OBJECTIVE: This study has a purpose to investigate the side effects of three EGFR-TKIs targeted therapeutic agents (gefitinib, erlotinib, and afatinib) and all-cause mortality in patients with metastatic lung cancer.
METHODS: We performed a prospective cohort study. We selected all patients with newly diagnosed metastatic lung cancer between January and November 2019. Main exposure was daytime versus nighttime use of targeted EGFR TKIs. The study outcome was a symptom change using the mobile application, and all-cause mortality between January 2019 and March 2023.
RESULTS: Among the 87 study participants, 35 (40%) took their medication at night. Among the 87 study participants, 35 (40%) took their medication at night. At 6 weeks of treatment, acne (1.36; 95% confidence interval [CI] 1.09, 1.64; p for interaction = 0.04) and dry skin (1.35; 95% CI 1.09, 1.61, p for interaction = 0.01) in the day group showed a much increase from baseline compared to the night group. In contrast, the night group reported greater reductions in lung cancer-related symptoms from baseline compared to the day. During follow-up (median 43 months), the night group had a lower risk of all-cause death than the day group, especially in younger patients (adjusted hazard ratio = 0.34; 95% CI 0.13, 0.87).
CONCLUSIONS: The group taking EGFR-TKIs at night experienced fewer side effects and had longer overall survival compared to the day group. Clinicians should consider recommending that lung cancer patients take their once-daily oral anticancer drugs in the evening rather than the morning to improve treatment outcomes.

Ten percent of non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutations harbor uncommon variants. These mutations are mainly involved in lung adenocarcinomas but are rare in lung squamous cell carcinoma (LSCC). In 2018, the Food and Drug Administration-approved afatinib for this specific patient population. However, there is limited information regarding the effectiveness of afatinib for LSCC with EGFR mutations. This case report documented a unique case of a patient with LSCC, which had a rare compound EGFR mutation (G719C and S768I) and showed significant response to afatinib treatment, with 10 months of progression-free survival. New NTRK1 and RET gene mutations may play a potential role in the development of acquired resistance to afatinib following clinical progression. This case highlights the importance of genetic profiling in patients with LSCC. Although these patients have a low positive rate of EGFR mutations, searching for EGFR mutations in these patients might broaden their treatment options.

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OBJECTIVE: Limited data are available comparing the efficacy of osi versus earlier generation TKIs for mNSCLC with atypical EGFR mutations (AMs) such as L861Q, G719X, S768I and exon20.
METHODS: We performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007 to 2023 with 1L TKIs, comparing outcomes for AM patients treated with osi, afatinib, and erlotinib. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the electronic medical record and compared between TKIs using independent sample t-tests and chi-square analyses. Median progression free survival (mPFS) and overall survival (mOS) were compared via Kaplan-Meier log-rank analysis and Cox multivariable regression.
RESULTS: Among 355 patients with EGFR-mutated mNSCLC, 36 (10 %) harbored AMs in G719X (N=21; 6 %), Exon 20 (N=11; 3 %), L861Q (N=7; 2 %), S768I (N=4; 1 %), C797S (N=1; 0.3 %); 6 patients had compound mutations. Patients with classical mutations (CMs) vs AMs had similar baseline demographic and disease characteristics and usage of TKIs (p = 0.124). Among AM patients, osi yielded superior mPFS (22 m) vs afatinib (12 m; p = 0.005) or erlotinib (9 m; p = 0.001). mOS was likewise superior for osi (32 m) vs afatinib (21 m; p = 0.032) or erlotinib (17 m; p = 0.011). Dose-reduction rates due to AEs were lower for osi (19 %) vs afatinib (24 %; p = 0.003) or erlotinib (23 %; p = 0.002). Discontinuation rates due to AEs were lower for osi vs afatinib (1 % vs 2 %; p < 0.001) or erlotinib (2 %; p = 0.004).
CONCLUSIONS: In a large real-world analysis, osi demonstrated superior progression-free and overall survival and improved tolerability compared to afatinib or erlotinib for atypical EGFR-mutated mNSCLC.

Epidermal growth factor receptor (EGFR) gene mutations are prevalent in about 50% of lung adenocarcinoma patients. Highly effective tyrosine kinase inhibitors (TKIs) targeting the EGFR protein have revolutionized treatment for the prevalent and aggressive lung malignancy. However, the emergence of new EGFR mutations and the rapid development of additional drug resistance mechanisms pose substantial challenge to the effective treatment of NSCLC. To investigate the underlying causes of drug resistance, we utilized next-generation sequencing data to analyse the genetic alterations in different tumor genomic states under the pressure of drug selection. This study involved a comprehensive analysis of whole exome sequencing data (WES) from NSCLC patients before and after treatment with afatinib and osimertinib with a goal to identify drug resistance mutations from the post-treatment WES data. We identified five EGFR single-point mutations (L718A, G724E, G724K, K745L, V851D) and one double mutation (T790M/L858R) associated with drug resistance. Through molecular docking, we observed that mutations, G724E, K745L, V851D, and T790M/L858R, have negatively affected the binding affinity with the FDA-approved drugs. Further, molecular dynamic simulations revealed the detrimental impact of these mutations on the binding efficacy. Finally, we conducted virtual screening against structurally similar compounds to afatinib and osimertinib and identified three compounds (CID 71496460, 73292362, and 73292545) that showed the potential to selectively inhibit EGFR despite the drug-resistance mutations. The WES-based study provides additional insight to understand the drug resistance mechanisms driven by tumor mutations and helps develop potential lead compounds to inhibit EGFR in the presence of drug resistance mutations.

Non-small cell lung cancer (NSCLC) poses a global health threat, and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib, afatinib, and osimertinib have achieved significant success in clinical treatment. However, the emergence of resistance limits the long-term efficacy of these treatments, necessitating urgent exploration of novel EGFR-TKIs. This review provides an in-depth summary and exploration of the resistance mechanisms associated with EGFR-TKIs, with a specific focus on representative drugs like gefitinib, afatinib, and osimertinib. Additionally, the review introduces a therapeutic strategy involving the combination of Chinese herbal medicines (CHMs) and chemotherapy drugs, highlighting the potential role of CHMs in overcoming NSCLC resistance. Through systematic analysis, we elucidate the primary resistance mechanisms of EGFR-TKIs in NSCLC treatment, emphasizing CHMs as potential treatment medicines and providing a fresh perspective for the development of next-generation EGFR-TKIs. This comprehensive review aims to guide the application of CHMs in combination therapy for NSCLC management, fostering the development of more effective and comprehensive treatment modalities to ultimately enhance patient outcomes.

UNASSIGNED: Lung cancer, especially non-small cell lung cancer (NSCLC), poses a significant health challenge globally due to its high mortality. Afatinib, a second-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has shown superior efficacy over traditional chemotherapy in NSCLC treatment. However, issues like secondary resistance and adverse effects call for alternative therapies. HAD-B1, comprising 4 herbal medicines, has shown promise in lung cancer treatment in both preclinical and clinical settings. This study assesses the combination of HAD-B1 and Afatinib in advanced NSCLC patients to potentially improve outcomes by addressing the limitations of current EGFR-TKI therapies.
UNASSIGNED: A randomized, open-label trial evaluated the efficacy and safety of HAD-B1 with Afatinib in 90 EGFR-mutation-positive NSCLC patients. Participants were divided into treatment and control groups, receiving Afatinib with or without HAD-B1. The study focused on the initial dose maintenance rate and disease control rate (DCR) of Afatinib, alongside secondary outcomes like survival rates and quality of life, under continuous safety monitoring.
UNASSIGNED: Among the 90 participants, no significant difference was found in initial dose maintenance (60.98% in the treatment group vs 52.50% in the control, P = .4414) or DCR (80.49% vs 90.00%, P = .2283). Secondary outcomes like PFS, TTP, and OS showed no notable differences. However, physical functioning significantly improved in the treatment group (P = .0475, PPS group). The control group experienced higher rates of adverse events of special interest and adverse drug reactions (P = .01), suggesting HAD-B1 with Afatinib might enhance physical function without increasing adverse effects.
UNASSIGNED: Combining HAD-B1 with Afatinib potentially improves quality of life and reduces adverse events in advanced NSCLC patients. Further research is necessary to confirm the long-term benefits of this combination therapy, aiming to advance NSCLC treatment outcomes.
UNASSIGNED: Clinical Research Information Service (CRIS) of the Republic of Korea, https://cris.nih.go.kr/ (ID: KCT0005414).

BACKGROUND: The relative occurrence of infection in patients treated with cytotoxic chemotherapeutic drugs and molecularly targeted drugs is unclear.
OBJECTIVE: To compare the occurrence of respiratory and urinary tract infections in patients treated for lung cancer with docetaxel versus afatinib and to predict the occurrence of the respiratory and urinary tract infections.
METHODS: Data on patients who received docetaxel or afatinib were obtained from a health insurance claims database. After propensity score matching, the occurrence of respiratory and urinary tract infections in each group was compared. Factors associated with respiratory and urinary tract infections were evaluated using multivariable conditional logistic regression analysis.
RESULTS: Each group included 855 patients. The occurrence of respiratory infections was significantly higher in the docetaxel group than in the afatinib group (22.6% [193/855] vs. 13.9% [119/855]; p < 0.01). The occurrence of urinary tract infections did not differ significantly by group. Docetaxel was independently associated with a significantly increased risk of respiratory infections (adjusted odds ratio: 1.68, 95% confidence interval: 1.23-2.29), but not urinary tract infections.
CONCLUSIONS: Patients with lung cancer treated with docetaxel should be closely monitored for the occurrence of respiratory infection in clinical settings.

OBJECTIVE: National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH) was a multicohort phase 2 trial that assigned patients with advanced pretreated cancers to molecularly targeted therapies on the basis of tumor genomic testing. NCI-MATCH Arm A evaluated afatinib, an EGFR tyrosine kinase inhibitor (TKI) approved for advanced non-small cell lung cancer, in patients with tumors other than lung cancer harboring EGFR mutations.
METHODS: Patients with advanced pretreated cancers other than lung cancer found to have selected actionable EGFR mutations were offered participation in Arm A. Previous therapy with an EGFR TKI was not allowed. Patients received afatinib 40 mg once daily continuously until disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), 6-month PFS, and overall survival (OS).
RESULTS: Seventeen patients received protocol therapy. Tumor types included glioblastoma multiforme (GBM) (13), gliosarcoma (1), adenocarcinoma not otherwise specified (NOS) (2), and adenosquamous carcinoma of the breast (1). Fifty-nine percent of patients received ≥2 lines of previous therapy. The ORR was 11.8% (90% CI, 2.1 to 32.6), with one complete response lasting 16.4 months (GBM harboring a rare exon 18 EGFR-SEPT14 fusion) and one partial response lasting 12.8 months (adenocarcinoma NOS with the classic EGFR mutation, p.Glu746_Ala750del). Three patients had stable disease. The 6-month PFS was 15% (90% CI, 0 to 30.7); the median OS was 9 months (90% CI, 4.6 to 14.0). Rash and diarrhea were the most common toxicities.
CONCLUSIONS: Afatinib had modest activity in a cohort of patients with heavily pretreated cancer with advanced nonlung, EGFR-mutated tumors, but the trial\'s primary end point was not met. Further evaluation of afatinib in GBM with EGFR exon 18 fusions may be of interest.

UNASSIGNED: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce.
UNASSIGNED: We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib.
UNASSIGNED: A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib.
UNASSIGNED: In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.