted in increased p21 expression, senescence, and suppressed tumor growth in our osimertinib-resistant preclinical model. Conclusion: Overall, our research underscores the novel potential of YTHDF3 as a new pharmacological target in GBM treatment, specifically for patients with osimertinib-resistant or refractory tumors.

Targeted therapy with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is a standard modality of the 1st-line treatments for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC), and substantially improves their prognosis. However, EGFR T790M mutation is the primary mechanism of 1st- and 2nd-generation EGFR-TKI resistance. Osimertinib is a representative of the 3rd-generation EGFR-TKIs that target T790M mutation, and has satisfactory efficacy in the treatment of T790M-positive NSCLC with disease progression following use of 1st- or 2nd-generation EGFR-TKIs. Other 3rd-generation EGFR-TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. However, the occurrence of acquired resistance is inevitable, and the mechanisms of 3rd-generation EGFR-TKI resistance are complex and incompletely understood. Genomic studies in tissue and liquid biopsies of resistant patients reveal multiple candidate pathways. The present review summarizes the recent findings in mechanisms of resistance to 3rd-generation EGFR-TKIs in advanced NSCLC, and provides possible strategies to overcome this resistance. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin-like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial-mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib-resistant patients, and multiple clinical studies on novel combined therapies are ongoing.

Abstract Background Osimertinib became the standard treatment for patients with untreated EGFR-mutant advanced non-small cell lung cancer (aNSCLC) following results reported in the phase III randomized FLAURA trial. Because of strict exclusion criteria, patient populations included in pivotal trials are only partially representative of real-world patients. Methods We designed an observational, prospective, multicenter study enrolling patients with EGFR-mutant aNSCLC receiving first-line osimertinib to evaluate effectiveness, safety, and progression patterns in the real-world. Results At data cutoff, 126 White patients from nine oncology centers were included. At diagnosis, 16 patients (12.7%) had a performance status (PS) ≥2 and 38 (30.2%) had brain metastases. Overall response rate (ORR) was 73%, disease control rate (DCR) 96.0%. After a median follow-up of 12.3 months, median time to treatment discontinuation (mTTD) was 25.3 months, median progression-free-survival (mPFS) was 18.9 months and median overall survival (mOS) was not reached (NR). One hundred and ten patients (87%) experienced adverse events (AEs), 42 (33%) of grade 3–4, with venous thromboembolism (VTE) as the most common (n = 10, 7.9%). No difference in rates of VTE was reported according to age, PS, comorbidity, and tumor load. We observed longer mTTD in patients without symptoms (NR vs. 18.8 months) and with fewer than three metastatic sites at diagnosis (NR vs. 21.4 months). Patients without brain metastases experienced longer mPFS (NR vs. 13.3 months). No difference in survival outcome was observed according to age, comorbidity, and type of EGFR mutation. Isolated progression and progression in fewer than three sites were associated with longer time to treatment discontinuation (TTD). Conclusion Osimertinib confirmed effectiveness and safety in the real world, although thromboembolism was more frequent than previously reported. The FLOWER study is an observational prospective multicenter study focusing on outcome, safety, progression pattern, and clinical management of untreated patients with EGFR-mutant advanced non-small cell lung cancer receiving first-line osimertinib in the real world.

[This corrects the article DOI: 10.3389/fphar.2023.1177003.].

To assess outcomes in patients with mutation-positive (Del19, L858R) non-small-cell lung cancer receiving sequential afatinib and osimertinib in a real-world clinical setting. In this retrospective, observational, multicenter study, patients (n = 204) had T790M-positive disease following first-line afatinib and started osimertinib treatment ≥10 months prior to data entry. Primary outcome was time on treatment. Overall median time on treatment was 27.6 months (90% CI: 25.9-31.3), 30.3 months (90% CI: 27.6-44.5) in Del19-positive patients and 46.7 months (90% CI: 26.8-not reached) in Asians. The 2-year overall survival was 78.9%. In real-world clinical practice, sequential afatinib and osimertinib facilitates prolonged, chemotherapy-free treatment in patients with T790M acquired resistance, and is a potentially attractive strategy, especially for Del19-positive tumors. NCT03370770

This study aimed to measure relative telomere length (RTL) in blood leukocytes of advanced-stage NSCLC patients either with or without Osimertinib-induced ADRs and determine whether RTL could serve as a biomarker of Osimertinib-induced ADRs. Blood leukocytes RTL were measured in 63 advanced-stage NSCLC patients and 62 age-matched healthy controls using real-time polymerase chain reaction. In patients with advanced-stage NSCLC, RTL was significantly shorter than that in healthy controls ( P  < 0.001). Compared to patients without ADRs and those with mild/moderate ADRs, patients with severe ADRs exhibited significantly decreased RTL ( P  < 0.001, P  < 0.001, respectively). ROC curve analysis uncovered a diagnostic value of RTL as a biomarker of Osimertinib-induced ADRs (AUC = 1.000, P  < 0.001). Kaplan-Meier analysis revealed a significant association between shorter RTL and increased cumulative incidence of Osimertinib-induced ADRs in patients with advanced-stage NSCLC ( P  < 0.001). Shorter RTL in blood leukocytes would reflect the occurrence of Osimertinib-induced ADRs and might emerge as a promising biomarker for identifying advanced-stage NSCLC patients who are at risk of experiencing Osimertinib-induced ADRs, particularly those with severe ADRs.