Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non-small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment-naïve tumor tissues. Survival benefits and resistance mechanisms of first-line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression-free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41-0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti-vascular therapy (HR: 0.55, 95% CI: 0.39-0.77). Furthermore, EGFRL858Q/M patients showed enhanced first-line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10-0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first-line EGFR TKIs than those with the classical EGFRL858R.

Osimertinib administration has been approved as an adjuvant treatment after complete surgical resection in patients with EGFR-mutated NSCLC. This article presents the first report of life-threatening postoperative osimertinib-induced interstitial lung disease. An 83-year-old male patient underwent right upper lobectomy (pathologic stage IIA) and osimertinib (80 mg/d) was initiated on postoperative day 75. On day 44 of osimertinib administration, chest computed tomography revealed diffuse ground-glass opacities; accordingly, osimertinib-induced interstitial lung disease was diagnosed. Steroid pulse therapy was initiated using a high-flow nasal cannula to treat dyspnea and hypoxemia, rapidly improving the respiratory status and imaging findings; moreover, the patient\'s clinical course was excellent. This case report suggests that the postoperative occurrence of severe osimertinib-induced interstitial lung disease is a crucial factor that must be considered in patient decision-making regarding perioperative treatment.

Background: The treatment paradigm for advanced non-small-cell lung cancer (NSCLC) is rapidly changing. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anti-programmed death-1 (PD-1) antibodies have increasingly been incorporated into routine care for nearly all patients with NSCLC. Toripalimab was recently approved as the first-line treatment for advanced non-squamous NSCLC in combination with chemotherapy. Stevens-Johnson syndrome (SJS) is a rare but potentially fatal complication of TKI and anti-PD-1 therapy. We reported a case of SJS after sequential use of EGFR-TKIs and toripalimab in an NSCLC patient with EGFR mutations 19 del/T790M/C797S in trans and cis. Case presentation: A 58-year-old man with stage IV NSCLC received gefitinib because next-generation sequencing (NGS) revealed an EGFR 19del, followed by osimertinib and pemetrexed with the emergence of EGFR T790M. Four EGFR mutations 19 del/T790M/C797S in trans and cis were detected after osimertinib resistance. The combination of toripalimab and docetaxel was administered as a third-line treatment. The patient developed SJS at 21 days, and toripalimab was discontinued. After treatment with methylprednisolone and prednisolone, the skin toxicity of the patient gradually decreased and eventually disappeared. The patient received osimertinib and anlotinib after recovery, and SJS has not recurred. The ongoing treatment is still effective and results in stable disease. Conclusion: We reported the first case of SJS induced by toripalimab in a patient with lung adenocarcinoma harboring multiple EGFR mutations. The TKI treatment after SJS was well tolerated and effective.

BACKGROUND: The absence of thyroid transcription factor 1 (TTF-1) is associated with a lower frequency of epidermal growth factor receptor (EGFR) mutations in lung adenocarcinoma (LUAD). The aim of this study was to assess the impact of TTF-1 expression on the clinical response to EGFR-tyrosine kinase inhibitor (TKI) treatment in patients with advanced LUAD.
METHODS: The data of patients with advanced LUAD who were admitted to the Beijing Tiantan Hospital and Peking University Cancer Hospital (China) between April 2009 and May 2023 was retrospectively analyzed.
RESULTS: A total of 227 patients diagnosed with advanced LUAD were included, of which 28.2% (64/227) had TTF-1-negative adenocarcinoma, while 54.6% (124/227) harbored EGFR mutations. Negative TTF-1 expression significantly correlated with male sex (68.8% vs. 42.3%, p < 0.001), history of heavy smoking (57.8% vs. 36.2%, p = 0.003), poorly differentiated tumors (86.5% vs. 43.2%, p < 0.001), and lower frequency of EGFR mutations (26.6% vs. 65.6%, p < 0.001) compared with TTF-1 positivity. Multivariable logistic regression showed that low prevalence of EGFR mutations (p < 0.001) and male sex (p = 0.006) were independent predictive factors for the negative expression of TTF-1. Patients lacking TTF-1 also exhibited worse overall response rate (ORR; 23.5% vs. 54.2%, p = 0.019), disease control rate (DCR; 58.8% vs. 89.7%, p = 0.003), and median progression-free survival (PFS; 2.9 vs. 11.6 months, p < 0.001) following treatment with EGFR-TKIs compared to the TTF-1-positive patients with EGFR mutations.
CONCLUSIONS: Patients with TTF-1-negative and EGFR-mutant LUAD show a diminished response to EGFR-TKIs.

UNASSIGNED: EGFR tyrosine kinase inhibitors are standard therapeutic agents for patients with advanced NSCLC harboring EGFR mutations. Nevertheless, some patients exhibit primary resistance to EGFR tyrosine kinase inhibitors in the first-line treatment setting. AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is involved in primary resistance to EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC.
UNASSIGNED: We investigated spatial tumor heterogeneity using autopsy specimens and a patient-derived cell line from a patient with EGFR-mutated NSCLC having primary resistance to erlotinib plus ramucirumab.
UNASSIGNED: Quantitative polymerase chain reaction analysis revealed that AXL mRNA expression differed at each metastatic site. In addition, AXL expression levels were likely to be negatively correlated with the effectiveness of erlotinib plus ramucirumab therapy. Analysis of a patient-derived cell line established from the left pleural effusion before initiation of treatment revealed that the combination of EGFR tyrosine kinase inhibitors and an AXL inhibitor remarkably inhibited cell viability and increased cell apoptosis in comparison with EGFR tyrosine kinase inhibitor monotherapy or combination therapy of these inhibitors with ramucirumab.
UNASSIGNED: Our observations suggest that AXL expression may play a critical role in the progression of spatial tumor heterogeneity and primary resistance to EGFR tyrosine kinase inhibitors in patients with EGFR-mutated NSCLC.

Uncommon epidermal growth factor receptor (EGFR) mutations account for 10%-20% of all EGFR mutations in non-small-cell lung cancer (NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors (TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC. Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models (V769-D770insASV and L861Q mutations) and a patient-derived xenografts model (H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

Erlotinib is an oral and reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor and is now used exclusively to non-small cell lung carcinoma (NSCLC) harboring mutated EGFR. However, there was historically a transient period when erlotinib was widely used regardless of EGFR mutation status. We report two cases with adenocarcinoma and wild-type EGFR status, which responded to erlotinib for unusual long time. We also retrospectively analyzed patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital. A 60-year-old woman received the second-line and tri-weekly regimen of pemetrexed (500 mg/m2 on day 1) and intermittent erlotinib (150 mg on days 2 - 16). Pemetexed was discontinued 18 months after the initiation of this regimen, but erlotinib was continued for more than 11 years. This chemotherapy successfully reduced her brain metastasis and prevented recurrence. A 58-year-old man received erlotinib monotherapy as the third-line regimen, by which multiple brain metastases disappeared. Although we tried stopping erlotinib 9 years after the initiation of erlotinib, a solitary metastasis appeared in the brain 3 months after the discontinuation of erlotinib. Between December 2007 and October 2015, 39 patients with wild-type EGFR status initiated erlotinib-containing regimens at our hospital. The response rate, progression-free survival and overall survival were 17.9% (95% confidence interval (CI): 7.5-33.5%), 2.7 months (95% CI: 1.8 - 5.0 months) and 10.3 months (95% CI: 5.0 - 15.7 months), respectively. We reported two long-term responders and survivors to erlotinib for more than 9 years, which was much longer than patients with adenocarcinoma and wild-type EGFR mutation status who had received erlotinib-containing regimen in our hospital.

In the non-small-cell lung cancer (NSCLC) subtype, adenocarcinoma is the most common histology. The choice of first-line treatment depends on the mutational status. We present a case of a 54-year-old non-smoker woman with lung adenocarcinoma and extensive metastatic disease at diagnosis. The genetic analysis demonstrated a sensitizing epidermal growth factor receptor (EGFR) exon 19 mutation and she began treatment with a first-generation EGFR tyrosine kinase inhibitor (TKI), erlotinib. Due to successively acquired resistances and disease progression, six treatment lines were pursued, including third-generation EGFR TKI and chemotherapy. The patient accomplished an overall survival of 47 months. This case emphasized the importance of monitoring tumor mutational alterations, allowing us to implement a multi-line treatment. Targeted therapy in advanced NSCLC largely improved the overall survival of these patients.

EGFR-TKI is widely used for EGFR-mutant NSCLC patients. Bleeding is reported as a neglected adverse effect induced by EGFR-TKI. Female patients with lung adenocarcinoma have a high frequency of EGFR mutations. This study investigated the effect of EGFR-TKI on the menstrual cycle, especially on bleeding, in women of childbearing age. The underlying mechanism was further investigated in a patient with severe bleeding. We retrospectively investigated the effects on menstrual cycle in premenopausal female NSCLC patients who underwent EGFR-TKI treatment during 2013 to 2019. Menstrual changes including cycle disorders and prolonged bleeding were investigated via questionnaire survey. EGFR signaling, ER, PR and tissue factor expression were analyzed in endometrium tissue obtained from a 43-year-old patient who suffered from continuous vaginal bleeding during treatment with erlotinib and osimertinib. Among 42 premenopausal female patients taking EGFR tyrosine kinase inhibitor, 69.05% patients experienced abnormal menstruation. In women with abnormal menstruation, 41.37% had profuse menstruation and 20.69% had irregular menstruation. In most cases, the abnormal vaginal bleeding stopped when suspending EGFR-TKI. The EGFR-TKI induced abnormal vaginal bleeding might be associated with low progesterone level, decreased EGFR activation and tissue factor (TF) expression in endometrial tissues. EGFR-TKI unusually induce abnormal vaginal bleeding in premenopausal female NSCLC patients, which may be attributed to progesterone/EGFR/TF signaling. Megestrol acetate may be an available and effective drug for the uncommon adverse effect.

The current study investigated the cytotoxic effect of ten sulfonamide-derived isatins, following molecular hybridization, based on the association principles, on hepatocellular carcinoma (HCC) HepG2 and Huh7 cell lines, compared for safety using human normal retina pigmented epithelial (RPE-1) cells. The ten compounds showed variable in vitro cytotoxicity on HepG2 and Huh7 cells, using the MTT assay. Four compounds (4/10) were highly cytotoxic to both HepG2 and HuH7. However, only 3 of these 4 were of the highest safety margin on RPE-1 cells in vitro and in the in vivo acute (14-day) oral toxicity study. These later, superior three compounds\' structures are 3-hydroxy-3-(2-oxo-2-(p-tolyl)ethyl)-5-(piperidin-1-ylsulfonyl)indolin-2-one (3a), N-(4-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4b), and N-(3-(2-(2-oxo-5-(piperidin-1-ylsulfonyl)indolin-3-ylidene)acetyl)phenyl)acetamide (4c). The half-maximal inhibitory concentration (IC50) of the tested compounds (3a, 4b, and 4c) on HepG2 cells were approximately 16.8, 44.7, and 39.7 μM, respectively. The 3a, 4b, and 4c compounds significantly decreased the angiogenic marker epithelial growth factor receptor (EGFR) level and that was further confirmed via molecular docking inside the EFGR active site (PDB: 1M17). The binding free energies ranged between -19.21 and -21.74 Kcal/mol compared to Erlotinib (-25.65 Kcal/mol). The most promising compounds, 3a, 4b, and 4c, showed variable anticancer potential on \"hallmarks of cancer\", significant cytotoxicity, and apoptotic anti-angiogenic and anti-invasive effects, manifested as suppression of Bcl-2, urokinase plasminogen activation, and heparanase expression in HepG2-treated cells\' lysate, compared to non-treated HepG2 cells. In conclusion, compound \"3a\" is highly comparable to doxorubicin regarding cell cycle arrest at G2/M, the pre-G0 phases and early and late apoptosis induction and is comparable to Erlotinib regarding binding to EGFR active site. Therefore, the current study could suggest that compound \"3a\" is, hopefully, the most safe and active synthesized isatin sulfonamide derivative for HCC management.