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Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR‐mutant non–small‐cell lung cancer (NSCLC) cells. However, little is known about the mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR‐mutant cells. Using EGFR‐mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR‐TKI treatment, we found that EGFR‐mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first‐generation EGFR‐TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre‐treatment samples. Monocyte‐derived macrophages facilitated antibody‐dependent cellular phagocytosis when EGFR‐TKI‐treated EGFR‐mutant cells were incubated with anti‐CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR‐mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell‐free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP‐1 monocytes in a stimulator of interferon genes‐dependent manner. Our study indicates that EGFR inhibition in EGFR‐mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR‐mutant NSCLC. EGFR inhibition in EGFR‐mutant lung cancer cells results in the upregulation of tumor CD24. It also accelerates the release of tumor‐derived cell‐free DNA, triggering the type I interferon pathways. These biomarkers are potential targets to overcome the resistance to EGFR‐targeted therapy.

Brain metastases (BM) are common in patients with epidermal growth factor receptor (EGFR)‐mutant non‐small cell lung cancer (NSCLC) and confer poor prognoses. Zorifertinib (AZD3759), an EGFR‐tyrosine kinase inhibitor (TKI) with high blood‐brain barrier penetration, has previously demonstrated promising systemic and intracranial antitumor activity in phase 1–3 studies. This is the first report of a patient with EGFR‐mutant (exon 21 L858R) NSCLC and symptomatic untreated multiple BM who achieved a long overall survival (OS) of more than 65 months after sequential treatment with zorifertinib and a third‐generation EGFR‐TKI. This new treatment paradigm offers a new treatment option and deserves further clinical exploration to prolong OS of patients with EGFR‐mutant NSCLC and untreated multiple BM. Long OS achieved in NSCLC patients with EGFR mutation and untreated multiple BM after zorifertinib treatment.

Background Indication for treatment with osimertinib after first/second generation (1/2G) epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) resistance depends on T790M mutation detected by rebiopsy. The aim of our study was to analyze the data on clinical practice at our hospital where histological rebiopsy is actively carried out multiple times. Methods We retrospectively reviewed our electronic medical records of EGFR‐mutant non‐small cell lung cancer (NSCLC) patients to examine clinical rebiopsy situation, T790M detection rate, osimertinib introduction rate and associated outcomes. Results Among 95 patients with EGFR‐mutant NSCLC, 72 patients received 1/2G EGFR‐TKIs. Of 60 with progressive disease on 1/2G EGFR‐TKIs, 50 (83%) underwent rebiopsy. T790M was detected in 40 (80%) of 50, resulting in a 79% osimertinib introduction rate, as one patient refused osimertinib. T790M was detected by first rebiopsy in 18 (36%) of 50 patients, and by second or subsequent rebiopsy in 22 (44%). Median time to treatment failure of T790M‐positive patients at first rebiopsy was 22.6 (95% confidence interval [CI]: 10.2–32.8) months, and those at multiple repeated rebiopsy was 20.9 (95% CI: 8.6–not reached) months (p = 0.64). Median overall survival (OS) in osimertinib introduced group was 92.5 (95% CI: 62.9–not reached), while in nonosimertinib median OS was 39.0 months (95% CI: 22.2–not reached) (p = 0.04). Conclusions T790M detection rate was increased by multiple repeated rebiopsy, achieving a higher osimertinib introduction rate. This higher introduction rate could contribute to better prognosis of EGFR‐mutant NSCLC patients. Times of rebiopsy in T790M positive patients. In 18 patients, T790M was positive at first rebiopsy. In 22 patients, T790M was positive at second or later rebiopsy. T790M detection rate increased from 36% to 80% by multiple repeated rebiopsy.T790M detection rate was increased by multiple repeated rebiopsy, achieving a higher osimertinib introduction rate. This higher introduction rate could contribute to better prognosis of EGFR‐mutant NSCLC patients.

The addition of pembrolizumab to chemotherapy for metastatic lung cancer without EGFR or ALK mutations resulted in better progression-free and overall survival than chemotherapy alone. Immune-related adverse effects were more common with the combination.

Afatinib's efficacy and dose-adjustment strategies have been validated in clinical trials and increasingly supported by real-world evidence. This study aimed to provide additional real-world insights into afatinib use and to assess the impact of initial dosing and subsequent dose modifications on treatment outcomes and tolerability in patients with advanced epidermal-growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). We conducted a multicenter retrospective analysis of patients with advanced EGFR-mutated NSCLC who received first-line afatinib between April 2018 and June 2022. Patients were categorized into four subgroups based on their starting and optimal afatinib doses. The primary endpoints were to analyze the association between afatinib dosing and time-to-treatment failure (TTF), overall survival (OS), and toxicity. A total of 343 patients were included. The most common starting afatinib dose was 30 mg (58.6%), followed by 40 mg (39.9%). The optimal dose maintained during treatment was 30 mg in 62.1% of patients, 40 mg in 33.2%, and 20 mg in 4.7%. Dose reductions due to toxicity occurred in 23.6% of cases. Regarding four subgroups: 53.1% of patients started and remained on <40 mg, 25.4% started and maintained 40 mg, 14.6% started at 40 mg but de-escalated to <40 mg, and 7.0% started <40 mg and escalated to 40 mg. After a median follow-up of 36.8 months, the median OS for all patients was 31.3 months (95% confidence interval: 29.3-33.1). Multivariate Cox regression analysis identified smoking status, Eastern Cooperative Oncology Group performance status, and EGFR mutation subtype as independent prognostic factors for OS. Notably, patients who initiated treatment at 40 mg but de-escalated to <40 mg had the longest median TTF and OS. In terms of safety, the highest incidence of adverse events was observed in this group, followed by those who started and remained at <40 mg. In this real-world cohort, flexible afatinib dosing-either by initiating at 40 mg followed by dose reduction or starting at <40 mg with later escalation-was associated with favorable survival outcomes and manageable tolerability. These findings support the use of individualized afatinib dosing strategies to optimize both efficacy and safety in patients with EGFR-mutant NSCLC.

Background Afatinib is an oral irreversible epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) indicated in first-line treatment of advanced EGFR-mutant (EGFRm+) non-small cell lung cancer (NSCLC). Dose dependent side effects can limit drug exposure, which may impact on extracranial and central nervous system (CNS) disease control. Methods We performed a retrospective study of 125 patients diagnosed with advanced EGFRm+ NSCLC treated with first-line afatinib at a tertiary Asian cancer center, exploring clinicopathological factors that may influence survival outcomes. Median progression free survival (PFS) was estimated using the Kaplan-Meier method. Comparison of PFS between subgroups of patients was done using log-rank tests and Cox proportional hazards models. Results Out of 125 patients, 62 (49.6%) started on 40 mg once daily (OD) afatinib, 61 (48.8%) on 30 mg OD and 1 (0.8%) on 20 mg OD. After median follow-up of 13.8 months from afatinib initiation, the observed response rate was 70.4% and median PFS 11.9 months (95% CI 10.3–19.3). 42 (33.6%) patients had baseline brain metastases (BM) and PFS of those who started on 40 mg OD ( n  = 17) vs. 30 mg OD ( n  = 25) was 13.3 months vs. 5.3 months (HR 0.39, 95% CI 0.15–0.99). BM+ patients who started on 40 mg had similar PFS to patients with no BM (13.3 months vs. 15.0 months; HR 0.79, 95% CI 0.34–1.80). Conclusion In patients with advanced EGFRm+ NSCLC with BM+, initiating patients on afatinib 40 mg OD was associated with improved PFS compared to 30 mg OD, underscoring the potential importance of dose intensity in control of CNS disease.

Methods and Material: A cross-sectional study was performed by interviewing with the patients using EQ 5D 5L questionnaire in RSUP Dr. Sardjito, Yogyakarta and RSUP Dr. Kariadi, Semarang, Indonesia Patients' health status was consisted of Progression Free / PF (no progression), Progressive Disease 1 / PD1 (experiencing progression before or when diagnosed NSCLC with mutation of EGFR), and Progressive Disease2/PD2 (experiencing progression after being diagnosed NCLC with mutation of EGFR) Result: There were 74 patients identified, 29 patients had not experienced disease progression (PF), 21 patients experienced the progress before or altogether after being diagnosed with NSCLC EGFR mutation positive (PD1), and 24 patients experienced the progression of the disease after being diagnosed with NSCLC EGFR mutation positive (PD2). Non-Small Cell Lung Cancer is one of the types of lung cancer that mostly occurred, where patients with advanced stage experienced a mutation of epidermal growth factor receptors (EGFR). Here in Indonesia, a study about HRQOL on NSCLC EGFR mutationpositive patients with EQ-5D-5L questionnaire has not been performed yet. [...]scientists are eager to perform this study. According to the statistic test with more than a = 0,05 significance value, the EQ-5D index score were age (0,884), gender (0,948), and mutation type (0,421).

EGFR-mutant NSCLCs frequently respond to EGFR tyrosine kinase inhibitors (TKIs). However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency. Here, we applied a genome-wide CRISPR-Cas9 screening to identify genetic determinants of EGFR TKI sensitivity and uncovered putative candidates. We show that knockout of RIC8A, essential for G-alpha protein activation, enhanced EGFR TKI-induced cell death. Mechanistically, we demonstrate that RIC8A is a positive regulator of YAP signaling, activation of which rescued the EGFR TKI sensitizing phenotype resulting from RIC8A knockout. We also show that knockout of ARIH2, or other components in the Cullin-5 E3 complex, conferred resistance to EGFR inhibition, in part by promoting nascent protein synthesis through METAP2. Together, these data uncover a spectrum of previously unidentified regulators of EGFR TKI sensitivity in EGFR-mutant human NSCLC, providing insights into the heterogeneity of EGFR TKI treatment responses. Cancer is caused by cells growing and dividing uncontrollably as a result of mutations in certain genes. Many human lung cancers have a mutation in the gene that makes the protein EGFR. In healthy cells, EGFR allows a cell to respond to chemical signals that encourage healthy growth. In cancer, the altered EGFR is always on, which allows the cell to rapidly grow without any control, resulting in cancer. One approach to treating these cancers is with drugs that block the activity of mutant EGFR. Although these drugs have been very successful, they do not always succeed in completely treating the cancer. This is because over time the cancer cells can become resistant to the drug and start forming new tumors. One way that this can happen is if random mutations lead to changes in other proteins that make the drug less effective or stop it from accessing the EGFR proteins. However, it is unclear how other proteins in cancer cells affect the response to these EGFR inhibiting drugs. Now, Zeng et al. have used gene editing to systematically remove every protein from human lung cancer cells grown in the laboratory to see how this affects resistance to EGFR inhibitor treatment. This revealed that a number of different proteins could change how cancer cells responded to the drug. For instance, cells lacking the protein RIC8A were more sensitive to EGFR inhibitors and less likely to develop resistance. This is because loss of RIC8A turns down a key cell survival pathway in cancer cells. Whereas, cancer cells lacking the ARIH2 protein were able to produce more proteins that are needed for cancer cell growth, which resulted in them having increased resistance to EGFR inhibitors. The proteins identified in this study could be used to develop new drugs that improve the effectiveness of EGFR inhibitors. Understanding how cancer cells respond to EGFR inhibitor treatment could help determine how likely a patient is to develop resistance to these drugs.

Non-small cell lung cancer (NSCLC) with EGFR mutations presents a unique challenge due to the development of oligometastasis during treatment with first-line tyrosine kinase inhibitors (TKIs). The optimal timing of radiotherapy in EGFR-mutant oligometastatic NSCLC remains debated. This study aims to investigate the timing of radiotherapy in relation to disease progression to optimize treatment outcomes. We conducted a retrospective analysis of stage IIIB-IV EGFR-mutant NSCLC patients who received first-line TKI therapy and developed oligoprogressive disease between January 2019 and October 2024. Two groups were compared: one receiving radiotherapy before disease progression ( n  = 41) and the other post-progression ( n  = 26). The primary outcomes were progression-free survival (PFS1), progression-free survival after radiotherapy (RT-PFS), and the duration of first-line TKI therapy. Statistical analyses were performed using Kaplan-Meier curves and Cox regression. A total of 67 patients were included. The median PFS1 was 13.8 months in the upfront consolidative radiotherapy group versus 9.8 months in the post-progression group ( P  = 0.391). The median duration of first-line TKI therapy was significantly longer in the post-progression radiotherapy group (20.3 months vs. 13.3 months, P  < 0.001). Kaplan-Meier survival analysis showed a significant difference in TKI duration, suggesting delayed radiotherapy improved TKI duration. This retrospective study suggests that the timing of radiotherapy may influence the duration of first-line EGFR-TKI therapy in patients with oligometastatic NSCLC. Administering local therapy at the time of oligoprogression may help prolong TKI benefit without premature treatment escalation. However, given the study’s retrospective design and potential baseline imbalances, these findings should be interpreted with caution and require validation in future prospective trials.

Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial-mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR-TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs. ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.