The application of bronchoscopy in the assessment of immune checkpoint inhibitor-related pneumonitis severity and recurrence.

To explore the role of bronchoscopy for the assessment of checkpoint inhibitor pneumonitis (CIP), a retrospective single-center study was conducted to assess patients diagnosed with CIP at grade 2 or above and also underwent bronchoscopy between January 2020 and December 2022. Clinical data and bronchoscopic findings were recorded. The treatment data and prognosis information were collected. Twenty-one patients who underwent bronchoscopy and were diagnosed with CIP were enrolled in this study. All patients underwent bronchoalveolar lavage fluid (BALF) analysis. Of them, T lymphocyte subsets of BALF were tested in 15 cases. Transbronchial cryobiopsy (TBCB) was performed in 8 patients, and transbronchial lung biopsy was performed in 5 patients. 3 patients developed pneumothorax after TBCB and all recovered without serious compilations.14 patients experienced grade 2 CIP, while 7 patients ≥ grade 3 CIP. Symptoms were improved in 19 (90.5%) patients after standard treatment adhering to CIP guidelines. However, 5 patients relapsed during steroid tapering. Factors related to the severity and recurrence of CIP were analyzed. Patients with previous interstitial lung disease (ILD) were more likely to develop high grade CIP than those without [83.3% (5/6) versus 15.4% (3/15), P = 0.011].The odds ratio (OR) was 32.5 (95% CI 2.284-443.145, P = 0.009). Increased BALF lymphocyte percentage was associated with high grade CIP, OR 1.095 (95% CI 1.001-1.197, P = 0.047), and higher possibility of CIP relapse, OR 1.123 (95% CI, 1.005-1.225, P = 0.040). Lymphocyte subsets were tested in 15 patients. CD4/CD8 > 1 was found in 80% (4/5) of relapsed patients and 20% (2/10) of patients without relapse (P = 0.047). The OR was 16.00 (95% CI 1.093-234.24, P = 0.043). In this retrospective study, patients with previous ILD was more likely to develop high grade CIP. Higher lymphocyte percentage in BALF was associated with high grade CIP and susceptibility to relapse during treatment of CIP. A CD4/CD8 ratio greater than 1 in lymphocyte subsets of BALF was associated with higher possibility of CIP relapse. We found that TBCB is a safe procedure in CIP patients.

Efficacy of cross-line anti-programmed death 1/programmed cell death-ligand 1 antibody in the treatment of advanced nonsmall cell lung cancer: A retrospective study.

Background and Aims: Immune checkpoint inhibitors (ICIs) across multiple treatment lines have not yet been evaluated comprehensively. The purpose of this research was to investigate whether or not continuous cross-line ICIs therapy is effective in treating non-small cell lung cancer (NSCLC). Methods: We conducted a retrospective investigation into the medical histories of 47 patients diagnosed with advanced NSCLC and treated with ICIs at the Peking University First Hospital between January 2018 and June 2022. Results: Due to the progression of their disease, 14 patients were given the same ICIs, 5 patients were given different ICIs, and 6 patients discontinued taking ICIs altogether. The objective response rates were 7.140% in the ICIs cross-line treatment group, 0% in the replacement of ICIs treatment group, and 0% in the discontinuation of ICIs treatment group. The disease control rates were 64.260% in the ICIs cross-line treatment group, 60% in the replacement of ICIs treatment group, and 0% in the discontinuation of ICIs treatment group. The average overall survival durations of the three groups were 24.020 (95% confidence interval [CI]: 17.061-30.979), 31.643 (95% CI: 23.513-39.774), and 7.997 (95% CI: 3.746-12.247) months, respectively (p = 0.003). The median second progression-free survival (PFS2) durations of the three groups were 4.570 (95% CI: 3.276-5.864), 3.530 (95% CI: 0.674-6.386), and 1.570 (95% CI: 0-4.091) months, respectively (p = 0.091). Conclusions: Cross-line ICIs cannot improve the prognosis and PFS2 of patients with NSCLC, but compared to discontinuing ICIs, OS may be prolonged. A few patients may benefit from prolonged ICIs therapy.

Prevalence and management of pain in lung cancer patients in northern China: A multicenter cross-sectional study.

BACKGROUND: Pain is a fearful yet common symptom among lung cancer patients. This multicenter, cross-sectional study was conducted to examine the current status of pain prevalence and management in lung cancer patients in northern China. METHODS: A total of 18 hospitals across northern China were selected. Patients with primary lung cancer who visited the outpatient clinic or were admitted in the wards on a preplanned day were invited to complete a questionnaire. Meanwhile, physicians who had experience of treating primary lung cancer patients were also surveyed. RESULTS: A total of 533 patients and 197 physicians provided valid responses to the survey, of which 45.4% (242/533) of patients reported pain during the course of disease and 24.2% (129/533) of patients had experienced pain within the past 24 h. The mean average pain intensity by the brief pain inventory was 3.47 ± 1.55. The binary logistic regression analysis showed female gender and stage IV disease were significantly associated with the presence of pain. A total of 74.4% (96/129) of patients reporting pain within 24 h were taking analgesics. The most common reason for patients not using analgesics was that the pain was tolerable (48.2%), while the most common barriers to prescribing opioids as reported by physicians were fear of adverse reactions (43.7%) and fear of addiction (43.1%). CONCLUSION: Despite recognition of the importance of pain control by most physicians and an improvement in cancer pain management, inadequate treatment of cancer pain still exists in lung cancer patients in northern China. High-quality pain education for both patients and physicians is needed in the future.

Cytokine release syndrome and successful response to pembrolizumab therapy in a patient with EGFR-mutated non-small-cell lung cancer: A case report.

A therapeutic option for advanced non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) resistance is a clinical challenge. The clinical outcomes of pembrolizumab in those patients is inconclusive. Cytokine release syndrome (CRS) is a rarely reported immune-related adverse event in the field of immune checkpoint inhibitors therapy, raising challenges given the paucity of data with such presentations. We present the unique case of a 67-year-old female with advanced EGFR-mutated NSCLC who successfully responded to pembrolizumab after EGFR-TKI resistance. However, the patient developed CRS after pembrolizumab initiation and presented with fever, rash, hypotension, hypoxemia, tachycardia, and multiple organ dysfunction. Blood tests showed elevated levels of peripheral CD8+ T cells, C-reactive protein, and tumor necrosis factor-α. The symptoms rapidly improved after corticosteroid initiation. Based on the present case, we propose that pembrolizumab might be a potential salvage therapy for patients with advanced EGFR-mutated NSCLC after EGFR-TKI resistance; CRS would be a sign of the antitumor effect of PD-1 inhibitors in those patients. However, CRS can be a fatal adverse effect and clinicians must remain vigilant for the rare toxicities to make prompt diagnosis and treatment.

Diffuse large B-cell lymphoma presenting as reversible intrapulmonary arteriovenous shunts with hypoxia, fever and progressive jaundice: a case report and literature review.

BACKGROUND: Intrapulmonary arteriovenous shunts is rare seen in a patient without lung involvement. CASE PRESENTATION: This is the first report of reversible intrapulmonary arteriovenous shunts secondary to extrapulmonary lymphoma as one initial symptom. The patient presented as fever of unknown origin and dyspnea, and examinations of infection were negative. Diagnosis of DLBCL was finally confirmed through bone marrow and splenic biopsies. Intrapulmonary arteriovenous shunts were diagnosed through 100% oxygen inhalation test and transthoracic contrast echocardiography (TTCE). After the treatment of lymphoma, his respiratory failure was relieved. We rechecked the 100% oxygen inhalation test and TTCE, which both indicated that his intrapulmonary arteriovenous shunts had resolved. CONCLUSIONS: We speculated the prominent inflammation from active DLBCL was the most possible mechanism associated with the reversible intrapulmonary shunt in this patient. These findings will assist us to better understand the mechanism of intrapulmonary shunts.

Clinical Outcomes of Immune Checkpoint Inhibitor Therapy in Patients With Advanced Non-small Cell Lung Cancer and Preexisting Interstitial Lung Diseases: A Systematic Review and Meta-analysis.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) and preexisting interstitial lung disease (ILD) are often excluded from clinical trials of immune checkpoint inhibitors (ICIs), leaving a gap in knowledge. RESEARCH QUESTION: What are the clinical outcomes of ICIs in patients with NSCLC and preexisting ILD? STUDY DESIGN AND METHODS: Systematic searches were conducted of PubMed, EMBASE, and Cochrane Library through April 2021 with no language or study design restrictions. Studies reporting the safety and efficacy data among patients with cancer and ILD receiving ICI therapy were collected. The primary end points were clinical efficacy to immunotherapy and the incidence of immune-related adverse events, especially for checkpoint inhibitor pneumonitis (CIP). RESULTS: A total of 179 patients in 10 studies were included. The pooled overall response rate (ORR) and pooled disease control rate (DCR) were 34% (95% CI, 20-47) and 66% (95% CI, 56-75), respectively. The ORR in patients with preexisting ILD was significantly higher than that in patients without ILD (OR, 1.99; 95% CI, 1.31-3.00). The DCR and progression-free survival in patients with preexisting ILD were not inferior to those without ILD (pooled OR, 1.46; 95% CI, 0.94-2.25 for DCR). The pooled incidences of any grade and grade 3 or higher CIP were 27% (95% CI, 17-37) and 15% (95% CI, 9-22) in patients with preexisting ILD, and 10% (95% CI, 6-13) and 4% (95% CI, 2-6) in patients without ILD. Meta-analysis found a significantly higher incidence rate of any grade and grade 3 or higher CIP in patients with NSCLC and preexisting ILD than in those patients without ILD (OR, 3.23 [95% CI, 2.06-5.06]; OR, 2.91 [95% CI, 1.47-5.74]). INTERPRETATION: Programmed cell death protein 1/programmed cell death ligand 1 inhibitors had favorable efficacy in NSCLC with preexisting ILD. CIP is frequent in patients with preexisting ILD who receive ICI therapy but is often mild and easily manageable. Clinicians should be cautious when using ICIs in patients with preexisting ILD.

Pembrolizumab and chemotherapy in non-small cell lung cancer with EGFR ex20ins mutation: A case report.

The efficacy of immunotherapy in non-small cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (EGFR) mutations is not well clarified, even though immunotherapy has brought revolutionary improvements in EGFR wild-type NSCLC. In addition, pseudoprogression has increased the difficulty in immunotherapy management and data on the incidence of pseudoprogression in patients with EGFR exon 20 insertions (ex20ins) is rarely reported. Here, we discuss the case of an advanced lung adenocarcinoma patient with EGFR ex20ins alteration. The patient received pembrolizumab plus chemotherapy as first-line therapy and disease control was achieved. Progression-free survival (PFS) was 9 months. The patient was subsequently treated with pembrolizumab plus docetaxel and bevacizumab as second-line therapy and the disease remained stable. After two cycles of first-line treatment, the patient showed improvement in performance and the primary left upper lung lesion was stable; however, there was an increase in size as well as number of small diffuse bilateral pulmonary nodules. Therapy was maintained with the original regimen and complete regression of the bilateral lung nodules was achieved after a third cycle of treatment. Pseudoprogression was diagnosed. In the case reported here, we advocate the use of a PD-L1 inhibitor plus conventional chemotherapy in advanced NSCLC patients harboring EGFR ex20ins mutation and hope that our experience might be beneficial to other clinicians in distinguishing pseudoprogression from true progression.

Primary resistance to alectinib in a patient with STRN-ALK-positive non-small cell lung cancer: A case report.

Anaplastic lymphoma kinase (ALK) rearrangements are drivers of a subset of non-small cell lung cancer (NSCLC). The rapid progression of ALK inhibitors has significantly prolonged the progression-free survival of patients with ALK gene-sensitive mutations. However, the response of patients with rare ALK rearrangements to tyrosine kinase inhibitors remains unknown. Here, we report a rare case of striatin (STRN)-ALK-positive NSCLC showing primary resistance to first-line therapy alectinib and limited clinical activity of crizotinib in the alectinib-resistant setting.

Early Onset Acute Coronary Artery Occlusion After Pembrolizumab in Advanced Non-Small Cell Lung Cancer: A Case Report.

Myocarditis, arrhythmia, and cardiomyopathy are the most reported acute cardiotoxicities in cancer patients receiving immune checkpoint inhibitor (ICI) therapy. But it is not clear whether ICI can cause acute coronary occlusive disease. We reported acute coronary artery occlusion in an 83-year-old male non-small cell lung cancer (NSCLC) patient after 2 days of pembrolizumab infusion. This patient had a server-underlying three-vessel coronary artery disease without symptoms. The patient was discharged from the hospital two weeks after percutaneous coronary intervention. Pembrolizumab may cause destabilization of severely stenosed atherosclerotic plaques, which contributes to acute myocardial infarction. We should take more caution about lung cancer patients with baseline coronary disease when treat with ICI. CRP may be a useful predictor factor of early-onset coronary events in these patients.

Early-onset interstitial pneumonitis in a patient with advanced non-small cell lung cancer treated with crizotinib and osimertinib.

Both crizotinib and osimertinib have been reported to have an adverse effect of interstitial pneumonitis in the treatment of non-small cell lung cancer (NSCLC). Here, we report the case of a 60-year-old male patient with advanced NSCLC resistant to osimertinib. Crizotinib was administered in combination with osimertinib due to elevated mesenchymal epithelial transition (MET) copy number amplification. However, early-onset interstitial pneumonitis occurred within two days.

A rapid liquid biopsy of lung cancer by separation and detection of exfoliated tumor cells from bronchoalveolar lavage fluid with a dual-layer "PERFECT" filter system.

Separation and detection of exfoliated tumor cells (ETCs) from bronchoalveolar lavage fluid (BALF), namely the liquid biopsy of BALF, has been proved to be a valuable tool for the diagnosis of lung cancer. Herein, we established a rapid liquid biopsy of BALF based on a dual-layer PERFECT (precise, efficient, rapid, flexible, easy-to-operate, controllable and thin) filter system for the first time. Methods: The dual-layer PERFECT filter system consists of an upper-layer filter with large micropores (feature size of 49.4 ± 0.5 µm) and a lower-layer filter with small micropores (9.1 ± 0.1 µm). The upper-layer filter contributes to the isolation of cell clusters and removal of mucus from BALF samples, meanwhile the lower-layer one targets for the separation of single ETCs. First, separation of 10000 spiked A549s (cultured lung cancer cells) from 10 mL clinical BALF samples (n=3) were performed to investigate the performance of the proposed system in rare cell separation. Furthermore, separation and detection of ETCs and ETC clusters from clinical BALF samples were performed with this system to test its efficacy and compared with the routine cytocentrifuge. The clinical BALF samples were collected from 33 lung cancer-suspected patients with visible lesions under bronchoscope. The final histopathological results showed that 20 samples were from lung cancer positive patients while the other 13 cases were from lung cancer negative patients. Results: The recovery rate of spiked A549 cells from clinical BALF samples with the developed system (89.8 ± 5.2%) is significantly higher than that with the cytocentrifuge (13.6 ± 7.8%). In the preliminary clinical trial, although 33 clinical BALF samples with volume ranging from 6 mL to 18 mL showed greatly varied turbidity, filtrations could be finished within 3 min for 54.6% of samples (18/33), and 10 min at most for the rest. The dual-layer PERFECT filter system is proved to have a much higher sensitivity (80.0%, 95% CI: 55.7%-93.4%) than the routine cytocentrifuge (45.0%, 95% CI: 23.8%-68.0%), p=0.016 (McNemar test, two-tail). Moreover, the sensitivity of this platform is neither interfered by the variations of turbidity of the BALF samples, nor associated with the types of lung cancer. Conclusions: The easy and rapid processing of BALF samples with varying volume and turbidity, competitive sensitivity and good versatility for different lung cancer types will make the established dual-layer PERFECT filter system a promising approach for the liquid biopsy of BALF. The high-performance BALF-based liquid biopsy will improve the cytopathological identification and diagnosis of lung cancer.

Comparison of Endostar continuous versus intermittent intravenous infusion in combination with first-line chemotherapy in patients with advanced non-small cell lung cancer.

BACKGROUND: Intravenous infusion of Endostar for three to four hours per day for 14 days reduces patient compliance and affects quality of life. Continuous intravenous infusion (CI) represents a novel method of administration; however, it is unclear whether it is effective and safe when compared to the traditional method. METHODS: We retrospectively reviewed patients with advanced non-small cell lung cancer (NSCLC) administered CI (20 patients) or intermittent intravenous infusion (II, 49 patients) of Endostar combined with first-line chemotherapy. Three patients in the II group discontinued therapy because of adverse effects. RESULTS: Median progression-free survival was 6.0 months in the CI group and 3.8 months in the II group, with no significant difference (P = 0.1). The objective response and disease control rates were also similar in the CI and II groups (40.0 vs. 32.6%, P = 0.562; 65 vs. 69.6%, P = 0.714, respectively). CONCLUSION: CI of Endostar combined with first-line chemotherapy for advanced NSCLC had similar progression-free survival, objective response, and overall response rates as II, with tolerable adverse effects.

Real-world data on EGFR/ALK gene status and first-line targeted therapy rate in newly diagnosed advanced non-small cell lung cancer patients in Northern China: A prospective observational study.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) can significantly prolong overall survival for patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR)-mutation or anaplastic lymphoma kinase (ALK)-rearrangement. However, the real-world evaluation status of ALK/EGFR in China remains unclear. METHODS: We conducted a prospective study including 1134 patients with cytologically or histologically confirmed advanced NSCLC (stage IIIb-IV) at 12 Chinese hospitals. RESULTS: The most common evaluation methods were amplification-refractory mutation system for EGFR status and immunohistochemistry targeting D5F3 for ALK status. Among patients with non-squamous, the EGFR mutation rate was 44.1% and the ALK rearrangement rate was 10.0%. Among patients with squamous cell carcinoma, the EGFR mutation rate was 8.3% and the ALK rearrangement rate was 3.7%. Among all patients, gender (HR = 1.7, 95%CI = 1.2-2.4, P = 0.006), smoking history (HR = 1.8, 95%CI = 1.3-2.7, P = 0.001), histology (HR = 5.0, 95%CI = 2.4-10.1, P < 0.001), and brain metastases (HR = 1.5, 95%CI = 1.1-2.2, P = 0.017) were independent predictors of EGFR mutation, while age (HR = 2.6, 95%CI = 1.7-4.1, P < 0.001) was an independent predictor of ALK rearrangement. The median time from tumor diagnosis to EGFR or ALK status confirmation was 7 and 5 days, respectively. Targeted therapy rate was 73.8% in EGFR-positive patients and 51.4% in ALK-positive patients. There was a negative correlation between the first-line targeted therapy rate and the EGFR mutation detection period (r = -0.152, P = 0.02), while no significant correlation among patients with ALK rearrangement (r = -0.179, P = 0.076). CONCLUSION: Squamous NSCLC patients should also be routinely tested to determine their EGFR/ALK statuses. The first-line targeted therapy rate remains low in Chinese patients with NSCLC.

A high-throughput liquid biopsy for rapid rare cell separation from large-volume samples.

Liquid biopsy techniques for rare tumor cell separation from body fluids have shown enormous promise in cancer detection and prognosis monitoring. This work established a high-throughput liquid biopsy platform with a high recovery rate and a high cell viability based on a previously reported 2.5D micropore-arrayed filtration membrane. Thanks to its high porosity (>40.2%, edge-to-edge space between the adjacent micropores <4 µm), the achieved filtration throughputs can reach >110 mL min-1 for aqueous samples and >17 mL min-1 for undiluted whole blood, only driven by gravity with no need for any extra pressure loading. The recoveries of rare lung tumor cells (A549s) spiked in PBS (10 mL), unprocessed BALF (10 mL) and whole blood (5 mL) show high recovery rates (88.0 ± 3.7%, 86.0 ± 5.3% and 83.2 ± 6.2%, respectively, n = 5 for every trial) and prove the high performance of this platform. Successful detection of circulating tumor cells (CTCs) from whole blood samples (5 mL) of lung cancer patients (n = 5) was demonstrated. In addition, it was both numerically and experimentally proved that a small edge-to-edge space was significant to improve the viability of the recovered cells and the purity of the target cell recovery, which was reported for the first time to the best of the authors' knowledge. This high-throughput technique will expand the detecting targets of liquid biopsy from the presently focused CTCs in whole blood to the exfoliated tumor cells (ETCs) in other large-volume clinical samples, such as BALF, urine and pleural fluid. Meanwhile, the technique is easy to operate and ready for integration with other separation and analysis tools to fulfill a powerful system for practical clinical applications of liquid biopsy.

Establishment of a prospective multicenter cohort for advanced non-small cell lung cancer in China (CAPTRA-Lung study).

The CAPTRA-Lung study (NCT03334864) is a prospective observational study that will capture real-world data of patients with advanced or metastatic non-small cell lung cancer (NSCLC) across China. The study aims to complement the results from current therapeutic regimens to improve the standard of diagnosis and treatment, evaluate the effectiveness and safety of systemic therapy, and determine the factors influencing the outcomes and responses to treatment. From January 2018 to December 2023, eligible patients with advanced or metastatic NSCLC who are receiving treatment and participating in follow-up at 16 institutions in China, will be enrolled. The demographic, clinical, laboratory, and treatment characteristics and responses to treatment will be recorded in a case report form and transcribed into an electronic data capture system. Overall survival, progression-free survival, overall response rate, and incidence of adverse events will be calculated from the time of initial enrolment until progression evaluated by physicians, last contact, date of death, or analysis cutoff date, respectively. Based on the disease characteristics and treatment strategies, four sub-cohorts will also be established. This study cohort could serve as a pool of patients with advanced or metastatic NSCLC to support further research.

Efficacy, safety and predictive indicators of apatinib after multilines treatment in advanced nonsquamous nonsmall cell lung cancer: Apatinib treatment in nonsquamous NSCLC.

AIM: Patients with advanced nonsquamous nonsmall cell lung cancer (NSCLC) who experienced progression with two or more lines chemotherapy have no treatment options that clearly confer a survival benefit. As a novel vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor, apatinib has a certain antitumor effect for various solid tumors. The present study evaluated the efficacy and safety of apatinib in advanced nonsquamous NSCLC as salvage treatment in Chinese real-world practice. METHODS: Twenty-eight patients were enrolled in this observational study from October 2015 to May 2017. Progression-free survival (PFS) and overall survival (OS) were graphed by Kaplan-Meier curve and intergroup comparisons were carried out by log-rank test. Objective response rate (ORR), disease control rate (DCR) and adverse effects (AEs) were also evaluated. RESULTS: Seven patients obtained partial response, and 18 obtained stable disease, representing an ORR of 26% and a DCR of 93%. Median PFS and OS were 3 (95% confidence interval [CI] 2.6-3.4) and 7.4 (95% CI 1.3-13.5) months, respectively. The efficacy analysis showed that Eastern Cooperative Oncology Group (ECOG) performance status 0-1 was correlated with prolonged OS and PFS (P < 0.05), and hypertension during apatinib treatment was correlated with prolonged OS (P < 0.05). Cox regression showed that ECOG performance status (P < 0.01) (RR = 0.231) (95% CI 0.083-0.642) and hypertension during apatinib treatment (P = 0.05) were predictive indicators for apatinib treatment. Grade 3-4 AEs with incidences of 10% or greater were hypertension (21%), hand-foot syndrome (14%) and proteinuria (11%) which could be relieved by dose reduction. CONCLUSION: In conclusion, apatinib has a certain therapeutic effect in patients with advanced nonsquamous NSCLC. ECOG performance status and hypertension during apatinib might be predictive indicators for treatment efficacy.

[Mechanisms of Resistance to the Third-generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer].

Targeted therapy of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKIs) has been the standard modality as first-line treatment of advanced EGFR-mutated non-small cell lung cancer (NSCLC). The third-generation EGFR-TKIs has been approved to overcome the EGFR T790M mutation in patients resistant to the first-or second-generation TKIs, which brings more survival benefits for patients with advanced NSCLC. Unfortunately, acquired resistance inevitably develops after application of approximately 10 months. Heterogeneities of the tumor determines the diversity of resistance. Mechanisms of resistance to the third-generation TKIs includs EGFR-dependent pathway (such as new EGFR mutations, T790M reduction/disappearance and EGFR amplification, etc.) and EGFR-independent pathway (such as bypass pathway activation and histological transformation, etc.). In this paper, we reviewed principle mechanisms of acquired resistance to third-generation EGFR-TKIs.