osimertinib and Adenocarcinoma-of-Lung

Osimertinib, the third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the standard treatment for nonsmall cell lung cancer with EGFR mutation. However, osimertinib-induced interstitial lung disease (OsiILD) is considered to be a serious adverse event, so some patients will have to discontinue the use of osimertinib due to OsiILD. Almonertinib is a novel third-generation EGFR-TKI. We herein report a patient who developed OsiILD after the use of osimertinib and then switched to almonertinib for further treatment with success. This is the first report of a successfull rechallenge with low-dose almonertinib after OsiILD. We also reviewed the literature to explore the possible risk factors and the subsequent treatment of OsiILD, suggesting that low-dose almonertinib may be an option for follow-up treatment of OsiILD.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

The development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) represents a paradigm shift in the treatment of lung cancer with EGFR mutations. Aumolertinib has been shown to be a safe agent in the registry study. However, successful rechallenge with aumolertinib following osimertinib-induced myocardial damage has not been reported. In this article, a case of neoadjuvant therapy for lung adenocarcinoma is retrospectively analyzed, and the relevant literature is reviewed. The patient was diagnosed with stage IIIA lung adenocarcinoma, and genetic testing revealed EGFR exon 19 deletion mutation combined with Tumor Protein p53 (TP53) mutation. The mutation abundance is 33.5 and 14%, respectively. One month after osimertinib treatment, the patient developed myocardial damage, and abnormal indicators such as myocardial enzyme spectrum showed abnormalities and cardiac insufficiency, followed by pulmonary hypertension and pulmonary edema. Aumolertinib was subsequently used for treatment, following which the myocardial enzyme spectrum returned to normal, and the symptoms of bilateral interstitial edema disappeared. In addition to the disappearance of adverse reactions, the therapeutic effect was excellent; the lung lesions and mediastinal lymph nodes were significantly reduced, and the operation was successfully conducted. This is the first report of successful neoadjuvant treatment of EGFR exon 19 deletion combined with TP53 mutation in NSCLC using aumolertinib after osimertinib-induced myocardial damage. The results suggested that aumolertinib had fewer adverse reactions in patients with EGFR exon 19 deletion combined with TP53 mutation, and aumolertinib may be a potential neoadjuvant therapy for stage IIIA lung cancer.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Exons; Humans; Lung Neoplasms; Mutation; Neoadjuvant Therapy; Protein Kinase Inhibitors; Retrospective Studies; Tumor Suppressor Protein p53

With the advancement of targeted therapies, epidermal growth factor receptor tyrosine kinase inhibitors have become the preferred initial treatment for patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is effective against exon 19 and 21 mutations as well as the T790M mutation. It has been approved by both the food and drug administration and European Medicines Agency for the treatment of non-small cell lung cancer patients with locally advanced or metastatic EGFR-mutated tumors, including those who have acquired T790M mutations.. To evaluate the effectiveness of osimertinib in treating patients with EGFR-mutated advanced lung adenocarcinoma and bone metastases, we present the treatment outcomes of 3 patients with EGFR 19 deletion-mutated advanced lung adenocarcinoma and bone metastases who received osimertinib treatment in recent years. All 3 cases involved elderly female patients, aged 62, 62, and 54, respectively.. All 3 cases exhibited a diagnosis of pulmonary adenocarcinoma accompanied by osseous metastases, with genetic testing revealing the presence of an EGFR 19del mutation.. In the first case, following 17 months of gefitinib therapy, disease progression prompted a switch to osimertinib treatment. In the second case, bone metastases were detected after 20 months of pemetrexed-carboplatin chemotherapy, leading to a transition to osimertinib therapy. In the third case, after 11 months of erlotinib treatment, bone metastases were identified. Subsequent interventions, including radiation therapy, pemetrexed-carboplatin chemotherapy, pemetrexed-bevacizumab maintenance therapy, and docetaxel chemotherapy, failed to arrest the progression of bone metastases. As a result, a combination of osimertinib and anlotinib targeted therapy was administered.. All 3 patients experienced relatively good and favorable survival outcomes, with a progression-free survival of 22.7 months, 12 months, and 17.7 months, respectively.. These cases suggest that osimertinib is a promising treatment option for patients with EGFR 19 deletion-mutated lung adenocarcinoma and bone metastases, although further clinical studies are needed to confirm its efficacy.

Topics: Adenocarcinoma of Lung; Aged; Bone Neoplasms; Carboplatin; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Pemetrexed; Protein Kinase Inhibitors; Tyrosine Kinase Inhibitors; United States

Comprehensive next-generation sequencing panels are leading to detection of rare gene fusion events. EFGR-RAD51 fusion is a rare oncogenic finding and clinical data for management of this condition is scarce. We report a widely metastatic non-small cell lung cancer in a never-smoker young male patient with sustained near-complete systemic and intracranial response to osimertinib, a third-generation EGFR tyrosine-kinase inhibitor (TKI). We also review the available data of other TKIs in this scenario and underscore the role of comprehensive molecular testing for NSCLC.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Gene Fusion; Humans; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors; Rad51 Recombinase

Osimertinib, as a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), targeting EGFR exon 19 deletions, L858R, and T790M, has shown robust clinical efficacy and promising survival advantages in a subset of non-small cell lung cancer (NSCLC) patients. However, osimertinib-treated patients ultimately develop secondary resistance. Besides EGFR C797S mutation and EGFR amplification, a rare EGFR mutation, L718V, has been reported to confer osimertinib resistance in the literature, which is developed in about 8.0% of osimertinib-resistant NSCLC patients. Although the National Comprehensive Cancer Network or Chinese Society of Clinical Oncology NSCLC guidelines recommend radiotherapy, anti-angiogenesis therapy, chemotherapy and or immunotherapy for the treatment of NSCLC patients who acquire resistance to osimertinib, the feasible treatment options for patients harboring EGFR L718V remain elusive. There is an unmet need to develop effective strategies to treat EGFR L718X-positive NSCLC patients. Herein, we report that a lung adenocarcinoma patient with acquired EGFR L718V mutation-mediated resistance towards osimertinib derived durable response to the second-generation EGFR-TKI afatinib with a progression-free survival of 18 months and counting. Our work provides clinical evidence to administer afatinib in metastatic NSCLC patients who develop EGFR L718V at progression to osimertinib and paves the way for its potential clinical utilization.

Topics: Acrylamides; Adenocarcinoma of Lung; Afatinib; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Multiple ground-glass nodules (mGGNs) in the lung has been defined as synchronous multiple primary lung cancer (SMPLC), it is has been very difficult challenging to differentiate SMPLC from intrapulmonary metastases, and its treatment remains controversial.. We report a case simultaneously involving mGGNs and lung adenocarcinoma harboring primary EGFR-T790M mutation, in which the patient underwent the radical resection of lesions in the left upper lung, and continued the osimertinib treatment for the residual mGGNs in all lobes of the right lung. These mGGNs displayed different responses to osimertinib.. We reported a successful strategy on the postoperative treatment for mGGNs. For those that cannot be completely resected, the chemotherapy, radiotherapy, stereotactic body radiation therapy, immunotherapy and targeted therapy have been performed instead. The EGFR-TKI therapy strategy showed significant advantages, but how to achieve even better therapeutic effect needs more researches.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Pneumonectomy; Protein Kinase Inhibitors

The occurrence of ureteral metastasis from distant primary tumors is uncommon, and appears to be especially rare when it originates from the lungs. In the case presented here, a patient with lumbago and left hydronephrosis was diagnosed with left ureteral metastasis of pulmonary adenocarcinoma after a CT-guided percutaneous transthoracic needle biopsy of the lung and retroperitoneal laparoscopic left nephroureterectomy. He accepted the targeted therapy because the lung tumor epidermal growth factor receptor mutation (exon19 deletion) was positive, and preoperative staging of lung adenocarcinoma was stage IVA. After an 8-month follow-up, he is still alive and well, with no local recurrence or distant metastases. The therapy outcome assessment is stable disease. Although rare, our case has demonstrated that pulmonary adenocarcinoma has the possibility of metastasizing to the ureter, a risk that should be considered in some lung cancer patients.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aniline Compounds; Humans; Lung Neoplasms; Male; Nephroureterectomy; Protein Kinase Inhibitors; Ureteral Neoplasms

Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib's growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility.. All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Animals; Azithromycin; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Chemotherapy, Adjuvant; Cyproheptadine; Drug Repositioning; Drug Resistance, Neoplasm; ErbB Receptors; Glioblastoma; Humans; Loratadine; Lung Neoplasms; Mice; Neoplasm Metastasis; Pyrimethamine; Spironolactone

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carbazoles; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Oncogene Proteins, Fusion; Piperidines; Prognosis

An increasing number of tyrosine kinase inhibitors (TKIs) are available for the treatment of non-small cell lung cancer (NSCLC). QT prolongation is one of the known, but relatively rare, adverse events of several TKIs (e.g. osimertinib, crizotinib, ceritinib). Screening for QT prolongation in (high risk) patients is advised for these TKIs. When a QT prolongation develops, the physician is challenged with the question whether to (permanently) discontinue the TKI. In this perspective, we report on a patient who developed a grade III QT prolongation during osimertinib (a third-generation epidermal growth factor receptor [EGFR]-TKI) treatment. On discontinuation of osimertinib, she developed a symptomatic disease flare, not responding to subsequent systemic treatment. The main aim of this perspective is to describe the management of QT prolongation in stage IV EGFR driver mutation NSCLC patients. We also discuss the ethical question of how to weigh the risk of a disease flare due to therapy cessation against the risk of sudden cardiac death. A family history of sudden death and a prolonged QT interval might indicate a familiar long QT syndrome. We have summarised the current monitoring advice for TKIs used in the treatment of lung cancer and the most common drug-TKI interactions to consider and to optimise TKI treatment in lung cancer patients.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Clinical Decision-Making; Drug Monitoring; Electrocardiography; ErbB Receptors; Fatal Outcome; Female; Genetic Predisposition to Disease; Humans; Long QT Syndrome; Lung Neoplasms; Middle Aged; Mutation; Neoplasm Staging; Phenotype; Piperazines; Predictive Value of Tests; Protein Kinase Inhibitors; Risk Assessment; Risk Factors; Tomography, X-Ray Computed

Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been approved for EGFR-mutant non-small-cell lung cancer (NSCLC). We aimed to evaluate the efficacy and safety of neoadjuvant osimertinib in patients with EGFR-mutant resectable locally advanced NSCLC.. This single-arm, phase 2b trial (ChiCTR1800016948) was conducted at six centers in mainland China. Patients with a measurable stage IIA-IIIB (T3-4 N2) lung adenocarcinoma and EGFR exon 19 and/or 21 mutations were enrolled. The patients were treated with osimertinib 80 mg orally once per day for six weeks, followed by surgical resection. The primary endpoint was the objective response rate (ORR) assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1.. Between October 17, 2018, and June 08, 2021, 88 patients were screened for eligibility. Forty patients were enrolled and treated with neoadjuvant osimertinib therapy. The ORR was 71.1 % (27/38) (95 % confidence interval: 55.2-83.0) in 38 patients who completed the 6-week osimertinib treatment. Thirty-two patients underwent surgery, and 30 (93.8 %) underwent successful R0 resection. Thirty (75.0 %) of 40 patients had treatment-related adverse events during neoadjuvant treatment, and three (7.5 %) had treatment-related adverse events of grade 3. The most common treatment-related adverse events were rash (n = 20 [50 %]), diarrhea (n = 12 [30 %]), and oral ulceration (n = 12 [30 %]).. The third-generation EGFR TKI osimertinib, with satisfying efficacy and acceptable safety profile, could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Neoadjuvant Therapy; Protein Kinase Inhibitors

In non-small cell lung cancer patients with acquired resistance to first- or second-generation EGFR-TKIs, osimertinib is approved in the presence of the T790 M resistance mutation. We assessed the efficacy of osimertinib in both T790M-positive and T790M-negative patients.. The TREM-study is an investigator-initiated, multi-centre, single-arm, phase 2 clinical trial conducted in five Northern European countries. Patients with progression on at least one previous EGFR-TKI were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Patients were included regardless of the presence of T790 M. The primary endpoint was objective response rate (ORR).. Of 199 included patients, 120 (60 %) were T790M-positive, 52 (26 %) were T790M-negative and 27 (14 %) had unknown T790M-status. 24 % had brain metastases and 15 % had an ECOG performance status of 2. Overall ORR was 48 % (95 % CI, 41 %-55 %), 60 % (51 %-69 %) for T790M-positive patients and 28 % (15 %-41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001. Duration of response was similar between the T790M-positive and -negative groups (11.8 vs 10.7 months, p = 0.229). Overall median progression-free survival (PFS) was 8.9 months (95 % CI, 7.4-10.5), and 10.8 vs 5.1 months for T790M-positive vs -negative patients (HR 0.62, p = 0.007). Median overall survival (OS) was 17.9 months (95 % CI, 14.4-21.3). For T790M-positive vs -negative median OS was 22.5 vs 13.4 months, (HR 0.55, p = 0.002).. This study confirms the efficacy of osimertinib for T790M-positive patients. There was also clinically significant activity of osimertinib in a proportion of T790M-negative patients.. This trial is registered with ClinicalTrials.gov (NCT02504346).

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; ErbB Receptors; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Survival Rate

Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce.. To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib.. In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib.. Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number.. EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Afatinib; Aged; Aged, 80 and over; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Female; Follow-Up Studies; Humans; Liquid Biopsy; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Survival Rate

Osimertinib is a standard treatment for epidermal growth factor receptor (EGFR)-mutated, T790M-positive patients with progression during EGFR-tyrosine kinase inhibitor (TKI) therapy. Osimertinib, a third-generation EGFR-TKI, allows progression-free survival of around 10 months, but its toxicity is well-tolerated compared with other EGFR-TKIs. Preclinical and clinical evidence suggests that EGFR-TKI may work synergistically with vascular endothelial growth factor inhibitors. We therefore plan a phase I/II study to investigate this possibility. In phase I, the primary endpoint is assessment of the tolerability of osimertinib and bevacizumab in 6 patients. Phase II then explores the efficacy of combined treatment compared with osimertinib monotherapy with progression-free survival as the primary endpoint. Secondary endpoints are overall response rate, time to treatment failure, overall survival, and safety. Eighty patients will be enrolled in phase II.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; ErbB Receptors; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Mutation; Prospective Studies; Protein Kinase Inhibitors; Survival Analysis; Young Adult

Osimertinib is a third-generation tyrosine kinase inhibitor for non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-sensitizing mutations and acquired drug-resistant mutation T790M. Despite promising treatment benefits of osimertinib in first- and second-line settings, drug resistance has been an inevitable clinical issue. The resistance to osimertinib is heterogeneous, which may involve EGFR-dependent and independent mechanisms as well as histological transformation from NSCLC to small cell lung cancer (SCLC). Current clinical studies of NSCLC were mainly focused on patients with EGFR-sensitizing mutations or acquired T790M mutation or both. The treatments and drug-resistant mechanisms in patients with de-novo T790M mutation remain undefined. Herein, we reported the presence of the less common de-novo EGFR T790M mutation in a stage IV NSCLC patient. The patient received osimertinib as first-line treatment and achieved durable progression-free survival (PFS) for 24 months. After osimertinib resistance, tumor biopsy indicated histologic transformation from NSCLC to SCLC. Given persistent presence of de-novo T790M mutation, osimertinib was used in combination with etoposide and cisplatin as second-line treatment and the patient achieved partial response with PFS of 7 months. Our study suggested that NSCLC patients with de-novo T790M mutation could also benefit from osimertinib and the SCLC transformation may be a potential resistance mechanism that could be targeted through the combination of targeted therapy and chemotherapy.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Small Cell Lung Carcinoma

Information on genetic alterations, notably EGFR mutations, is important for guiding non-small-cell lung cancer (NSCLC) treatment. Circulating tumor DNA (ctDNA) analysis represents a less invasive alternative to tissue biopsy for analyzing mutation status, but its clinical value may vary across disease stages.. To explore clinical correlates of ctDNA and tissue/plasma-based EGFR mutation (EGFRm) status across all NSCLC stages.. Ninety patients were analyzed, representing three cohorts: newly-diagnosed early-stage, advanced-stage, and recurrent NSCLC. Relationships among clinical/surgical parameters, ctDNA, EGFRm status, and survival outcomes were analyzed.. Plasma/tissue EGFRm concordance was lower in early-stage (58.6%) than in advanced-stage patients (87.5%). In early-stage patients, ctDNA levels were variable and not significantly associated with clinical/surgical parameters. In advanced-stage patients, time to EGFR-TKI treatment failure (TTF), but not overall survival (OS), was significantly longer in EGFRm-positive vs. EGFRm-negative patients. In patients with recurrent disease, 40% of plasma samples were EGFRT790M-positive at recurrence. In T790M-positive patients, we noted slight trends toward longer OS with vs. without osimertinib treatment and longer OS and TTF with second-line vs. later-line osimertinib.. Our results affirm the use of ctDNA testing in advanced-stage and recurrent NSCLC. Further studies on osimertinib as early-line therapy, clinical correlates and the utility of plasma-based testing in early-stage NSCLC are warranted.

Topics: Adenocarcinoma of Lung; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors

The landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinib in patients with resected EGFR-mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population.. We performed routine unbiased testing of all cases, regardless of TNM stage, with targeted next-generation sequencing on 486 lung adenocarcinoma cases between 01- January 2014 and 01 February 2020. Clinical and pathological data, including co-mutations and morphology, were collected. EGFR-mutated cases were compared to KRAS-mutated cases to investigate EGFR-specific characteristics.. In total, 53 of 486 lung adenocarcinomas (11%) harboured an EGFR mutation. In early stages (stage 0-IIIA), the prevalence was 13%, versus 9% in stage IIIB-IV. Nine out of 130 (7%) stage IB-IIIA patients fit the ADAURA criteria. Early stage cases harboured more L858R mutations (p = 0.02), fewer exon 20 insertions (p = 0.048), fewer TP53 co-mutations (p = 0.007), and were more frequently never smokers (p = 0.04) compared to late stage cases with EGFR mutations. The KRAS-mutated cases were distributed more evenly across TNM stages compared to the EGFR-mutated cases.. As (neo-)adjuvant targeted therapy regimes enter the field of lung cancer treatment, molecular analysis of early stage non-small cell lung cancer becomes relevant. Testing for EGFR mutations in early stage lung adenocarcinoma holds a substantial yield in our population, as our number needed to test ratio for adjuvant osimertinib was 14.4. The observed differences between early and late stage disease warrant further analysis to work towards better prognostic stratification and more personalised treatment.

Topics: Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Prevalence; Proto-Oncogene Proteins p21(ras)

Lung cancers bearing oncogenically-mutated EGFR represent a significant fraction of lung adenocarcinomas (LUADs) for which EGFR-targeting tyrosine kinase inhibitors (TKIs) provide a highly effective therapeutic approach. However, these lung cancers eventually acquire resistance and undergo progression within a characteristically broad treatment duration range. Our previous study of EGFR mutant lung cancer patient biopsies highlighted the positive association of a TKI-induced interferon γ transcriptional response with increased time to treatment progression. To test the hypothesis that host immunity contributes to the TKI response, we developed novel genetically-engineered mouse models of EGFR mutant lung cancer bearing exon 19 deletions (del19) or the L860R missense mutation. Both oncogenic EGFR mouse models developed multifocal LUADs from which transplantable cancer cell lines sensitive to the EGFR-specific TKIs, gefitinib and osimertinib, were derived. When propagated orthotopically in the left lungs of syngeneic C57BL/6 mice, deep and durable shrinkage of the cell line-derived tumors was observed in response to daily treatment with osimertinib. By contrast, orthotopic tumors propagated in immune deficient nu/nu or Rag1

Topics: Adaptive Immunity; Adenocarcinoma of Lung; Aniline Compounds; Animals; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Lung Neoplasms; Mice; Mice, Inbred C57BL; Mutation; Protein Kinase Inhibitors

Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance.. We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation.. Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%).. We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Prospective Studies; Protein Kinase Inhibitors

Topics: Adenocarcinoma of Lung; Aniline Compounds; ErbB Receptors; Exons; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Resistance to epidermal growth factor receptor (EGFR) inhibitors, from the first-generation erlotinib to the third generation osimertinib, is a clinical challenge in the treatment of patients with EGFR-mutant lung adenocarcinoma. Our previous work found that a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1), HKB99, restrains erlotinib resistance in lung adenocarcinoma cells. However, the role of HKB99 in osimertinib resistance and its underlying molecular mechanism remains to be elucidated. Herein, we found that IL-6/JAK2/STAT3 signaling pathway is aberrantly activated in both erlotinib and osimertinib resistant cells. Importantly, HKB99 significantly blocks the interaction of PGAM1 with JAK2 and STAT3 via the allosteric sites of PGAM1, which leads to inactivation of JAK2/STAT3 and thereby disrupts IL-6/JAK2/STAT3 signaling pathway. Consequently, HKB99 remarkably restores EGFR inhibitor sensitivity and exerts synergistic tumoricidal effect. Additionally, HKB99 alone or in combination with osimertinib down-regulated the level of p-STAT3 in xenograft tumor models. Collectively, this study identifies PGAM1 as a key regulator in IL-6/JAK2/STAT3 axis in the development of resistance to EGFR inhibitors, which could serve as a therapeutic target in lung adenocarcinoma with acquired resistance to EGFR inhibitors.

Topics: Adenocarcinoma of Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Interleukin-6; Janus Kinase 2; Lung Neoplasms; Mutation; Phosphoglycerate Mutase; Protein Kinase Inhibitors; Signal Transduction

Osimertinib (OSI), a third-generation tyrosine kinase inhibitor (TKI), efficiently benefits lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutations. However, combined OSI and immune checkpoint inhibitor in EGFR-mutant patients increases the incidence of interstitial lung disease (ILD), although the mechanism is unknown. Here, we investigated the interaction between dendritic cells (DCs), a potential critical player in ILD, and OSI. Seventeen LUAD patients received TKI therapy, and only the OSI therapy group (N = 10) showed a significant increase in CD40 and CD83 on immature DCs (iDCs), and an elevated trend for both markers on mature DCs (mDCs) during short- and long-term OSI therapy. Our results indicated that OSI therapy may potentially activate DC functions, which might increase the potential immune toxicity when combined with onco-immunotherapy.

Topics: Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Dendritic Cells; ErbB Receptors; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Although uncommon epidermal growth factor receptor (EGFR) mutations account for 10-15% EGFR mutant non-small cell lung cancer (NSCLC) patients, clinical evidence for uncommon EGFR mutations, such as complex mutations remain limited. In this study, we reported a NSCLC patient harboring complex EGFR L833V / H835L mutation in exon 21, who had a complete response to first-line osimertinib monotherapy. The patient admitted to our hospital for space-occupying lesions of right lower lung during an annual health checkup, and was diagnosed as stage IIIA lung adenocarcinoma. Targeted next-generation sequencing (NGS) on tumor samples showed a complex EGFR mutation: L833V / H835L in exon 21. Therefore, she was treated with osimertinib monotherapy and complete remission achieved soon. During follow-up period, no metastasis was found and serum carcinoembryonic antigen returned to normal. In addition, NGS monitoring of mutations in circulating tumor DNA maintained negative. The patient remain benefitted for osimertinib monotherapy over 22 months with no disease progression. Our case firstly provided clinical evidences of first-line osimertinib therapy in lung cancer patients with rare L833V / H835L EGFR mutation.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) that specifically target mutational points in the EGFR gene have significantly reduced suffering and provided greater relief to patients with lung adenocarcinoma (LUAD). The third-generation EGFR-TKI, Osimertinib, has been successfully employed in clinical treatments to overcome resistance to both original and acquired T790M and L858R mutational points. Nevertheless, the issue of treatment failure response has emerged as an insurmountable problem.. By employing a combination of multiple and integrated approaches, we successfully identified a distinct population within the tumor group that plays a significant role in carcinogenesis, resistance, and recurrence. Our research suggests that addressing TKI resistance may involve targeting the renewal and repopulation of stem-like cells. To investigate the underlying mechanisms, we conducted RNA Microarray and m6A Epi-Transcriptomic Microarray analyses, followed by assessment of transcription factors. Additionally, we specifically designed a tag to detect the polypeptide circRNA-AA, and its expression was confirmed through m6A regulations.. We initially identified unique molecular signatures present in cancer stem cells that contributed to poor therapeutic responses. Activation of the alternative Wnt pathway was found to sustain the renewal and resistant status of these cells. Through bioinformatics analysis and array studies, we observed a significant decrease in the expression of circFBXW7 in Osimertinib-resistant cell lines. Notably, the abnormal expression pattern of circFBXW7 determined the cellular response to Osimertinib. Functional investigations revealed that circFBXW7 inhibits the renewal of cancer stem cells and resensitizes both resistant LUAD cells and stem cells to Osimertinib. In terms of the underlying mechanism, we discovered that circFBXW7 can be translated into short polypeptides known as circFBXW7-185AA. These polypeptides interact with β-catenin in an m6A-dependent manner. This interaction leads to reduced stability of β-catenin by inducing subsequent ubiquitination, thereby suppressing the activation of canonical Wnt signaling. Additionally, we predicted that the m6A reader, YTHDF3, shares common binding sites with hsa-Let-7d-5p. Enforced expression of Let-7d post-transcriptionally decreases the levels of YTHDF3. The repression of Let-7d by Wnt signaling releases the stimulation of m6A modification by YTHDF3, promoting the translation of circFBXW7-185AA. This creates a positive feedback loop contributing to the cascade of cancer initiation and promotion.. Our bench study, in vivo experiments, and clinical validation have unequivocally shown that circFBXW7 effectively inhibits the abilities of LUAD stem cells and reverses resistance to TKIs by modulating Wnt pathway functions through the action of circFBXW7-185AA on β-catenin ubiquitination and inhibition. The regulatory role of circRNA in Osimertinib treatment has been rarely reported, and our findings reveal that this process operates under the influence of m6A modification. These results highlight the tremendous potential of this approach in enhancing therapeutic strategies and overcoming resistance to multiple TKI treatments.

Topics: Adenocarcinoma of Lung; beta Catenin; ErbB Receptors; F-Box-WD Repeat-Containing Protein 7; Humans; Lung Neoplasms; Mutation; RNA, Circular; Tyrosine Kinase Inhibitors; Wnt Signaling Pathway

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-targeted therapy has emerged as a viable treatment for patients with advanced non-small cell lung cancer with common EGFR mutations. The uncommon G719X and S768I mutations can co-occur as complex mutations in the same tumor. Here we report a case of a 72-year-old male patient with double lung carcinoma, with G719X and S768I complex mutations detected in the right upper lung lobe along with brain metastases. Osimertinib (80 mg/day) was administered as the first-line treatment, and a reduction in the right lobe tumor and brain lesions was achieved. However, the left upper lung lobe mass remained unchanged; histopathological examination via a lobectomy revealed pleomorphic carcinoma. Thus, the patient was diagnosed with multiple primary lung cancers. In conclusion, osimertinib is a viable treatment option for lung cancer with rare EGFR G719X and S768I complex mutations.

Topics: Adenocarcinoma of Lung; Aged; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors

Although the use of osimertinib can significantly improve the survival time of lung adenocarcinoma (LUAD) patients with epithelial growth factor receptor mutation, eventually drug resistance will limit the survival benefit of most patients. This study aimed to develop a novel prognostic predictive signature based on genes associated with osimertinib resistance.. The differentially expressed genes (DEGs) associated with osimertinib resistance in LUAD were screened from Gene Expression Omnibus datasets and The Cancer Genome Atlas datasets. Multivariate cox regression was used to establish a prognostic signature, and then a nomogram was developed to predict the survival probability of LUAD patients. We used ROC curve and DCA curve to evaluate its clinical prediction accuracy and net benefit. In addition, the differentially expressed genes significantly associated with prognosis were selected for immune infiltration analysis and drug sensitivity analysis, and their roles in the progression of lung adenocarcinoma were verified by in vitro experiments.. Our evaluation results indicated that the new nomogram had higher clinical prediction accuracy and net benefit value than the TN nomogram. Further analysis showed that patients with low STRIP2 expression had a higher level of immune response, and may be more likely to benefit from immune checkpoint inhibitors and conventional antitumor drugs. This may help to select more precise and appropriate therapy for LUAD patients with osimertinib resistance. Furthermore, in vitro experiments showed that STRIP2 promoted the LUAD cells proliferation, migration and invasion. This further demonstrates the importance of this gene signature for prognostic prediction.. We developed a reliable prognostic model based on DEGs associated with osimertinib resistance and screened for biomarker that can predict the immune response in LUAD patients, which may help in the selection of treatment regimens after osimertinib resistance.

Topics: Acrylamides; Adenocarcinoma of Lung; Humans; Lung Neoplasms; Prognosis

Gastric metastasis of lung cancer is rare, and the cases of disappearance of gastric metastasis and liver metastasis caused by oxitinib treatment have not been reported.. A 47-year-old male patient with no history of diabetes, hypertension or smoking presented with chest discomfort after eating. At the time of consultation, the diagnosis of adenocarcinoma of the right lower lobe of the lung with liver and gastric metastasis was considered by pathological examination of biopsy of the fundus of the stomach near the cardia, pathological examination of CT-guided lung aspiration and pathological examination of liver occupancy aspiration, combined with immunohistochemical results. He was found to have exon 19 deletion in next generation sequencing. We performed osimertinib on him (EGFR-TKI) systemic therapy, followed by local radiation therapy to the right lower lung primary lesion.. After systemic treatment with osimertinib and local radiotherapy of the primary site, the metastases disappeared and the primary site showed post-radiotherapy changes, and the evaluated efficacy was complete remission.. This is the first report to our knowledge of a patient who presented with gastric and hepatic metastases from lung cancer and achieved complete remission with osimertinib and local radiotherapy, with good quality of life, which also provides a basis for future clinical work and is of great significance.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aniline Compounds; ErbB Receptors; Humans; Liver Neoplasms; Lung; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Quality of Life; Stomach

CAGE, a cancer/testis antigen, was originally isolated from the sera of patients with gastric cancers. Previously, we have shown the role of CAGE in resistance to chemotherapy and target therapy. The aim of this study was to investigate the role of CAGE in osimertinib resistance and determine the prognostic value of CAGE in patients with pulmonary adenocarcinomas. The clinicopathological correlation with CAGE and autophagy flux in patients was examined using immunohistochemistry and in situ hybridization. The possible role of autophagy in osimertinib resistance was analyzed using immune blot, immune fluorescence staining and immunohistochemistry. This study found that immunohistochemical staining (IHC) showed CAGE expression in more than 50% of patients with pulmonary adenocarcinomas (pADCs). CAGE expression was increased in pADCs after the acquisition of EGFR-TKIs resistance. High expression of CAGE was correlated with shorter overall survival and progression free survival in patients with pADCs. Thus, CAGE mediates osimertinib resistance and predicts poor prognosis in patients with pADCs. Osimertinib-resistant non-small cell lung cancer cells (PC-9/OSI) were established and mechanistic studies of CAGE-mediated osimertinib resistance were performed. PC-9/OSI cells showed increased autophagic flux and CAGE expression compared with parental sensitive PC-9 cells. PC-9/OSI cells showed higher tumorigenic, metastatic, and angiogenic potential compared with parental PC-9 cells. CAGE CRISPR-Cas9 cell lines showed decreased autophagic flux, invasion, migration potential, and tumorigenic potential compared with PC-9/OSI cells in vitro and in vivo. CAGE plays a crucial role in the cancer progression by modulating autophagy and can predict the poor prognosis of patients with pulmonary adenocarcinomas. Our findings propose CAGE as a potential therapeutic target for developing anticancer drugs that can overcome osimertinib resistance.

Topics: Adenocarcinoma of Lung; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Testis

To evaluate the correlation between contrast-enhanced (CE) MRI and cerebrospinal fluid (CSF) cytology for the evaluation of leptomeningeal metastasis (LM) on MRI after targeted therapy with tyrosine kinase inhibitors.. We retrospectively reviewed the data of nonsmall cell lung cancer patients registered with NCT03257124 from May 2017 to December 2018, with progressive disease despite targeted therapy. Twenty-nine patients whose MRI scans exhibited LM at the time of registration were enrolled. During the targeted therapy with osimertinib, MRI scans, and subsequent CSF examinations were performed in every 2 months. In total, 113 MRI scans and CSF cytology data after treatment were collected. For each CE MRI scan, LM positivity was evaluated on 3D T1-weighted image (T1WI) and 2D FLAIR. The correlation between MRI and CSF cytology results and the diagnostic performance of MRI with CSF cytology as a reference standard were evaluated.. After treatment, MRI revealed positivity for LM in 81 and negativity in 32. CSF results were positive in 69 examinations and negative in 44. The diagnostic accuracy of CE 3D T1WI and 2D FLAIR was 0.52 and 0.46, respectively. After targeted therapy, discrepancy in the CSF and MRI results tended to increase over time. The proportions of concordant MRI and CSF cytology results after targeted therapy were 66%, 58%, 62%, and 47% at the first, second, third, and fourth follow-up, respectively.. The discrepancy of MRI in evaluation of LM and CSF cytology increases over time after targeted therapy with osimertinib. LM positivity on MRI could be a surrogate imaging marker in the pre- and immediate posttargeted-treatment with Osimertinib but not after sessions of osimertinib.

Topics: Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Meningeal Carcinomatosis; Retrospective Studies; Tyrosine Kinase Inhibitors

Osimertinib is currently used as a first-line treatment for EGFR-mutated non-small cell lung cancer, and the emergence of drug resistance poses a substantial challenge. Liquid biopsy with a multi-gene panel can examine both the molecular mechanisms and possibility of early resistance diagnosis.. We used a molecular barcode library construction kit (Archer. Plasma DNA concentration was not associated with the presence or absence of resistance to osimertinib. The pathological mutations detected using next-generation sequencing in the resistant specimens were in MAP2K1, PIK3CA, TP53, BRAF, and EGFR. Among the recurrent cases, EGFR mutations identified at the initial diagnosis were detected within 6 months before relapse confirmation in four cases (average 88 days). Many of the recurrent cases without detection of known EGFR mutations in the liquid biopsy showed a longer interval between the detection of relapse and the last blood draw for the liquid biopsy (average 255 days).. Frequent liquid biopsies are useful for identifying known EGFR mutations as markers for early detection of relapse. Several cancer driver mutations were observed, suggesting a variety of mechanisms of resistance in first-line osimertinib-treated lung adenocarcinoma.

Topics: Adenocarcinoma of Lung; Carcinoma, Non-Small-Cell Lung; Cell-Free Nucleic Acids; ErbB Receptors; Humans; Liquid Biopsy; Lung Neoplasms; Neoplasm Recurrence, Local; Recurrence

A 76-year-old man was referred to our hospital with a cough. Chest computed tomography (CT) revealed a 45-mm mass in the lingular segment of the left upper lobe. Transbronchial tumor biopsies showed adenocarcinoma. Contrast-enhanced CT and bone scintigraphy revealed lung, pleura, and bone metastases. The patient was diagnosed with left upper lobe adenocarcinoma cT2bN3M1c stage IVB. A genetic analysis of the primary tumor using the Oncomine Dx Target Test Multi-CDx system revealed positivity for epidermal growth factor receptor (EGFR) (L858R) and CTNNB1 mutations. Based on these findings, the patient was treated with osimertinib (80 mg/day) as first-line therapy. Six months later, the tumor increased in size, indicating progressive disease. Osimertinib was stopped and second-line therapy with carboplatin (area under the curve 5) and pemetrexed (500 mg/m2) was initiated. After three cycles of chemotherapy, the patient developed dementia and disorientation. Contrast-enhanced magnetic resonance imaging of the head showed miliary brain metastases. Miliary dissemination is a rare form of brain metastasis. Miliary patterns of lung metastases have been strongly associated with the EGFR exon 19 deletion. The radiological features of miliary brain metastases of non-small cell lung cancer with the exon 19 deletion have been reported. To the best of our knowledge, this is the first case report of lung cancer with miliary brain metastases and co-mutations of EGFR (L858R) and CTNNB1. In conclusion, co-mutations of EGFR (L858R) and CTNNB1 and the discontinuation of EGFR-tyrosine kinase inhibitor may contribute to the development of miliary brain metastases. Further case studies are warranted.

Topics: Adenocarcinoma; Adenocarcinoma of Lung; Aged; beta Catenin; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Male; Mutation

Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) for lung adenocarcinoma (LUAD) harboring activating mutations, but patients ultimately develop acquired resistance. Circular RNAs are involved in EGFR-TKI resistance, while the role of hsa_circ_0005576 in the osimertinib resistance of LUAD remains unknown. In this study, we demonstrated that hsa_circ_0005576 could facilitate osimertinib-resistant LUAD cells. Briefly, knockdown of hsa_circ_0005576 not only suppressed the proliferation and promoted the apoptosis of resistant LUAD cells, but also increased their sensitivity to osimertinib. Mechanistically, hsa_circ_0005576, serving as an miRNA sponge, could directly interact with miR-512-5p and subsequently upregulate the miR-512-5p-targeted insulin-like growth factor 1 receptor. Rescue assays indicated that miR-512-5p inhibition could reverse the effects of hsa_circ_0005576 knockdown in LUAD cells resistant to osimertinib. Overall, our study revealed that hsa_circ_0005576 regulates proliferation and apoptosis through miR-512-5p/IGF1R signaling, which contributes further to the resistance of LUAD cells to osimertinib. In addition, this study provides a novel insight into the mechanisms underlying osimertinib resistance of LUAD.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Animals; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Mice; MicroRNAs; Neoplasm Transplantation; Receptor, IGF Type 1; RNA, Circular; Up-Regulation

The echinoderm microtubule associated protein-like 4 gene (EML4) encodes the predominant anaplastic lymphoma kinase (ALK) fusion partner in non-small-cell lung cancer (NSCLC); however, the dynactin subunit 1 (DCTN1)-ALK rearrangement is extremely rare. The co-occurrence of primary epidermal growth factor receptor (EGFR) T790M mutation with EGFR exon 19 deletion (del) in patients with NSCLC is uncommon. Here we report a female lung adenocarcinoma patient with brain metastases and possible coexistence of primary EGFR T790M mutation/EGFR exon 19 del/DCTN1-ALK translocation. The patient received multiline treatment including chemotherapy, antivascular, and targeted therapies. To overcome developed resistance to chemotherapy or targeted therapy to prolong overall survival, the patient's circulating tumor DNA (ctDNA) was dynamically monitored. The patient responded to successive osimertinib and alectinib treatment, and alectinib achieved a nearly complete response for lung and brain lesions after she acquired osimertinib resistance. Furthermore, we summarize 22 published cases of patients with lung adenocarcinoma with concurrent EGFR mutation and ALK rearrangement, including details of clinical characteristics, natural history, and pertinent therapy of this uncommon tumor subtype. This literature review shows that EGFR inhibition was an indispensable aspect of the treatment of patients with EGFR/ALK co-alterations in the pre-alectinib era and that ALK inhibition with crizotinib did not show more eye-catching therapeutic results. Considering the effectiveness achieved by alectinib, this case study provides a new perspective for the treatment of lung cancer brain metastasis patients with concurrent EGFR/ALK mutations.

Topics: Acrylamides; Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Aniline Compounds; Brain; Carbazoles; Carcinoma, Non-Small-Cell Lung; Dynactin Complex; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Piperidines; Protein Kinase Inhibitors

Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) used for the treatment of non-small cell lung cancer (NSCLC) presenting an EGFR mutation. Although Osimertinib has a better safety profile compared to older EGFR-TKIs and although adverse events (AEs) are described in literature, recently the relationship between Osimertinib therapy and cardiotoxicity is gaining attention.. A 79-years old woman, with a history of lung adenocarcinoma on treatment with Osimertinib since 2019, was recovered in our department because of acute respiratory failure and acute heart failure with QT prolongation. The patient's history included hypertension, type 2 diabetes, breast carcinoma, Tuberculosis.. The patient discontinued Osimertinib therapy and we treated her with diuretics, ß-blocker, and oxygen. After an initial improvement, the heart failure worsened further, and the therapy had to be increased. We ruled out other respiratory causes of heart failure and cardiological causes of QT prolongation. After stable clinical improvement, the patient underwent coronary artery disease which was negative. Therefore, the most likely cause of acute heart disease was Osimertinib therapy.. This is a rare case of concomitant QT prolongation and congestive heart failure induced by Osimertinib therapy. The cause of cardiotoxicity probably depends on factors related to the action of the drug and patient specific factors. The cardiotoxic risk in these patients seems underestimated and cardiotoxicity induced by new anticancer treatments is increasing in importance. Cardiac monitoring is recommended in neoplastic patients receiving Osimertinib therapy with cardiological risk factors.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Cardiotoxicity; Diabetes Mellitus, Type 2; ErbB Receptors; Female; Heart Failure; Humans; Long QT Syndrome; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Osimertinib is the standard treatment for non-small cell lung cancer (NSCLC) with an active epidermal growth factor receptor (EGFR) mutation and a T790M mutation-present in cases of acquired resistance. However, there have been no reports on the efficacy of osimertinib in patients with EGFR G719S and de novo T790M mutations. Here, we present the case of a 71-year-old woman who received first-line osimertinib for lung adenocarcinoma with G719S and de novo T790M mutations. A partial response was observed after osimertinib initiation; however, the disease progressed 5 months after. Next-generation sequencing using a rebiopsy sample from the brain metastases revealed no newly acquired resistance mutations, including EGFR C797S. From experience, the efficacy of osimertinib in NSCLC with G719S and T790M compound mutations may be poor. Therefore, optimal treatment for these cases should be determined.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

Asian patients with metastatic non-small cell lung cancer (NSCLC) have a higher prevalence of epidermal growth factor receptor (EGFR) mutations compared to Caucasians, 30-50% and 15%, respectively. Osimertinib is a tyrosine kinase inhibitor approved as first-line therapy in patients with metastatic NSCLC harboring exon 19 or exon 21 EGFR mutations.. We report a 68-year-old treatment-naïve Asian male patient with metastatic NSCLC harboring an exon 19 deletion mutation of EGFR treated with osimertinib. The patient developed an osimertinib-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after approximately two months of therapy. Following fluid restriction and osimertinib discontinuation, the hyponatremia improved significantly within one week. The patient was started on second-line erlotinib without any signs of hyponatremia after treatment initiation.. There is a lack of published data from randomized prospective clinical trials of osimertinib-induced SIADH in metastatic NSCLC. Further studies to evaluate the potential underlying mechanisms are warranted.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Hyponatremia; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Mutation; Oncogenes; Prospective Studies; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Small Cell; Humans; Indoles; Lung Neoplasms; Pleural Effusion; Pleural Effusion, Malignant; Pyrimidines

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor (EGFR) mutations are the most common accurate gene targets. However, the lack of case reports or cohort studies on the exceptionally rare mutations limit the acquisition of deeper insights.. A 76-year-old female nonsmoker presented to our hospital with a one-week disease history of cough accompanied by shortness of breath.. Contrast-enhanced CT scan showed right pleural effusion with scattered inflammation and consolidation in the right upper lung. Tumor marker display showed obvious increased. Histopathology of the pulmonary mass combined with Immunohistochemical staining indicated lung adenocarcinoma. Contrast-enhanced magnetic resonance imaging suggested brain metastases. ECT scan showed bone metastasis. The patient was thus diagnosed as right lung adenocarcinoma of stage IV (cT3N3M1c). Next generation sequencing was performed to profile the mutation status of known oncogenic driver mutations, and only EGFR-D761Y in exon 19 (allelic frequency, AF: 0.53%) mutation was found.. The patient was accordingly treated with the third generation EGFR-Epidermal growth factor receptor tyrosine kinase inhibitor (TKI) Osimertinib (80 mg, qd). Accompanied with whole brain radiotherapy (DT3000c Gy/10f) for brain metastases, technetium methylene diphosphonate injection was performed for bone metastases.. The efficacy of the first-line Osimertinib treatment for 1 month was assessed as PR per RECIST version 1.1. The NSCLC patient harboring EGFR-D761Y mutation detected prior to the EGFR L858R mutation was benefited from the third-generation EGFR-TKI Osimertinib and had a worse prognosis than with other EGFR mutations according to data from previous case reports.. This case reported a NSCLC patient with de novo mutation of EGFR-D761Y responding to third generation TKI Osimertinib.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Indoles; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrimidines

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Indoles; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyrimidines

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have significantly improved response in all stages of patients with EGFR positive mutations in nonsmall cell lung cancer. However, the primary resistance mechanism of EGFR-TKIs has not been thoroughly revealed. Here, we described a case of a 64-year-old male with lung adenocarcinoma presented primary resistance on osimertinib combined with bevacizumab and platinum-based chemotherapy, next-generation sequencing revealed EGFR exon 21 L858R mutation and MET gene amplification. Afterward, savolitinib monotherapy was started until now, and the treatment was temporarily successful, the last follow-up clinical evaluation was near complete response, the progression-free survival has over 7 months. Our case highlights that EGFR-TKIs may be not the optimal choice for lung adenocarcinoma with primary EGFR -sensitive mutation with MET amplification simultaneously, whereas MET inhibitor alone may be an effective treatment option. In clinical practice, we should fully consider the possibility of primary resistance in EGFR-TKIs administration.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Bevacizumab; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Indoles; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Pyrazines; Pyrimidines; Triazines

Studies of targeted therapy resistance in lung cancer have primarily focused on single-gene alterations. Based on prior work implicating apolipoprotein b mRNA-editing enzyme, catalytic polypeptide-like (APOBEC) mutagenesis in histological transformation of epidermal growth factor receptor (EGFR)-mutant lung cancers, we hypothesized that mutational signature analysis may help elucidate acquired resistance to targeted therapies.. APOBEC mutational signatures derived from an Food and Drug Administration-cleared multigene panel [Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)] using the Signature Multivariate Analysis (SigMA) algorithm were validated against the gold standard of mutational signatures derived from whole-exome sequencing. Mutational signatures were decomposed in 3276 unique lung adenocarcinomas (LUADs), including 93 paired osimertinib-naïve and -resistant EGFR-mutant tumors. Associations between APOBEC and mechanisms of resistance to osimertinib were investigated. Whole-genome sequencing was carried out on available EGFR-mutant lung cancer samples (10 paired, 17 unpaired) to investigate large-scale genomic alterations potentially contributing to osimertinib resistance.. APOBEC mutational signatures were more frequent in receptor tyrosine kinase (RTK)-driven lung cancers (EGFR, ALK, RET, and ROS1; 25%) compared to LUADs at large (20%, P < 0.001); across all subtypes, APOBEC mutational signatures were enriched in subclonal mutations (P < 0.001). In EGFR-mutant lung cancers, osimertinib-resistant samples more frequently displayed an APOBEC-dominant mutational signature compared to osimertinib-naïve samples (28% versus 14%, P = 0.03). Specifically, mutations detected in osimertinib-resistant tumors but not in pre-treatment samples significantly more frequently displayed an APOBEC-dominant mutational signature (44% versus 23%, P < 0.001). EGFR-mutant samples with APOBEC-dominant signatures had enrichment of large-scale genomic rearrangements (P = 0.01) and kataegis (P = 0.03) in areas of APOBEC mutagenesis.. APOBEC mutational signatures are frequent in RTK-driven LUADs and increase under the selective pressure of osimertinib in EGFR-mutant lung cancer. APOBEC mutational signature enrichment in subclonal mutations, private mutations acquired after osimertinib treatment, and areas of large-scale genomic rearrangements highlights a potentially fundamental role for APOBEC mutagenesis in the development of resistance to targeted therapies, which may be potentially exploited to overcome such resistance.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Chromothripsis; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Mutagenesis; Mutation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; ErbB Receptors; Humans; Indoles; Lung Neoplasms; Pyrazines; Pyrimidines; Triazines

Epidermal growth factor receptor (EGFR) T854A mutation in exon 21 is an uncommon EGFR mutation in patients with non-small cell lung cancer (NSCLC). It is a secondary EGFR mutation after first- and second-generation EGFR tyrosine kinase inhibitors (TKIs). All EGFR T854A mutations were co-occurred with EGFR L858R mutation in cis. There is still no clear evidence to guide the therapeutic options for patients with both EGFR T790M and T854A mutations.. A 60-year-old Chinese woman with no smoking history presented with a maximum diameter of 32.9 mm mass located in the right lower lung lobe.. The patient was diagnosed with stage IVA lung adenocarcinoma with an exceptionally uncommon EGFR T854A mutation in exon 21 was detected concomitantly with EGFR T790M in blood by next-generation sequencing (NGS).. The patient was initially treated with first-line afatinib. After disease progression, osimertinib was administered.. Our patient exhibited a partial response (PR) to osimertinib with progression-free survival of nearly 8 months.. Our study indicates that patients with NSCLC who are positive for uncommon EGFR T854A and T790M mutations might benefit from treatment with osimertinib.

Topics: Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Protein Kinase Inhibitors

Recent studies prove that epidermal growth factor receptor (EGFR) inhibitors combined with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) are more effective than EGFR TKI monotherapy for treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC); however, the adverse effects associated with this treatment require further investigation. We report a case of fingerprint loss secondary to combination therapy using osimertinib (an EGFR TKI that targets mutated EGFR kinases) and anlotinib (a TKI that acts on multiple targets including mutated VEGFR kinases).. A 55-year-old man with stage IV lung adenocarcinoma and an EGFR L858R mutation received a 5-month course of platinum-based chemotherapy and icotinib. This regimen was subsequently switched to osimertinib plus anlotinib to achieve a better tumour response. This therapy led to fingerprint loss, which recovered following discontinuation of anlotinib treatment but subsequently recurred.. To our knowledge, this is the first report that describes fingerprint loss during combination therapy using osimertinib and anlotinib.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Dermatoglyphics; ErbB Receptors; Humans; Indoles; Lung Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Quinolines

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Crizotinib; ErbB Receptors; Erlotinib Hydrochloride; Female; Gefitinib; Humans; Intensive Care Units; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Noninvasive Ventilation; Oxygen Inhalation Therapy; Protein Kinase Inhibitors; Respiration, Artificial; Respiratory Insufficiency; Retrospective Studies; Survival Rate

EGFR mutation has been detected in more than half of non-small cell lung cancer (NSCLC) patients in Asia. Lung cancer is the main cause of malignant tumor-related death worldwide. Although distant metastases often occurs in patients with advanced NSCLC, uterine cervical metastasis is rare. Here, we report a case of EGFR-mutated lung adenocarcinoma with cervical metastasis. A 63-year-old female with known lung adenocarcinoma was found to have abnormal vaginal bleeding during osimertinib follow-up visits. Immunohistochemical (IHC) staining and next-generation sequencing (NGS) of the biopsy sample from the uterine cervical tumor confirmed metastatic dissemination from the primary lung malignancy. NGS assisted the diagnosis of uterine cervical metastasis from the primary lung. This is another major clinical application of NGS in addition to medication guidance and identification of drug resistance mechanisms.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Female; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Middle Aged; Sequence Analysis, DNA; Uterine Cervical Neoplasms

There was no standard treatment for patients who acquired resistance to osimertinib mediated by epidermal growth factor receptor (EGFR) T790M-cis-C797S. The aim of this study was to investigate the association between different therapeutic strategies and survival outcomes among these patients.. This retrospective cohort study analyzed 46 patients with metastatic lung adenocarcinoma and EGFR T790M-cis-C797S after osimertinib progression from January 1, 2017 to October 31, 2020. Among them, 13 patients received brigatinib-based therapy, 23 patients received chemotherapy in combination of anti-angiogenics or not, and 10 patients received other targeted treatments like dacomtinib, bevacizumab, or a combined therapy of osimertinib and other targeted drugs.. Compared to other targeted therapy, brigatinib-based therapy (median progression-free survival [mPFS]: 4.40 vs. 1.63 months, hazard ratio [HR] = 0.39, 95% confidence interval [CI]: 0.21-0.73, p = 0.001) and chemotherapy-based treatment (mPFS: 4.70 vs. 1.63 months, HR = 0.18, 95% CI: 0.06-0.50, p < 0.001) presented a better survival outcome and there was no significant difference between brigatinib-based therapy and chemotherapy-based treatment (mPFS: 4.40 vs. 4.70 months, HR = 1.24, 95% CI: 0.57-2.67, p = 0.58). Chemotherapy combined with anti-angiogenics achieved a better efficacy than only chemotherapy (mPFS: 5.50 vs. 1.03 months, HR = 0.30, 95% CI: 0.11-0.83, p = 0.02). Patients carrying EGFR exon 19 deletion mutation had a longer PFS than those who harboring EGFR exon 21 p.L858R mutation (4.57 vs. 1.03 months, HR = 0.18, 95% CI: 0.06-0.54, p = 0.001), no matter they received brigatinib-based therapy (mPFS: 5.00 vs. 3.23 months, HR = 0.19, 95% CI: 0.01-0.96, p = 0.05) or chemotherapy-based treatment (mPFS: 7.23 vs. 1.03 months, HR = 0.05, 95% CI 0.01-0.49, p < 0.001).. Brigatinib-based therapy and chemotherapy plus anti-angiogenics could be considered beyond progression from osimertinib therapy. For patients harboring EGFR exon 19 deletion/T790M/cis-C797S mutation, the clinical efficacy was superior to patients harboring EGFR exon 21 p.L858R/T790M/cis-C797S mutation.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Angiogenesis Inhibitors; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; China; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Organophosphorus Compounds; Pyrimidines; Retrospective Studies

To investigate the survival benefit with first/second generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and osimertinib in different treatment sequences.. We retrospectively screened 3807 patients diagnosed with cancer between 2013 and 2019 at Kaohsiung Chang Gung Memorial Hospital. In total, 76 patients with EGFR T790M mutation who received osimertinib after re-biopsy or liquid biopsy were enrolled for the analysis.. The median progression-free survival (PFS), median overall survival (OS), and median OS2 of the 76 patients were 11.93, 66.53, and 29.57 months, respectively. A significant difference was observed in the disease control rate between those who received osimertinib treatment after chemotherapy (group A) and those who received osimertinib immediately following EGFR-TKI therapy (group B) (34 [94.4%] vs. 31 [77.5%], p = 0.036). In addition, chronic obstructive pulmonary disease tended to be a poor prognostic factor for PFS and OS.. This real-world analysis revealed that previous chemotherapy could affect the treatment outcomes of patients with non-small cell lung cancer treated with osimertinib. Osimertinib treatment following first/second generation EGFR-TKI treatment or chemotherapy resulted in improved survival benefit.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Afatinib; Aged; Aged, 80 and over; Aniline Compounds; Drug Therapy; Erlotinib Hydrochloride; Female; Gefitinib; Genes, erbB-1; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies

Tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) are the standard treatment for lung cancer patients with activating EGFR mutation. The traditional direct polymerase chain reaction (PCR) has lower sensitivity in the detection of EGFR mutations in patient tissue samples. Whilst PCR amplification kits increase the sensitivity in detecting some types of EGFR mutations, not many types of rare mutations are found. Here, we report a patient who had lung adenocarcinoma harboring EGFR T751_I759delinsS mutation and had good response to afatinib initially and osimertinib after developing resistance to afatinib. This rare EGFR mutation was not detected by Scorpion and ARMS method but was found using the next-generation sequencing method. There are less prospective trials in the treatment of lung adenocarcinoma with very rare EGFR mutations. Our case report could therefore provide clinical experience to the clinicians in the management of their patients.

Topics: Acrylamides; Adenocarcinoma of Lung; Afatinib; Aniline Compounds; Drug Therapy, Combination; ErbB Receptors; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors

Exon 18 mutations account for only 3.6% of EGFR mutations, and tumors with exon 18 mutations are often unresponsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We present a novel case of a lung adenocarcinoma with an exon 18 mutation resulting in a glycine to serine substitution at position 719 of the EGFR protein. The patient received osimertinib, a third generation EGFR-TKI, as the first-line treatment, but the disease progressed during treatment. Analysis of circulating free DNAs via next generation sequencing revealed TP53 mutations and EGFR and MET amplifications, as well as the exon 18 mutation. On the basis of these results, we administered afatinib, a second-generation TKI, and bevacizumab, a vascular endothelial growth factor inhibitor, as the second-line treatment. The patient's symptoms improved, and this treatment was continued for 12 months. This report suggests that afatinib plus bevacizumab can effectively treat osimertinib-refractory lung tumors with an exon 18 mutation.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Afatinib; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Drug Resistance, Neoplasm; ErbB Receptors; Exons; Humans; Lung Neoplasms; Male; Mutation

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Proto-Oncogene Proteins B-raf; Treatment Outcome; Vemurafenib

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aniline Compounds; Carcinoma, Squamous Cell; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Male; Mutation; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Carcinoma, Neuroendocrine; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Fusion; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Receptor, Notch2; Receptor, trkA

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Pyridines

Lung cancer and pulmonary infections can have similar clinical and radiographic manifestations. Treatment for the coexistence of epidermal growth factor receptor (EGFR)-mutant pulmonary adenocarcinoma and tuberculosis remains unclear.. We reported a case of EGFR-mutant lung adenocarcinoma (mimicking pulmonary infections) that coexisted with pulmonary tuberculosis during the course of the disease.. The patient was initially diagnosed with pneumonia-like pulmonary adenocarcinoma with EGFR exon 19 deletions based on computed tomography scan, fiberoptic bronchoscopy, pathology, and genetic analysis, and then coexistence with active tuberculosis (TB) was confirmed via laboratory examinations and TB-DNA polymerase chain reaction.. Antibiotics and gefitinib were administered initially. A combination of gefitinib and anti-TB treatment was then administered when active TB was confirmed, and osimertinib was then prescribed because the disease was progressive and EGFR T790 M mutation was detected.. The patient has survived with a stable disease status to date.. Exploring and ruling out differential diagnoses between pulmonary malignancies and infectious diseases is vital for treatment decisions and outcomes. The combined gefitinib-anti-TB regimen was safe, though it needed modification.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Anti-Bacterial Agents; Antineoplastic Agents; Antitubercular Agents; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Tuberculosis, Pulmonary

Here, we report a rare case involving a 66-year-old man with epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma and antisynthetase syndrome (ASS) treated with osimertinib. The patient presented with respiratory failure and bilateral pulmonary opacities; he was diagnosed with ASS accompanied by interstitial lung disease (ILD), consistent with paraneoplastic syndrome. After steroid pulse therapy, osimertinib was administered for lung adenocarcinoma without ILD exacerbation. Osimertinib could therefore be a treatment option for EGFR-mutant lung cancer with paraneoplastic ILD.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; ErbB Receptors; Humans; Lung Neoplasms; Male; Myositis

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Chemotherapy, Adjuvant; ErbB Receptors; Gene Expression Profiling; Humans; Lung Neoplasms; Molecular Targeted Therapy; Mutation; Pneumonectomy; Prognosis; Randomized Controlled Trials as Topic

In lung adenocarcinoma, oncogenic

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Animals; Antineoplastic Agents; Disease Models, Animal; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Mice

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Female; Humans; Receptor, Notch2; Receptor, trkA

It has been well reported that non-small-cell lung cancer (NSCLC) patients with single epithelial growth factor receptor (EGFR) activating mutation have high objective response rate when treated with EGFR-TKIs. However, due to rarity of cases, the response of patients with EGFR double or multiple mutations is not yet well understood. Patient-derived organoid technology has become to a powerful tool in cancer personalized medicine.. A 60-year-old nonsmoking female was admitted to hospital for lung cancer after Chest CT.. The patient had no obvious clinical symptoms. Postoperative pathology confirmed a stage I of NSCLC. An EGFR double mutation 19Del/L643V was detected in the sequence of patient's cancer specimen.. The patient was in good condition after surgical resection, with no sign of lung cancer recurrence. The patient has not yet started on targeted medicine.. A lung cancer organoid culture was established from the cancer tissue of the patient, which recapitulated the morphological and molecular characteristics of cancer tissue. The drug sensitivity test showed that the cancer organoids that retained original mutations were sensitive to anticancer agents osimertinib and gefitinib, while resistant to erlotinib and icotinib.. The uncommon EGFR double mutation exhibits distinctive sensitivities towards different target drugs of EGFR-TKIs. Our findings provide a better understanding of EGFR-TKIs' effects on patient-derived cancer organoids harboring uncommon EGFR double mutation(s).

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Middle Aged; Mutation; Pharmacogenomic Variants

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Humans; Lung Neoplasms; Mutation; Quinazolinones

Although osimertinib overcomes the T790M mutation acquired after traditional epidermal growth factor receptor (EGFR) gene tyrosine kinase inhibitor (TKI) treatment, resistance to osimertinib eventually occurs. We explored resistance mechanisms of second-line osimertinib and their clinical implications by comparing next-generation sequencing (NGS) results before and after resistance acquisition.. We enrolled 34 patients with advanced EGFR-mutant adenocarcinoma whose biopsied tumour tissues were subjected to targeted NGS at the time of progression on osimertinib. For comparison, NGS was also performed on archived tumour tissues from each patient excised before osimertinib initiation.. The tumours of three patients' were observed to have transformed to small-cell carcinoma and those of two patients to squamous cell carcinoma. Among the remaining 29 patients, T790M mutations were maintained in seven patients (24.1%), including four patients (13.8%) acquiring C797S mutations and one with MET amplification. Among the 22 patients (75.9%) with T790M loss, a variety of novel mutations were identified, including KRAS mutations, PIK3CA mutations, and RET fusion, but MET amplifications (n = 4, 18.2%) were most frequently identified variations. Progression-free survival (PFS) on osimertinib was shorter among patients with T790M loss than among those who maintained T790M (5.36 versus 13.81 months, p = 0.009), and MET-amplified patients were found to have much worse PFS among patients with T790M loss (2.10 versus 6.35 months, p = 0.01).. Loss of the T790M mutation was associated with early resistance to osimertinib, and this was exacerbated by MET amplification. Further work is needed to fully understand the implications of each resistance mechanism.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Female; Follow-Up Studies; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors; Survival Rate

A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear.. A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31.. Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect.. Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Protein Kinase Inhibitors; Receptor, IGF Type 1

Autophagy and glycolysis are associated with osimertinib resistance. The energy complement and dynamic balance between these two processes make it difficult to block the process of drug resistance; breaking the complementary relationship between them may effectively overcome drug resistance. However, the exact mechanisms and the key players for regulating autophagy and glycolysis remain unclear. In this study, we demonstrate that autophagy and glycolysis levels in osimertinib-resistant cells were markedly higher than parental cells, and a dynamic balance existed between them. Inhibition of the class III phosphoinositide 3-kinase vacuolar protein sorting 34 (VPS34) with 3-methyladenine or small interfering RNA can not only inhibit abnormally enhanced autophagy but also inhibit glycolysis by inhibiting the location of epidermal growth factor receptor (EGFR) and the expression of hexokinase II. By demonstrating that VPS34 is the key player controlling autophagy and glycolysis simultaneously, our study may provide a new strategy for overcoming osimertinib resistance for treatment of EGFR-mutant non-small cell lung cancer patients.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Apoptosis; Autophagy; Cell Proliferation; Class III Phosphatidylinositol 3-Kinases; Drug Resistance, Neoplasm; ErbB Receptors; Glycolysis; Humans; Lung Neoplasms; Mutation; Tumor Cells, Cultured

The EGFR-A763_Y764insFQEA is a unique mutation among EGFR exon 20 insertion mutations in that it is associated with sensitivity to conventional EGFR-tyrosine kinase inhibitors. This mutation, which was not initially covered by conventional reverse transcription polymerase chain reaction (RT-PCR) genotyping method, has only been detected in clinical practice when a next-generation sequencing (NGS)-based cancer panel is implemented. We present the case of a female patient with recurrent lung adenocarcinoma from a lung tumor resected 10 years earlier. Sequential single-gene investigations and the OncomineTM Comprehensive Assay (ver.3) analysis of the recurrent tumor did not reveal any targetable driver mutations. However, the second NGS analysis with the OncoGuideTM NCC oncopanel found the EGFR-A763_Y764insFQEA mutation after tumor progression with carcinomatous lymphangiomatosis and multiple brain metastases. Osimertinib treatment improved her condition immediately. The identical EGFR-A763_Y764insFQEA mutation was detected in the tumor resected 10 years earlier. Based on this common mutation the patient was diagnosed with late recurrence of lung cancer harboring the EGFR-A763_Y764insFQEA mutation. The OncoGuideTM NCC oncopanel covered whole exons of the EGFR gene and was able to detect this mutation. In the present clinical practice, the EGFR-A763_Y764insFQEA mutation is the only treatable mutation among EGFR Ex.20 insertion mutations. We need to understand the gene mutation profile identified by each panel and consider reexamining them for this mutation.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Base Sequence; Brain; ErbB Receptors; Exons; Female; Humans; Lung Neoplasms; Magnetic Resonance Imaging; Mutagenesis, Insertional; Mutation; Neoplasm Recurrence, Local; Thorax; Tomography, X-Ray Computed

To assess the clinical relevance of genome-wide somatic copy-number alterations (SCNAs) in plasma circulating tumor DNA (ctDNA) from advanced epidermal growth factor receptor (. We included 43 patients with advanced. SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 31 (32%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before the initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 81%,. Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach enables the comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aged, 80 and over; Aniline Compounds; Biomarkers, Pharmacological; Carcinoma, Non-Small-Cell Lung; Cell-Free Nucleic Acids; Circulating Tumor DNA; DNA Copy Number Variations; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Liquid Biopsy; Lung; Lung Neoplasms; Male; Middle Aged; Progression-Free Survival; Protein Kinase Inhibitors

(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Colorectal Neoplasms; DEAD-box RNA Helicases; Drug Resistance, Neoplasm; ErbB Receptors; Eukaryotic Initiation Factor-4A; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Inhibitory Concentration 50; Lung Neoplasms; Models, Biological; Mucin-1; Mutation; Protein Kinase Inhibitors; RNA, Long Noncoding; Signal Transduction

This study was designed to investigate the difference between brain metastases (BM) and non-brain metastases (non-BM) treated by osimertinib in advanced patients with an acquired EGFR T790M mutation after obtaining first-generation EGFR-TKI resistance.. A total number of 135 first-generation EGFR-TKI-resistant patients with an acquired EGFR T790M mutation were retrospectively analyzed. The patients were divided into BM and non-BM groups. According to the type of treatment (whether brain radiotherapy), the BM patients were divided into an osimertinib combined with brain radiotherapy group and an osimertinib without brain radiotherapy group. In addition, according to the type of BM (the sequence between BM and osimertinib), the BM patients were subdivided into an osimertinib after BM group (initial BM developed after obtaining first-generation EGFR-TKI resistance) and an osimertinib before BM group (first-generation EGFR-TKI resistance then osimertinib administration performed; initial BM was not developed until osimertinib resistance). The progression-free survival (PFS) and overall survival (OS) were evaluated. The primary endpoint was OS between BM and no-BM patients. The secondary endpoints were PFS of osimertinib, and OS between brain radiotherapy and non-brain radiotherapy patients.. A total of 135 patients were eligible and the median follow-up time of all patients was 50 months. The patients with BM (n = 54) had inferior OS than those without BM (n = 81) (45 months vs. 55 months, P = 0.004). And in BM group, the OS was longer in patients that received osimertinib combined with brain radiotherapy than in those without brain radiotherapy (53 months vs. 40 months, P = 0.014). In addition, the PFS was analysed according to whether developed BM after osimertinib resistance. The PFS of the patients that developed BM after acquiring osimertinib resistance was shorter than that without BM development, whether patients developed initial BM after first-generation EGFR-TKI resistance (7 months vs. 13 months, P = 0.003), or developed non-BM after first-generation EGFR-TKI resistance (13 months vs. 17 months, P < 0.001).. In advanced patients with an acquired EGFR T790M mutation after obtaining first-generation EGFR-TKI resistance, osimertinib may be more limited in its control in BM than in non-BM. Also, osimertinib combined with brain radiotherapy may improve the survival time of BM patients.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Cranial Irradiation; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Progression-Free Survival; Protein Kinase Inhibitors; Retrospective Studies; Time Factors

A 39-year-old female Chinese non-smoker was diagnosed with epidermal growth factor receptor mutation-positive lung adenocarcinoma with cerebral metastases and commenced erlotinib. After 5 weeks, she presented with a 3-day history of severe bilateral facial weakness (House-Brackmann grade V/VI) and hypogeusia consistent with bilateral facial nerve palsies. MRI demonstrated new, symmetrical contrast-enhancing foci at the expected location of the facial nerves, consistent with leptomeningeal progression. Erlotinib was ceased and osimertinib was commenced. Facial nerve motor and sensory function began to improve within 1 week and by 2 weeks had returned to near normal. Review at 2 and 6 months demonstrated normal facial nerve function and progressive resolution of the facial nerve lesions on MRI. While rare, leptomeningeal malignancy may present as simultaneous bilateral facial nerve palsies. Osimertinib has superior central nervous system penetration and in this case was associated with rapid and sustained clinical and radiographical resolution of the facial nerve lesions.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aniline Compounds; Facial Nerve; Female; Humans; Lung Neoplasms

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in patients with non-small-cell lung cancer (NSCLC) harboring EGFR mutations. However, due to acquired resistance to EGFR-TKIs, even patients on third-generation osimertinib have a poor prognosis. Resistance mechanisms are still not fully understood. Here, we demonstrate that the increased expression of MUSASHI-2 (MSI2), an RNA-binding protein, is a novel mechanism for resistance to EGFR-TKIs. We found that after a long-term exposure to gefitinib, the first-generation EGFR-TKI lung cancer cells harboring the EGFR-TKI-sensitive mutations became resistant to both gefitinib and osimertinib. Although other mutations in EGFR were not found, expression levels of Nanog, a stemness core protein, and activities of aldehyde dehydrogenase (ALDH) were increased, suggesting that cancer stem-like properties were increased. Transcriptome analysis revealed that MSI2 was among the stemness-related genes highly upregulated in EGFR-TKI-resistant cells. Knockdown of MSI2 reduced cancer stem-like properties, including the expression levels of Nanog, a core stemness factor. We demonstrated that knockdown of MSI2 restored sensitivity to osimertinib or gefitinib in EGFR-TKI-resistant cells to levels similar to those of parental cells in vitro. An RNA immunoprecipitation (RIP) assay revealed that antibodies against MSI2 were bound to Nanog mRNA, suggesting that MSI2 increases Nanog expression by binding to Nanog mRNA. Moreover, overexpression of MSI2 or Nanog conferred resistance to osimertinib or gefitinib in parental cells. Finally, MSI2 knockdown greatly increased the sensitivity to osimertinib in vivo. Collectively, our findings provide proof of principle that targeting the MSI2-Nanog axis in combination with EGFR-TKIs would effectively prevent the emergence of acquired resistance.

Topics: A549 Cells; Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Survival; Drug Resistance, Neoplasm; ErbB Receptors; Gefitinib; Gene Expression Profiling; Gene Knockdown Techniques; Humans; Lung Neoplasms; Mutation; Nanog Homeobox Protein; Protein Kinase Inhibitors; RNA-Binding Proteins; Transcriptome; Transfection; Up-Regulation

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.

Topics: A549 Cells; Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Cell Cycle; ErbB Receptors; Humans; Lung Neoplasms; Mutation; Neoplasm Proteins; Receptor, EphB4

Cancer evolution poses a central obstacle to cure, as resistant clones expand under therapeutic selection pressures. Genome sequencing of relapsed disease can nominate genomic alterations conferring resistance but sample collection lags behind, limiting therapeutic innovation. Genome-wide screens offer a complementary approach to chart the compendium of escape genotypes, anticipating clinical resistance. We report genome-wide open reading frame (ORF) resistance screens for first- and third-generation epidermal growth factor receptor (EGFR) inhibitors and a MEK inhibitor. Using serial sampling, dose gradients, and mathematical modeling, we generate genotype-fitness maps across therapeutic contexts and identify alterations that escape therapy. Our data expose varying dose-fitness relationship across genotypes, ranging from complete dose invariance to paradoxical dose dependency where fitness increases in higher doses. We predict fitness with combination therapy and compare these estimates to genome-wide fitness maps of drug combinations, identifying genotypes where combination therapy results in unexpected inferior effectiveness. These data are applied to nominate combination optimization strategies to forestall resistant disease.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Genetic Fitness; Genotype; Humans; Lung Neoplasms; MAP Kinase Signaling System; Mutation

EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor-resistant tumors, with EGFRT790M and EGFRC797S mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib or osimertinib, respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib-treated patients after disease progression.

Topics: Acrylamides; Adenocarcinoma of Lung; Amino Acid Substitution; Aniline Compounds; Animals; Drug Resistance, Neoplasm; ErbB Receptors; Gefitinib; Lung Neoplasms; Mice; Mice, Transgenic; Mutation, Missense; Neoplasm Proteins; Protein Kinase Inhibitors; STAT3 Transcription Factor; Transcription Factor HES-1

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Benzamides; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Mutation; Triazines

Epidermal growth factor receptor (EGFR) exon 20 insertions comprise 4-10 % of EGFR mutations in non-small cell lung cancer (NSCLC) and are associated with primary resistance to first and second generation EGFR tyrosine kinase inhibitors (TKIs). In vitro and preclinical animal studies have shown that osimertinib exerts antitumor activity against EGFR exon 20 mutation positive NSCLC. We report on a cohort of advanced stage NSCLC patients who harbor an EGFR exon 20 mutation and received osimertinib treatment.. Twenty-one patients were treated with osimertinib 80 or 160 mg once daily from April 2016 to June 2018, in four institutions in the Netherlands. Data were obtained retrospectively. Progression free survival (PFS), disease control rate (DCR), overall survival (OS) and objective response rate (ORR) were assessed using RECIST v1.1.. Thirteen patients received prior platinum-based chemotherapy, and three patients a first - or second generation EGFR TKI. We observed 1 partial response, 17 patients with stable disease and 3 with progressive disease as best response to osimertinib (ORR 5 %). Median PFS was 3.6 (95 % CI, 2.6-4.5) months. PFS did not differ for patients with co-occurring TP53 mutations (p = 0.937). The DCR at three months was 71 %. Median OS was 8.7 (95 % CI, 1.1-16.4) months.. Osimertinib has limited antitumor activity in patients with EGFR exon 20 mutated NSCLC, with an ORR of 5 %.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Exons; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Survival Rate

Osimertinib is recommended for T790M mutation-positive advanced non-small cell lung cancer (NSCLC) resistant to first- and second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). Recently, some reports exist on the real-world use of osimertinib; however, reports involving third/later-line use are few. Hence, this study was conducted to evaluate the efficacy and safety of osimertinib used in various treatment lines for T790M-positive NSCLC patients.. This retrospective, observational, multicenter study included T790M-positive advanced/recurrent NSCLC patients treated with osimertinib from May 2016 to March 2018. The clinical characteristics, efficacy, and adverse events were retrospectively investigated. The Kaplan-Meier method was used to analyze progression-free survival (PFS) and overall survival (OS). PFS-associated clinical characteristics were evaluated using the Cox proportional hazards model.. The objective response rate (ORR) and disease control rate (DCR) were 60.7% and 91.1%, respectively; the median PFS was 11.0 months. There were no significant differences in the median PFS for patients treated with osimertinib as second-line and third-/later-line (14.5 vs. 11.0 months respectively, P = 0.327). Analysis using the Cox proportional hazards model for clinical features affecting PFS also revealed no significant factors. Adverse events of grade ≥ 3 were reported in 15 patients (26.8%); the most common were anemia (n = 3) and cutaneous toxicity (n = 3). Grade 4 neutropenia was observed in one patient; any-grade pneumonitis was observed in six patients (10.7%), including one with grade 3 pneumonitis.. Osimertinib demonstrated efficacy even when administered as third-/later-line treatment to NSCLC patients. Osimertinib-related pneumonitis was observed more frequently than previously reported.. Significant findings of the study Osimertinib shows efficacy even as later-line treatment in T790M mutation-positive NSCLC patients previously treated with EGFR-TKIs. However, the incidence of ≥ grade 3 adverse events, especially pneumonitis, was higher than that previously reported by other studies. What this study adds Osimertinib was approved for previously EGFR-TKI-treated EGFR T790M-positive NSCLC. With the increasing frequency of its use as first-line treatment, this study provides valuable evidence for the efficacy and safety of osimertinib for previously EGFR-TKI-treated NSCLC.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Survival Rate

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) showing longer progression free survival and overall survival than other EGFR-TKI with an improvement in tolerability.. We report about an advanced lung adenocarcinoma patient with severe aplastic anemia during first line osimertinib.. Severe hematologic toxicity is extremely rare but possible with osimertinib and clinicians should be careful about changes in blood cell count during the use of it.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Anemia, Aplastic; Aniline Compounds; Antineoplastic Agents; Humans; Lung Neoplasms; Male; Prognosis

Topics: Acrylamides; Adenocarcinoma of Lung; Afatinib; Aged; Aniline Compounds; Antineoplastic Agents; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Prognosis

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Squamous Cell; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Protein Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) are first line treatment choices for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC). However, responses vary among patients, therefore good biomarkers predicting better responses are required. EGFR mutations are detected in the blood from patients as circulating tumour DNA (ctDNA). Studies have shown that clearing ctDNA during first line TKI treatment predicts outcomes for first and second generation TKI treatments. We aimed to investigate the effects on outcome measures of ctDNA clearing in subsequent treatment lines to treatment with the third generation TKI osimertinib.. In total, 225 patients were included in a prospective, multicentre study, where consecutive blood samples were monitored for EGFR mutations during systemic treatment lines, using the Cobas® EGFR mutation test v2. This study focused on EGFR mutations in ctDNA of 82 systemically pre-treated patients receiving osimertinib.. Clearing all EGFR mutations from the blood after osimertinib treatment, significantly predicted progression-free survival, objective response rates and disease control rates. Primary sensitising EGFR mutations were found in ctDNA in 70 % of patients, and were accompanied by the T790 M mutation in nearly two thirds of cases. The T790 M mutation was cleared in all cases, while the accompanying sensitising mutations did not necessarily clear. However, T790 M clearing without simultaneously clearing of the primary sensitising mutation did not predict clinical responses. Neither the detection of T790 M before osimertinib treatment, nor the presence of EGFR mutations at the time of osimertinib initiation predicted clinical outcomes.. The clearing of EGFR mutations in ctDNA after osimertinib treatment initiation in patients with advanced NSCLC is useful as a positive predictor of clinical outcome.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Circulating Tumor DNA; ErbB Receptors; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Prospective Studies; Survival Rate

Desmoglein-2 (DSG2), a member of the cadherin superfamily, has been implicated in cell-cell adhesion and tumorigenesis. Here, we demonstrate that high DSG2 expression in both lung adenocarcinoma (LUAD) cell lines and tissues is associated with poor prognosis in LUAD patients. Notably, DSG2 overexpression promoted cell proliferation and migration, and increased resistance to the EGFR tyrosine kinase inhibitor osimertinib, whereas DSG2 silencing could reverse these results. Moreover, direct interaction between DSG2 and EGFR in the cell membrane stimulated EGFR signaling to promote tumorigenesis, and loss of DSG2 resulted in EGFR translocation into the cytoplasm. In addition, DSG2 was required for EGFR binding to Src; consequently, DSG2 silencing inhibited tumor cell malignancy via suppression of the EGFR-Src-Rac1-PAK1 signaling pathway. Consistent with these findings, a nude mouse xenograft model using H1975 cells demonstrated that DSG2 promoted LUAD cell growth in vivo and increased osimertinib resistance. Collectively, these observations are the first to elucidate a unique role for DSG2 in the development and progression of lung adenocarcinoma via EGFR signaling.

Topics: A549 Cells; Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Animals; Antineoplastic Agents; Desmoglein 2; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Mice, Inbred BALB C; Mice, Nude; Middle Aged; p21-Activated Kinases; Phosphorylation; Protein Kinase Inhibitors; rac1 GTP-Binding Protein; Signal Transduction; src-Family Kinases; Xenograft Model Antitumor Assays

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Circulating Tumor DNA; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Prognosis

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Middle Aged; Mutation; Prognosis

Germline mutations of TP53 are responsible for Li-Fraumeni syndrome in its 60-80%. We found a novel germline mutation, TP53: c.997del:p.R333Vfs*12 (NM_000546.6, GRCh, 17:7670713..7670713). The proband is a 40-year-old female, who was suffered from osteosarcoma in her right forearm at her age of 11. She was also suffered from lung adenocarcinoma in her right upper lobe and bone metastasis in her right scapula at her age of 37. She was treated with gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) because of EGFR mutation (L747-S752 del). Her bone metastasis became resistant after 1-year treatment. Bone metastasis had an additional EGFR mutation (T790M). The secondary treatment with osimertinib, an another EGFR-TKI, can successfully control the tumors for over 2 years. This TP53 mutation (R333Vfs*12) was first found in lung adenocarcinomas. The therapeutic effect of osimertinib for this triple mutant lung adenocarcinoma is better than the previous report.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aniline Compounds; Bone Neoplasms; Female; Gefitinib; Germ-Line Mutation; Humans; Li-Fraumeni Syndrome; Lung Neoplasms; Male; Pedigree; Protein Kinase Inhibitors; Tumor Suppressor Protein p53

Epidermal growth factor receptor (EGFR) gene-mutated non-small cell lung cancer may initially respond to EGFR tyrosine kinase inhibitors (TKIs), but may subsequently become resistant; however, the resistance mechanisms remain unclear. We report a rare case of acquired resistance to osimertinib associated with transformation to small cell lung cancer (SCLC) with cis-C797S mutation. A man with recurrent lung adenocarcinoma harboring an

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Small Cell Lung Carcinoma

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Crizotinib; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Proto-Oncogene Proteins c-met

Drug-induced pneumonitis is rare, and can result in death. Here, we present a report of a patient with adenocarcinoma harboring EGFR exon 19 deletion mutation treated with osimertinib as first-line treatment. After six days of treatment, extremely early onset severe pneumonitis was diagnosed. Discontinuation of osimertinib as well as administration of corticosteroid, and retreatment with osimertinib were successful. This case report highlights that extremely early onset severe pneumonitis can occur after osimertinib administration, and retreatment of osimertinib may be a useful treatment option after resolution of pneumonitis.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Female; Humans; Lung Neoplasms; Middle Aged; Pneumonia

Osimertinib is a third-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has demonstrated efficacy in the treatment of EGFR-mutant non-small-cell lung cancer (NSCLC) in prospective clinical trials.. This retrospective analysis evaluated the outcomes of 32 pretreated patients with EGFR T790M mutation who received osimertinib in clinical practice at seven centers in Poland within the Expanded Drug Access Program. Osimertinib was used in the second line in 59% of patients and in later lines in 41%.. Objective response was attained in 16 patients (50%), and 12 subjects (38%) had stable disease. Median progression -free survival was 11.3 months in the overall population, 12.6 months in patients with EGFR exon 19 mutation and 7.5 months in patients with EGFR exon 21 mutation (p = 0.045). Median overall survival (OS) was 18.3 months. Overall, 58.4% and 45.6% of patients remained in follow-up after 12 and 24 months, respectively. Median OS appeared longer for patients without cerebral metastases than for those with cerebral metastases (27.4 vs 9.4 months, respectively; p = 0.078), and for patients with the Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 than those with ECOG PS 2 (27.4 vs 11.8 months, respectively; p = 0.189), although neither result reached statistical significance. Median OS of patients with partial response, stable disease and progressive disease was 27.4, 12.7 and 4.5 months, respectively (p < 0.001). Age, comorbidities, line of treatment with osimertinib, and type of activating EGFR mutation did not impact on OS. Adverse events of any grade or grade 3/4 were reported in 38% and 9% of patients, respectively. One person discontinued due to interstitial pneumonia.. These results confirm the value of osimertinib in patients with previously treated EGFR T790M-mutant NSCLC. Clinical benefit was evident in patients with cerebral metastases and moderate performance status.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Poland; Retrospective Studies; Survival Analysis

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor-dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy.. We report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective.. Despite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor-mutant tumor.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Dermatomyositis; ErbB Receptors; Humans; Lung Neoplasms; Mutation

Cardiotoxicity related to osimertinib, including cardiac failure, QT prolongation, and atrial fibrillation, has been reported as an extremely rare incidence in patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the occurrence of osimertinib-induced cardiomyopathy.. A 76-year old woman was treated with afatinib (40 mg/day) as the 1st line treatment due to recurrence after surgical resection for pulmonary adenocarcinoma. However, she experienced recurrence with positive T790 M, and osimertinib (80 mg/day) was administered as the 2nd line therapy.. Four months after osimertinib initiation, she complained of fever and progressive dyspnea, and a diagnostic endomyocardial biopsy confirmed non-specific cardiomyopathy, indicating osimertinib-induced cardiomyopathy.. She was treated with furosemide, carvedilol, and enalapril, and her cardiac function, her symptoms, and condition improved 3 weeks after the withdrawal of osimertinib.. Physicians should be alert of the cardiomyopathy-causing potential of osimertinib in advanced NSCLC patients.

Topics: Acrylamides; Adenocarcinoma of Lung; Adrenergic beta-Antagonists; Afatinib; Aged; Angiotensin-Converting Enzyme Inhibitors; Aniline Compounds; Cardiomyopathies; Carvedilol; Diuretics; Enalapril; Female; Furosemide; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Recurrence; Treatment Outcome; Withholding Treatment

Tyrosine kinase inhibitors are used as first-line treatment for non-small cell lung cancer (NSCLC) patients harboring driver mutations in EGFR, ALK, ROS1, and BRAF. Currently, standard molecular testing approaches help identify single genes for such targetable driver mutations in NSCLC; however, next-generation sequencing (NGS)-based genetic profiling provides a more comprehensive approach and is hence strongly recommended. This case study aimed to highlight the benefits of NGS-based tests for the diagnosis of complex EGFR L858R mutations. A patient was diagnosed with stage IVB NSCLC using a government-approved in vitro diagnostic test and was noted to have a high programmed death-ligand 1 tumor proportion score. This patient was treated with pembrolizumab monotherapy followed by cisplatin and pemetrexed owing to the lack of actionable driver gene mutations, including EGFR mutations. After treatment failure, a sample harvested from the same transbronchial lung biopsy specimen (formalin-fixed and paraffin-embedded) used for the initial EGFR test was subjected to NGS-based broad genetic profiling. The NGS-based test identified an EGFR L858R-K860I cis doublet mutation; however, neither of these mutations was identified upon initial molecular testing. The patient was then successfully treated with a third-generation EGFR-tyrosine kinase inhibitor, osimertinib. In this study, we delved deeper into the realm of L858R and K860I mutations in NSCLC and discuss the potential causes underlying our initial negative diagnosis. Furthermore, this study highlighted the additional benefits of replacing typical molecular tests with NGS-based broad profiling approaches. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: The EGFR L858R-K860I cis doublet mutation was not detected by a PCR-based EGFR test. A next generation sequencing (NGS)-based test was able to identify the L858R-K860I cis doublet mutation. WHAT THIS STUDY ADDS: Osimertinib was effective in an NSCLC patient with EGFR L858R and K860I mutations.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; ErbB Receptors; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Female; Humans; Iris; Iris Neoplasms; Lung Neoplasms; Neoplasm Metastasis; Slit Lamp Microscopy

Guidelines recommend testing for multiple biomarkers in non-small cell lung cancer (NSCLC) tumors. Blood-based liquid biopsy analyzing cell-free DNA (cfDNA) could be used in addition to tumor biopsy genotyping, especially if tissue/time are limiting.. To investigate the clinical utility of early cfDNA analysis (Guardant360® CDx) in treatment-naïve NSCLC patients.. A prospective cohort of treatment-naïve patients with metastatic NSCLC who underwent tumor and cfDNA analysis between 12/2018 and 2/2019 were included.. Ten patients were included: 6 males, median age 70.5 years (range 48-87), 8 prior smokers. Liquid biopsy was sent when cancer cells were detected in the biopsy specimen. Median time from diagnosis to receiving the report on the last biomarker from the tumor biopsy was 20 days (range 9-34); median time from blood draw to receiving the cfDNA findings was 9 days (range 7-12). The median difference between the cfDNA and the tumor analysis reports was 20 days (range 9-28). Actionable biomarkers were identified in four patients by both the biopsy analysis and the cfDNA analysis (2cases with EGFR mutations, one with ROS1 fusion, and one with EML4-ALK fusion for whom the biopsy analysis also identified an EGFR mutation not detected in the cfDNA analysis). Overall, eight patients received treatment (2 died before treatment initiation). Three patients received biomarker-based treatment (1 osimertinib, 1 alectinib, and 1 crizotinib).. These findings suggest that cfDNA analysis should be ordered by the pulmonologists early in the evaluation of patients with NSCLC, which might complement the tumor biopsy.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; DNA, Neoplasm; Female; Genotyping Techniques; Humans; Lung Neoplasms; Male; Middle Aged; Piperidines; Prospective Studies

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Radiation Pneumonitis; Radiotherapy

Topics: Acrylamides; Adenocarcinoma of Lung; Angiopoietin-Like Protein 6; Angiopoietin-like Proteins; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Neoplasm Metastasis; Oncogene Proteins, Fusion; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Imidazoles; Lung Neoplasms; Male; Mutation; Oximes; Prognosis; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones

The understanding of histo-molecular mechanisms associated with resistance to osimertinib is a critical step to define the optimal treatment strategy in advanced EGFR-mutated Non-Small-Cell-Lung-Cancer (NSCLC).. We performed a multicentric retrospective analysis on a cohort of consecutive patients treated with osimertinib for an advanced EGFR-mutated NSCLC and collected histo-molecular data from plasma and tumor samples at the time of progression. Next-generation sequencing (NGS) was performed for all samples. Best Overall Response Rate (ORR), Progression Free Survival (PFS), Overall Survival (OS) and data on treatment post-progression efficacy were also collected.. Two-hundred and twenty-six patients were included from 9 Academic French Hospitals between April 2015-October 2018. Osimertinib was given in second-line or more in 219 patients (97%). Best ORR was 52% and best central nervous system ORR was 56%. Median PFS and OS were 9.5 months (IQR 4.0-17.2) and 24 months (IQR 12.4-NR) respectively. At the time of analysis, 150 patients (66%) had tumor progression. Among them, 73 contributive samples (56 tumor biopsies) were available. The most frequent molecular alterations were C797S mutation (n = 9 (13%)) and MET amplification (n = 8 (11%)). Histologic transformation occurred in 5 patients (9% of tumor biopsies). In T790M + NSCLC, loss of T790 M occurred in 68% of cases. Median PFS and OS with treatment beyond progression were 6.0 months (IQR 2.0-10.4) and 15.1 months (IQR 6.7-NR) respectively and longer in case of osimertinib continuation beyond progression.. We confirmed the efficacy of osimertinib in patients with advanced EGFR mutation positive NSCLC. At progression, the most frequent molecular alterations were MET amplification and C797S mutation.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Drug Resistance, Neoplasm; ErbB Receptors; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Survival Rate

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; ErbB Receptors; Exons; Humans; Lung Neoplasms; Mutation; Quinazolines; Quinolines

A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor (EGFR) 19 del mutation positive. Treatment with icotinib was given, but her disease progressed after 6 months remission. CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis, and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction (ARMS-PCR) confirmed EGFR T790M mutation. Treatment with osimertinib was initiated. After 2 months remission, the disease progressed. Re-biopsy was performed for the tumor in the inferior lobe of left lung, and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del. Icotinib was re-challenged, but disease progressed continuously. Bevacizumab was added, and partial response was achieved after 2-cycle of combination therapy. The non-small cell lung cancer (NSCLC) in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment. This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crown Ethers; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Middle Aged; Quinazolines; Tomography, X-Ray Computed; Treatment Outcome

Leptomeningeal metastases (LM) are much more frequent in patients of non-small lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFRTKI) shows promising efficacy for LM.. The aim of this study was to analyze the concentration of osimertinib and gene variation of circulating tumor DNA (ctDNA) in human plasma and cerebrospinal fluid (CSF). Furthermore, we explored whether ctDNA in CSF might be used as a biomarker to predict and monitor therapeutic responses.. The dynamic paired CSF and blood samples were collected from the NSCLC patient with LM acquired EGFR-TKI resistance. A method based on ultra-high performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) was developed and validated for detecting osimertinib in CSF and plasma samples. Gene variations of ctDNA were tested by next-generation sequencing with a panel of 1021 genes.. The concentrations of osimertinib in CSF were significantly lower than that in plasma (penetration rate was 1.47%). Mutations included mTOR, EGFR, CHECK1, ABCC11, and TP53 were explored in ctDNA from plasma and CSF samples. The detected mutation rate of CSF samples was higher than that of plasma samples (50% vs. 25%). Our data further revealed that the variations allele frequency (VAF) and molecular tumor burden index (mTBI) of ctDNA derived from CSF exhibited the negative correlation with efficacy of treatment.. ctDNA from CSF might be a useful biomarker for monitoring the efficacy of treatment and an effective complement to nuclear magnetic resonance imaging (MRI) for LM.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Female; Humans; Lung Neoplasms; Meningeal Neoplasms; Middle Aged; Mutation; Prognosis

A large number of EGFR mutant non-small cell lung cancer patients primordially benefit from first-line treatment with first-generation EGFR-tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. However, multiple acquired resistance mechanisms have been described that limit the clinical efficacy of first-generation EGFR-TKIs. Herein, we report a rare case of lung adenocarcinoma harboring an EGFR exon 19-deletion mutation before the administration of target therapy. This patient acquired resistance to first-generation EGFR-TKIs through small cell lung cancer (SCLC) transformation accompanied by the T790M mutation. Unexpectedly, this SCLC patient maintained a sensitive response to the third-generation EGFR-TKI osimertinib. This special case may indicate that osimertinib represents an effective target drug for SCLC patients who harbor an EGFR T790M mutation.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors; Small Cell Lung Carcinoma

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Axl Receptor Tyrosine Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Disease-Free Survival; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Knockdown Techniques; Heterocyclic Compounds, 2-Ring; Humans; Lung; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mutation; Neoplasm Recurrence, Local; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-3; RNA, Small Interfering; Treatment Outcome; Xenograft Model Antitumor Assays

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have been emerged as the standard selection in non-small cell lung cancer (NSCLC) patients with EGFR sensitive mutations. However, primary or acquired resistance to EGFR-TKIs seems inevitable, especially to third-generation TKIs, which has appeared absence of effective solutions so far.. Here we reported a NSCLC patient with EGFR sensitive mutation of deletion within EGFR exon 19, who had been resistant to icotinib and AZD9291 successively after a period of 18 months response duration. Next-generation sequencing (NGS) technique using plasma sample suggested an acquired EGFR Leu792H mutation, rather than C797S one. Interestingly, the patient obtained another 8 months of disease-free duration with symptoms greatly relieved after repeating icotinib administration. The overall survival of the patient has been thirty-six months and still in the extension.. The presentation of the case may provide some selective therapeutic thoughts for NSCLC patients with acquired EGFR Leu792H mutation suffering resistance to the third-generation TKIs.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Alleles; Amino Acid Substitution; Aniline Compounds; Antineoplastic Agents; Biomarkers; Brain Neoplasms; Combined Modality Therapy; Crown Ethers; ErbB Receptors; Humans; Magnetic Resonance Imaging; Male; Mutation; Neoplasm Metastasis; Neoplasm Staging; Quinazolines; Retreatment; Tomography, X-Ray Computed; Treatment Outcome

Immune checkpoint inhibitors targeting the programmed cell death receptor/ligand 1 (PD-1/PD-L1) pathway have profoundly improved the clinical management of non-small-cell lung cancer (NSCLC). Nevertheless, the superiority of single-agent PD-1/PD-L1 inhibitors in pretreated EGFR mutant patients has turned out to be moderate. One proposed mechanism for poor response to immune checkpoint inhibitors is an immunosuppressive tumor microenvironment. Therefore, we utilized two autochthonous EGFR-driven lung tumor models to investigate dynamic microenvironmental responses to EGFR-TKI treatment. We observed that at an early stage, sensitive EGFR-TKIs caused obvious tumor shrinkage accompanied by increased cytotoxic CD8

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Animals; Antineoplastic Agents; B7-H1 Antigen; Cytokines; Disease Models, Animal; ErbB Receptors; Gefitinib; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating; Macrophages; Mice; Mice, Transgenic; Molecular Targeted Therapy; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Random Allocation; Tumor Microenvironment

Pneumatosis intestinalis is a rare adverse event that occurs in patients with lung cancer, especially those undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Osimertinib is the most recently approved EGFR-TKI, and its usage is increasing in clinical practice for lung cancer patients who have mutations in the EGFR gene.. A 74-year-old woman with clinical stage IV (T2aN2M1b) lung adenocarcinoma was determined to have EGFR gene mutations, namely a deletion in exon 19 and a point mutation (T790 M) in exon 20. Osimertinib was started as seventh-line therapy. Follow-up computed tomography on the 97th day after osimertinib administration incidentally demonstrated intra-mural air in the transverse colon, as well as intrahepatic portal vein gas. Pneumatosis intestinalis and portal vein gas improved by fasting and temporary interruption of osimertinib. Osimertinib was then restarted and continued without recurrence of pneumatosis intestinalis. Overall, following progression-free survival of 12.2 months, with an overall duration of administration of 19.4 months (581 days), osimertinib was continued during beyond-progressive disease status, until a few days before the patient died of lung cancer.. Pneumatosis intestinalis should be noted as an important adverse event that can occur with administration of osimertinib; thus far, such an event has never been reported. This was a valuable case in which osimertinib was successfully restarted after complete recovery from pneumatosis intestinalis, such that further extended administration of osimertinib was achieved.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; ErbB Receptors; Exons; Fatal Outcome; Female; Humans; Mutation; Piperazines; Pneumatosis Cystoides Intestinalis; Point Mutation; Protein Kinase Inhibitors; Radiography, Thoracic; Sequence Deletion; Tomography, X-Ray Computed

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Mutation; Protein Kinase Inhibitors

The third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) osimertinib has become the standard treatment for patients with pretreated EGFR-mutated non-small cell lung cancer (NSCLC) who acquire the T790M resistance mutation. However, no standard treatment after osimertinib failure has been established.. This study was undertaken to explore the clinical resistance modality upon failure of osimertinib therapy and to assess post-progression treatments in a real-world setting.. Medical data were retrospectively collected in our cancer center of patients with advanced NSCLC treated between 1 March 2017 and 1 July 2018, and who developed resistance to osimertinib.. A total of 65 patients were analyzed. Clinical resistance modality varied among patients: 15 (23.1%) with local progression, 29 (44.6%) with gradual progression, and 21 (32.3%) with dramatic progression. Most patients experienced intrathoracic progression only (40/65, 61.5%), while ten (15.4%) cases presented intracranial failure only. Upon progressive disease, 20 patients (30.8%) received subsequent chemotherapy, and showed a trend for longer median overall survival (OS) than in those receiving a non-chemotherapy regimen (25.0 vs. 11.8 months, p = 0.106). Thirty-nine patients (60.0%) continued osimertinib beyond progression with a median post-progression treatment duration of 4.1 months. No significant difference in median OS was seen between patients who continued osimertinib and those who discontinued osimertinib (18.9 vs. 15.1 months, p = 0.802). In subgroup analyses, OS was improved in patients who experienced dramatic progression and were treated with chemotherapy, but data were immature for patients with local or gradual progression.. Chemotherapy could be an effective option after osimertinib failure in unselected patients.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease Management; Disease Progression; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Lung Neoplasms; Male; Middle Aged; Prognosis; Retrospective Studies; Survival Rate

We found that the L747-A750>P mutation, which represents about 4% of all Ex19Del mutations, displays unique inhibitor selectivity. L747-A750>P differs from other Ex19Del mutations in not being suppressed completely by erlotinib or osimertinib, yet is completely inhibited by low doses of afatinib. The HCC4006 cell line (with the L747-A750>P mutation) exhibited increased sensitivity to afatinib over erlotinib and osimertinib, and computational modeling suggests explanations for this sensitivity pattern. Clinically, patients with EGFR L747-A750>P mutant tumors showed inferior outcomes when treated with erlotinib than patients with E746-A750 mutant tumors.. These results highlight important differences between specific Ex19Del mutations that may be relevant for optimizing TKI choice for patients.

Topics: Acrylamides; Adenocarcinoma of Lung; Afatinib; Aniline Compounds; Animals; CHO Cells; Cricetulus; ErbB Receptors; Erlotinib Hydrochloride; Exons; Gene Deletion; Humans; Models, Chemical; Molecular Dynamics Simulation; Mutation; Protein Kinase Inhibitors; Treatment Outcome

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Prognosis

Osimertinib is an effective third-generation tyrosine kinase inhibitor (TKI) for EGFR-mutant lung cancers. However, treatment for patients with acquired resistance to osimertinib remains challenging. We characterized a novel EGFR mutation in exon 20 that was acquired while on osimertinib.. A 79-year-old woman had disease progression during third-line treatment with osimertinib for an EGFR L858R/T790M-mutant lung cancer. Sequencing of circulating cell-free DNA showed EGFR L858R, an acquired novel EGFR M766Q mutation in exon 20, and no evidence of EGFR T790M. Homology modeling was performed to investigate the effects of M766Q on binding to osimertinib. L858R and L858R/M766Q mutations were retrovirally introduced into Ba/F3 and NIH/3T3 cells and evaluated for sensitivity to first-generation (erlotinib), second-generation (afatinib, neratinib, and poziotinib), and third-generation TKIs (osimertinib) by cell viability and colony-formation assays. EGFR-mediated signaling pathways were interrogated by western blotting.. Modeling suggested that EGFR M766Q could disrupt osimertinib binding. L858R/M766Q double-mutant cells were 12-fold more resistant to osimertinib, and more than 250-fold more resistant to erlotinib and afatinib, as compared to L858R-mutant cells. In contrast, double-mutant cells remained sensitive to neratinib and poziotinib at clinically relevant doses (concentration that inhibits 50%, 4.3 and 1.3 nM, respectively). This was corroborated by the effects of the TKIs on colony formation and EGFR signaling.. Acquisition of EGFR M766Q exon 20 mutation is a novel mechanism of acquired resistance to osimertinib. EGFR-mutant lung cancers with an acquired EGFR M766Q mutation in the setting of osimertinib resistance may be sensitive to neratinib and poziotinib.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Animals; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Mice; Protein Kinase Inhibitors; Quinazolines; Quinolines; Tumor Stem Cell Assay

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Biomarkers, Tumor; Chemotherapy, Adjuvant; Computed Tomography Angiography; ErbB Receptors; Gefitinib; Humans; Lung Neoplasms; Metastasectomy; Multiple Pulmonary Nodules; Mutation; Neoplasm Recurrence, Local; Pneumonectomy; Protein Kinase Inhibitors; Reoperation; Time Factors; Treatment Outcome; Tumor Burden

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Anilides; Aniline Compounds; Crizotinib; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Piperazines; Pyridines

A 69-year-old man with post-operative recurrence of lung adenocarcinoma was treated with multiple chemotherapies, including epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. A second biopsy revealed an EGFR T790M mutation. As 10th-line chemotherapy, osimertinib was initiated. After 24 weeks, chest computed tomography (CT) revealed asymptomatic ground-glass opacities in both lobes. After four weeks of osimertinib discontinuation, imaging revealed rapid lung cancer progression. Osimertinib was resumed. After 11 weeks, CT revealed decreased lung nodules with no exacerbation of interstitial lung disease. We describe a patient who experienced transient asymptomatic pulmonary opacities during treatment with osimertinib, which was successfully managed by a "stop-and-go" approach.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Recurrence, Local; Piperazines; Treatment Outcome

The efficacy of osimertinib was compromised by the development of resistance mechanisms, such as MET amplification. However, cohort studies of osimertinib resistance mechanism, and the correlation of MET and progression-free survival (PFS) after osimertinib resistance have been poorly investigated.. This study was carried out to study the acquired MET amplification after osimertinib resistance in advanced lung adenocarcinoma patients, and interrogate the correlation of clinical prognosis and MET amplification.. We performed capture-based sequencing on longitudinal plasma and tissue samples obtained before osimertinib treatment and after resistance development from lung adenocarcinoma patients to investigate the underlying resistance mechanism. We also investigated the correlation of MET amplification and patient prognosis after osimertinib resistance using Kaplan-Meier analysis.. Paired biopsies before osimertinib treatment and after the resistance development revealed underlying resistance mechanisms. In addition, a cohort of 13 patients who developed disease progression after osimertinib resistance was investigated. Patients with MET amplification after osimertinib resistance commonly had inferior median progression-free survival (mPFS) than patients without MET amplification appearance or increase (3.5 months vs. 9.9 months, p = .117). Patients in MET amplification group also displayed poor median overall survival (mOS) compared to MET amplification negative group (15.6 months vs. 30.7 months, p = .885). Furthermore, combinatorial treatment of first/third-generation EGFR-TKI and crizotinib was efficaciously administrated into two patients with newly acquired MET amplification after osimertinib resistance. Partial responses were achieved by them, both clinically and radiographically.. We investigated the osimertinib resistance mechanism in a small cohort of lung adenocarcinoma patients, and demonstrated MET amplification was correlated with inferior PFS/OS after osimertinib treatment. Moreover, we reported the first clinical evidence of efficacy generated by combination of first-generation EGFR-TKI icotinib and crizotinib after the resistance to osimertinib.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cohort Studies; Crizotinib; Crown Ethers; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Amplification; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Quinazolines; Survival Analysis

The most common EGFR mutations in non-small cell lung cancer are exon 19 deletions and exon 21 point mutations, which are both sensitive to EGFR-tyrosine kinase inhibitors. However, rare EGFR mutations do exist and how these mutations respond to tyrosine kinase inhibitors is not well understood. A Chinese woman diagnosed with stage IV lung adenocarcinoma harbored a rare EGFR L747P (2239-2240 TT > CC) mutation, and treatment with gefitinib and osimertinib failed to achieve the desired effect. Herein, possible correlations between gene analysis and the outcomes of subsequent treatment are discussed.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Middle Aged; Mutation; Piperazines; Protein Kinase Inhibitors

The third-generation EGFR tyrosine kinase inhibitor osimertinib has been approved in many countries to treat advanced NSCLC in patients with the EGFR T790M mutation. As the development of acquired resistance is inevitable, it is urgent that the mechanisms of such resistance be clarified.. DNA samples from a cohort of 340 patients with lung adenocarcinoma who were taking osimertinib were subjected to next-generation sequencing and screened in terms of the frequencies of the L792H and G796R mutations. Ba/F3 cells stably expressing the EGFR L858R/T790M mutations (in cis) with either the L792H or G796R mutation were created to investigate the impact of the two novel mutations on EGFR tyrosine kinase inhibitors and other potential drug combinations in vitro. Structural analyses were performed by using Schrödinger/Maestro software (version 11.1.012, Schrödinger LLC, Cambridge, MA).. L792H and G796R were detected in 1.76% (six of 340) and 0.56% (two of 340) patients with lung adenocarcinoma treated with osimertinib, respectively. The introduction of L792H or G796R mutations against an L858R/T790M background caused dramatic reductions in osimertinib sensitivity. Structural modeling showed that mutations in cis with T790M either forced the ligand (osimertinib) to rotate out (breaking the binding) or pulled the hinge loop (breaking the hinge). Various other drug combinations. including cetuximab with EAI045, failed to inhibit either cis mutant effectively.. The EGFR L858R/T790M/L792H and L858R/T790M/G796R mutations conferred resistance to osimertinib both in vitro and in silico. For patients in whom the two resistance mutations occur at low frequency, more precise treatment strategies and additional combinational approaches are required.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Middle Aged; Models, Molecular; Mutation; Protein Kinase Inhibitors; Retrospective Studies

We aimed to investigate the clinical characteristics of lung adenocarcinomas with acquired EGFR T790M mutation focusing on brain metastasis and survival.. Our study included patients who had lung adenocarcinoma harboring EGFR mutation at 1st biopsy and then underwent 2nd biopsy after resistance to first- or second-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Statistical analyses were performed to examine the associations between clinicopathologic features of lung adenocarcinoma and presence of acquired T790M mutation.. A total of 111 patients were identified. Of these, 58 patients (52.3%) had acquired T790M mutations. Osimertinib was used in 29 patients (26.1%) after resistance to first- or second-generation TKIs. The T790M mutation was more frequently found in patients with exon 19 deletion than in those with L858R mutations (p = .026) and in patients who had longer treatment duration with EGFR-TKI (p = .0398). Multivariate analysis revealed that exon 19 deletion (p = .003) were independently associated with T790M mutation. Patients with acquired T790M mutation showed a longer progression-free survival. In addition, patients who had T790M mutation or who received osimertinib treatment had a longer overall and post-progression survival than patients who did not. Brain metastasis-free survival was also longer in the T790M-positive group or osimertinib-treated group among patients who had no brain metastasis at the time of diagnosis. Osimertinib treatment was independently associated with longer overall, post-progression, and brain metastasis-free survival.. The status of acquired T790M mutation was correlated with exon 19 deletion and longer progression-free survival to first- or second-generation EGFR-TKIs. A third-generation EGFR-TKI, osimertinib, was strongly associated with brain metastasis-free survival as well as other survival indicators in patients with EGFR-mutant lung adenocarcinoma.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Brain Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Metastasis; Piperazines; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Survival Analysis

Most patients with non-small cell lung cancer with common epidermal growth factor receptor (EGFR) mutations respond dramatically to EGFR tyrosine kinase inhibitors (TKIs), but data are limited on the response of tumours with uncommon mutations. We present the case of a 68-year-old man with stage IV lung adenocarcinoma with an uncommon EGFR mutation in exon 21 (L861Q). The disease progressed 2 years after he started erlotinib (150 mg daily). Using a transbronchial lung biopsy, we detected additional mutations in exon 20 (T790M) and exon 21 (L858R). He was treated with osimertinib (80 mg daily) and achieved a partial remission. This case demonstrates the value of repeating a biopsy after EGFR-TKI therapy in patients with uncommon EGFR mutations.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Neoplasms; Male; Mutation; Piperazines; Positron Emission Tomography Computed Tomography; Tomography, X-Ray Computed; Treatment Outcome

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Humans; Lung Neoplasms; Male; Myositis

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Brain Neoplasms; Chemoradiotherapy; ErbB Receptors; Female; Humans; Lung Neoplasms; Meningeal Carcinomatosis

A 53-year-old man with advanced lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) exon 19 deletion received erlotinib. After 12 months of disease control with erlotinib monotherapy, leptomeningeal metastases (LM) occurred. A cerebrospinal fluid examination demonstrated a pre-existing EGFR exon 19 deletion. Bevacizumab was combined with erlotinib, and the LM improved. After six months of combination therapy, however, the LM was exacerbated. A re-examination of the cerebrospinal fluid revealed a T790M mutation and exon 19 deletion. Osimertinib was administered, and the LM improved. The combination of bevacizumab and erlotinib was effective for erlotinib-resistant LM and resulted in the expression of a newly acquired T790M mutation, which enabled successful treatment with osimertinib.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; ErbB Receptors; Erlotinib Hydrochloride; Exons; Gene Deletion; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Piperazines; Treatment Outcome

Lung adenocarcinoma with EGFR activating mutations will inevitably acquire resistance to first generation TKIs. Acquired EGFR T790M mutation causes about 50% of these resistance cases. Droplet digital PCR (ddPCR) and cobas enables quantification of T790M mutation. Whether these methods can predict clinical response of osimertinib treatment is unknown.. Tumor and blood samples from 69 stage IIIB-IV NSCLC patients acquired resistance to EGFR-TKI were collected. Cobas® Mutation Test v2 kit was used to detect EGFR mutations in FFPE or plasma samples. Plasma T790M mutation of both osimertinib naïve and treated patients were quantified by Droplet digital PCR (ddPCR).. T790M mutation rate detected by FFPE tissue cobas, plasma ctDNA cobas and plasma ctDNA ddPCR test were 54.5, 21.3 and 30.4% respectively. The T790M positive rate was 52.2% considering all testing methods. The objective response rate (ORR) was 60.9% in 23 patients received osimertinib treatment. Quantification of T790M after treatment decreased to very low level, but no association was observed between clinical response and T790M mutation level decrease.. ddPCR is more sensitive in plama ctDNA testing and should be performed even in tumor tissue T790M test negative cases. EGFR T790M mutation level is not associated with clinical response after osimertinib treatment.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; DNA Mutational Analysis; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Liquid Biopsy; Male; Mutation; Neoplasm Staging; Piperazines; Polymerase Chain Reaction; Predictive Value of Tests; Protein Kinase Inhibitors; Reproducibility of Results; Treatment Outcome

Epidermal growth factor receptor (EGFR) T790M mutations are the most frequent mechanism of resistance to first- and second-generation tyrosine kinase inhibitors, and osimertinib is an effective treatment for patients with both EGFR-activating mutations and T790M resistance mutations. We describe the case of a 68-year-old woman with lung adenocarcinoma with G719S, S768I, and T790M mutations in which osimertinib treatment was unsuccessful. The patient died of disease progression one month after discontinuing osimertinib treatment. This case suggests that osimertinib may be ineffective for treating patients with uncommon mutations such as G719S when the patient has also acquired a T790M resistance mutation.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Disease Progression; Fatal Outcome; Female; Humans; Lung Neoplasms; Mutation; Piperazines; Protein-Tyrosine Kinases; Treatment Failure

A 90-year-old woman was referred to our hospital because of dyspnea with pleural effusion that was detected using a chest X-ray. Pleural fluid cell block specimens from the left pleural effusion were shown to be an adenocarcinoma harboring an epidermal growth factor receptor(EGFR)gene mutation(L858R). Erlotinib was administered and the patient responded to treatment for 15 months. Subsequent re-accumulation of the left pleural effusion was detected, and re-evaluation using cell block specimens revealed EGFR T790M mutation positivity. Osimertinib was initiated and the patient responded to treatment for 11 months. Re-evaluation of the left pleural effusion upon failure of osimertinib treatment revealed EGFR T790M mutation negativity. Hence this report summarizes the case of osimertinib therapy being administered to a 90-year-old patient who had EGFR T790M mutation positivity based on a pleural fluid cell block.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Female; Humans; Lung Neoplasms; Mutation; Piperazines; Pleural Effusion

Topics: Acrylamides; Adenocarcinoma of Lung; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Exons; Female; Humans

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Cell-Free Nucleic Acids; Disease Progression; DNA Mutational Analysis; ErbB Receptors; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Piperazines; Polymorphism, Restriction Fragment Length

Among non-small cell lung cancer (NSCLC) patients with acquired T790 M mutation resistance to first-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), 71% are likely to benefit from osimertinib. There have been several reports about the secondary resistance to osimertinib treatment in T790 M-positive patients, while primary resistance to osimertinib has been rarely reported.. A 62-year-old Asian male never smoker who presented with stage IV EGFR L858R-positive adenocarcinoma developed EGFR T790 M mutation after 14 months of treatment with erlotinib combined with thoracic radiotherapy as first-line therapy. The patient was initiated on osimertinib treatment with T790 M mutation detected (14.4%), but disease progressed 2 months later.. The mechanism of primary resistance to osimertinib remains unclear. There may be an association between T790 M mutation disappearance, TP53 mutation and radiotherapy, but further researches are needed to confirm this.

Topics: Acrylamides; Adenocarcinoma of Lung; Aniline Compounds; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Humans; Male; Middle Aged; Mutation; Piperazines; Protein Kinase Inhibitors; Tumor Suppressor Protein p53

AZD9291 is one of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). Interstitial lung disease (ILD) induced by AZD9291 is very seldom. We provide a case of NSCLC treated with AZD9291 who developed ILD and died in order to improve the knowledge on AZD9291.

Topics: Acrylamides; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Drainage; ErbB Receptors; Fatal Outcome; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Mutation; Pleural Effusion, Malignant; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors

Although mechanisms of acquired resistance to 1st and 3rd generation EGFR-TKI continue to be elucidated, there have been few clinical investigations into the mechanisms of acquired resistance to the 2nd generation EGFR-TKI afatinib. We analyzed data from 20 patients with advanced lung adenocarcinoma who acquired resistance to afatinib, including resistance during EGFR-TKI re-challenge. We examined EGFR T790M and C797S mutations, BRAF V600E mutation, and MET amplification with the MBP-QP method and with droplet digital PCR using ctDNA and re-biopsy samples obtained before and after afatinib treatment. Just before afatinib treatment, 15 of the 20 patients were T790M negative and five were positive. Among the T790M negative patients, 40.0% (6/15) became positive at the time of PD under afatinib. In patients positive for T790M, changes in T790M allele frequency were correlated with afatinib treatment efficacy. C797S was not detected in any patients just before afatinib treatment, but it appeared after treatment in three patients, although with very low allele frequency. Two of these three patients, although positive for both C797S and T790M, achieved PR to osimertinib. However, PFS of these patients was somewhat shorter than that of patients positive for T790M only. BRAF V600E was detected in one patient at PD under afatinib. MET amplification was not detected in this study. T790M is associated with acquired resistance to afatinib, as with 1st generation EGFR-TKI, but with somewhat lower frequency. The influence of C797S on resistance to afatinib is less than that of T790M, but C797S might cause shorter PFS under osimertinib.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Afatinib; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Circulating Tumor DNA; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Frequency; Humans; Liquid Biopsy; Lung Neoplasms; Male; Middle Aged; Mutation; Piperazines; Polymerase Chain Reaction; Progression-Free Survival; Protein Kinase Inhibitors

A 75-year-old man with stage IV lung adenocarcinoma was treated with osimertinib due to disease progression despite having been administered erlotinib. Both an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790M mutation on exon 20 were detected in a specimen from a recurrent primary tumor. Five weeks after osimertinib initiation, he developed general fatigue and dyspnea. Chest computed tomography scan revealed diffuse ground glass opacities and consolidation on both lungs. An analysis of the bronchoalveolar lavage fluid revealed marked lymphocytosis, and a transbronchial lung biopsy specimen showed a thickened interstitium with fibrosis and prominent lymphocytic infiltration. We diagnosed the patient to have interstitial lung disease induced by osimertinib.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Piperazines; Protein Kinase Inhibitors

Mutations in the epidermal growth factor receptor (EGFR) are drivers for a subset of lung cancers. Osimertinib is a third-generation tyrosine kinase inhibitor (TKI) recently approved for the treatment of T790M-positive non-small cell lung cancer (NSCLC); however, acquired resistance to osimertinib is evident and resistance mechanisms remain incompletely defined. The EGFR G724S mutation was detected using hybrid-capture based comprehensive genomic profiling (CGP) and a hybrid-capture based circulating tumor DNA (ctDNA) assays in two cases of EGFR-driven lung adenocarcinoma in patients who had progressed on osimertinib treatment. This study demonstrates the importance of both tissue and blood based hybrid-capture based genomic profiling at disease progression to identifying novel resistance mechanisms in the clinic.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Alleles; Amino Acid Substitution; Aniline Compounds; Antineoplastic Agents; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Exons; Fatal Outcome; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm Staging; Piperazines; Protein Kinase Inhibitors; Tomography, X-Ray Computed; Treatment Outcome

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Piperazines; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; ErbB Receptors; Female; Humans; Lung Neoplasms; Piperazines; Protein Kinase Inhibitors

We report a case of a 38-year-old woman who was diagnosed with stage IV lung adenocarcinoma, harboring an epidermal growth factor receptor (EGFR) L858R mutation on exon 21 and a T790 M mutation on exon 20. The patient was treated with osimertinib, a third-generation EGFR tyrosine kinase inhibitor (EGFR-TKI) following treatment with nivolumab, an anti-Programmed Cell Death 1 (anti-PD1) antibody. After initiating osimertinib treatment, the patient began to complain of low-grade fever and shortness of breath without hypoxemia, and her chest radiograph and a CT scan revealed a remarkable antitumor response, although faint infiltrations were observed in the bilateral lung field. Bronchoalveolar lavage fluid mainly contained lymphocytes (CD4+/CD8+ ratio of 0.3), and a transbronchial lung biopsy specimen showed lymphocytic alveolitis with partial organization in several alveolar spaces. Therefore we diagnosed the patient with osimertinib-induced interstitial lung disease (ILD) after treatment with anti-PD1 antibody. We considered anti-PD1 therapies may be the risk factor of EGFR-TKI-induced ILD.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aniline Compounds; Antibodies, Monoclonal; Antineoplastic Agents; Drug Therapy, Combination; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Nivolumab; Piperazines; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Tomography, X-Ray Computed

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antibodies, Monoclonal; Antineoplastic Agents; Female; Humans; Incidence; Lung Diseases, Interstitial; Lung Neoplasms; Male; Nivolumab; Piperazines

A 44-year-old male, never smoker, suffers from stage IV adenocarcinoma of the right lung with epidermal growth factor receptor (EGFR) exon-21 L858R point mutation on initial presentation. After 23 months of treatment with gefitinib, intercalated with multiple courses of radiotherapy, leptomeningeal metastases (LMs) developed. Acquired T790M mutation was confirmed by the droplet digital polymerase chain reaction plasma EGFR test. After switching to osimertinib at the standard dose, his neurocognitive function improved clinically, coupled with sustained radiological improvement. As this clinical entity is underrepresented in clinical trials, the practicability of plasma EGFR testing and the optimal dose-response relationship of osimertinib in T790M-positive lung cancer complicated with LM deserves further exploration.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Adult; Aniline Compounds; Antineoplastic Agents; Humans; Lung Neoplasms; Male; Piperazines; Protein Kinase Inhibitors

To identify novel mechanisms of resistance to third-generation EGFR inhibitors in patients with lung adenocarcinoma that progressed under therapy with either AZD9291 or rociletinib (CO-1686).. We analyzed tumor biopsies from seven patients obtained before, during, and/or after treatment with AZD9291 or rociletinib (CO-1686). Targeted sequencing and FISH analyses were performed, and the relevance of candidate genes was functionally assessed in in vitro models.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aged; Aniline Compounds; Antineoplastic Agents; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Pyrimidines

Metabolic plasticity is an emerging hallmark of cancer, and increased glycolysis is often observed in transformed cells. Small molecule inhibitors that target driver oncogenes can potentially inhibit the glycolytic pathway. Osimertinib (AZD9291) is a novel EGFR tyrosine kinase inhibitor (TKI) that is potent and selective for sensitising (EGFRm) and T790M resistance mutations. Clinical studies have shown osimertinib to be efficacious in patients with EGFRm/ T790M advanced NSCLC who have progressed after EGFR-TKI treatment. However experience with targeted therapies suggests that acquired resistance may emerge. Thus there is a need to characterize resistance mechanisms and to devise ways to prevent, delay or overcome osimertinib resistance. We show here that osimertinib suppresses glycolysis in parental EGFR-mutant lung adenocarcinoma lines, but has not in osimertinib-resistant cell lines. Critically, we show osimertinib treatment induces a strict dependence on mitochondrial oxidative phosphorylation (OxPhos), as OxPhos inhibitors significantly delay the long-term development of osimertinib resistance in osimertinib-sensitive lines. Accordingly, growth conditions which promote a less glycolytic phenotype confer a degree of osimertinib resistance. Our data support a model in which the combination of osimertinib and OxPhos inhibitors can delay or prevent resistance in osimertinib-naïve tumour cells, and represents a novel strategy that warrants further pre-clinical investigation.

Topics: Acrylamides; Adenocarcinoma; Adenocarcinoma of Lung; Aniline Compounds; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Glycolysis; Humans; Lung Neoplasms; Oxidative Phosphorylation; Piperazines; Protein Kinase Inhibitors