osimertinib and Adenocarcinoma

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening dermatologic adverse events in the same category, caused by a delayed-type drug hypersensitivity reaction. Although skin toxicity is common during treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib-associated TEN is quite rare-thus far, only one report has been published from China. We report a case of an 80-year-old Japanese woman with lung adenocarcinoma harboring an EGFR-sensitizing mutation who was treated with osimertinib as the first-line treatment. Forty-six days after osimertinib induction, diffuse erythematous rash rapidly spread over the patient's trunk along with vesicles and purpuric macules; furthermore, she developed targetoid erythema on the face. Despite osimertinib discontinuation and corticosteroid treatment, diffuse erythema with Nikolsky's sign, general epidermal detachment, erosion and loose blisters developed over her entire body including the face. Based on her symptoms, TEN was diagnosed and thus, intravenous immunoglobulin was immediately administered for 4 days. The treatment ameliorated TEN-associated skin toxicity and caused epithelialization. Reports on osimertinib-associated SJS/TEN are scarce and only one report each on SJS and TEN from China is available. This is the first report of osimertinib-associated TEN from Japan. Cases of EGFR-TKI-associated SJS/TEN have been reported predominantly from Asian countries, suggesting ethnicity and genetic linkage play a role in the underlying mechanism.

Topics: Acrylamides; Adenocarcinoma; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Asian People; ErbB Receptors; Female; Humans; Immunoglobulins, Intravenous; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Stevens-Johnson Syndrome

The onset of a new histology is a resistant mechanism to tyrosine kinase inhibitors (TKI) in lung adenocarcinoma (ADK), but this phenomenon has not yet been fully clarified. We present a pooled analysis of the outcomes of EGFR-mutated ADK patients with changed phenotype to squamous cell carcinoma (SqCC) following TKI, along with the description of an additional case. A 67-year-old woman with EGFR-mutated NSCLC received gefitinib and subsequently osimertinib, due to the presence of T790 M at progression. The re-biopsy after third-generation TKI revealed SqCC histology along with the basal EGFR mutation, while T790 M disappeared. The patient rapidly progressed and died despite two chemotherapy cycles. Since this first description of SqCC transformation appearing after treatment with the third-generation TKI osimertinib, other 16 patients, with EGFR-mutated ADK developing a transformation to SqCC histology after treatment with TKIs, were up to now published. From our pooled analysis emerged that most patients were female (82%), 41% were former smokers and no current smokers were identified. Median time to SqCC onset was 11.5 months. In all cases, basal EGFR mutation was maintained, and 11 patients (65%) developed an acquired mutation on exon 20. Interestingly also 790 M mutation appeared in 8 patients (47%). The median survival after SqCC diagnosis was 3.5 months regardless the treatments received. Therefore, EGFR-mutated lung ADK destined to develop a squamous phenotype were often smokers and maintained the baseline genomic alterations. The prognosis after SqCC diagnosis was extremely poor and current treatments largely inefficacious.

Topics: Acrylamides; Adenocarcinoma; Adult; Aged; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; ErbB Receptors; Female; Gefitinib; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Phenotype; Prognosis; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma; Aged; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Metastasis; Piperazines; Tomography, X-Ray Computed

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

Activating mutations in the epidermal growth factor receptor (EGFR) are present in approximately 15% of US patients with lung adenocarcinoma. EGFR tyrosine kinase inhibitors are associated with high response rate and progression-free survival for patients with non-small cell lung cancer with this genotype. Gefitinib, erlotinib, and afatinib are the EGFR tyrosine kinase inhibitors that are presently in clinical use. Understanding resistance mechanisms has led to the identification of a secondary mutational target, T790M, in more than half of patients, for which osimertinib has been approved. This article reviews the current treatments, resistance mechanisms, and strategies to overcome resistance.

Topics: Acrylamides; Adenocarcinoma; Afatinib; Amino Acid Substitution; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Drug Resistance, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Gefitinib; Humans; Lung Neoplasms; Mutation, Missense; Piperazines; Protein Kinase Inhibitors; Quinazolines

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Cell Transformation, Neoplastic; ErbB Receptors; Female; Humans; Lung Neoplasms; Middle Aged; Mutation; Prognosis; Small Cell Lung Carcinoma

The Graded Prognostic Assessment for lung cancer using molecular markers (Lung-molGPA) has not been validated for use with Japanese non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) and the factors impacting survival need to be assessed.. We retrospectively analyzed 294 NSCLC patients who were newly diagnosed with BM between 2013 and 2020 and had received radiotherapy for BM initially at the Hokkaido Cancer Center. We evaluated the effect on the prognosis of Lung-molGPA items, the expression of PD-L1 (classified as high, low, and no expression), and the treatment history. The main outcome was the survival measured from the day of the diagnosis of BM, and log-rank tests were performed to evaluate the results.. The median overall survival (OS) times for adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, 2.5‒3.0, and 3.5‒4.0) were 5.5, 14.8, 28.3, and 39.0 months (p < 0.0001), respectively. The median survival times for non-adenocarcinoma by groups of GPA scores (0‒1.0, 1.5‒2.0, and 2.5‒3.0) were 3.2, 11.0, and 16.0 months (p = 0.0011), respectively. In adenocarcinoma patients with gene mutations, osimertinib significantly improved the outcome (median OS: 34.2 and 17.6 months with and without osimertinib, respectively (p = 0.0164)). There was no significant difference in the OS between patients who were initially treated with tyrosine-kinase inhibitor for BM and those who initially received radiotherapy (p = 0.5337). In patients tested for PD-L1 expression, the median survival times after the diagnosis of BM were 5.6, 22.5, and 9.3 months for the high-, low- and no-expression groups (p = 0.2198), respectively. Also, in patients with high PD-L1 expressions, those with ICI had survival (median OS, 8.6 months) than those without (median OS, 3.6 months).. We confirmed that Lung-molGPA successfully classified Japanese NSCLC patients with BM by the prognosis. Osimertinib prolonged survival of EGFR-positive NSCLC patients with BM, and ICI was effective in patients with high PD-L1 expressions.

Topics: Adenocarcinoma; B7-H1 Antigen; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; East Asian People; Humans; Immune Checkpoint Inhibitors; Lung Neoplasms; Mutation; Prognosis; Retrospective Studies

A man in his 70s was detected an infiltrative shadow on the right lung. A bronchoscopy confirmed the diagnosis of adenocarcinoma of the lung, classified as cT2bN2M0 stage IIIA, with a deletion mutation in

Topics: Adenocarcinoma; Cardiotoxicity; ErbB Receptors; Humans; Lung; Male; Pleural Effusion

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

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 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

Pulmonary pleomorphic carcinoma (PPC) is well-known for its aggressive nature that is usually resistant to platinum-based chemotherapy. On the other hand, the efficacy of an immune checkpoint inhibitor-based regimen in PPC has been elucidated. PPCs harboring epidermal growth factor receptor (EGFR) mutations are extremely rare, and the efficacy of EGFR-tyrosine kinase inhibitors in PPC is limited compared to their efficacy in EGFR-mutated adenocarcinoma. A 43-year-old female patient presenting with a lung mass with multiple brain metastases, carcinomatous pericarditis, and multiple bone metastases was referred to our department. Transbronchial biopsy confirmed the diagnosis of PPC harboring an EGFR mutation with exon 19 deletion. Subsequently, she was treated with osimertinib, a third-generation EGFR-tyrosine kinase inhibitor, which resulted in partial response with shrinkage of the primary lesion and brain metastases. This partial response remained durable for 11 months with an ongoing regimen. The current case suggests that osimertinib would show promising effects as a first-line treatment for PPCs harboring EGFR mutations, as well as a reasonable sequence of therapy followed by immune checkpoint inhibitor-based regimens.

Topics: Acrylamides; Adenocarcinoma; Adult; Aniline Compounds; Antineoplastic Agents; Brain Neoplasms; ErbB Receptors; Female; Humans; Immune Checkpoint Inhibitors; Indoles; Lung; Lung Neoplasms; Mutation; Protein Kinase Inhibitors; Pyrimidines

Local ablative therapy (LAT) may be beneficial for patients with epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) with oligo-residual disease after treatment with EGFR tyrosine kinase inhibitor (EGFR-TKI). However, this has not been fully established. This study aimed to evaluate the predominant progressive disease (PD) pattern limited to residual sites of disease after treatment with EGFR-TKI.. Patients with advanced EGFR-mutated NSCLC treated with EGFR-TKIs as first-line therapy were retrospectively analysed during a 7-year period. Oligo-residual disease was defined as the presence of 1 - 4 lesions (including the primary site) at 3 months from the start of EGFR-TKI treatment. The predictive factors of PD patterns after EGFR-TKI treatment were evaluated.. A total of 207 patients were included. Three months after the start of EGFR-TKI treatment, 66 patients (32%) had oligo-residual disease. A total of 191 patients had PD, 60 with oligo-residual disease and 131 with non-oligo-residual disease. Regarding the pattern, 44 patients (73%) with oligo-residual disease and 37 patients (28%) with non-oligo-residual disease had PD limited to the residual sites. Multivariate logistic regression analysis at 3 months from the start of EGFR-TKI treatment revealed that oligo-residual disease (P < 0.001), the lack of residual central nervous system metastases (P = 0.032), and initial treatment with osimertinib (P = 0.028) were independent predictors of PD limited to residual disease sites.. This study provided a rationale for LAT to all sites of residual disease in patients with oligo-residual disease during EGFR-TKI treatment.

Topics: Acrylamides; Adenocarcinoma; Adult; Afatinib; Aged; Aged, 80 and over; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Disease Progression; ErbB Receptors; Erlotinib Hydrochloride; Female; Gefitinib; Genes, erbB-1; Humans; Logistic Models; Lung Neoplasms; Male; Middle Aged; Mutation; Neoplasm, Residual; Protein Kinase Inhibitors; Retrospective Studies; Time Factors; Treatment Failure

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

We performed additional mechanistic analyses to redefine neratinib biology and determined the mechanisms by which the multi-kinase inhibitor neratinib interacted with the thymidylate synthase inhibitor pemetrexed to kill NSCLC cells expressing either mutant KRAS (G12S; Q61H; G12A; G12C) or mutant NRAS (Q61K) or mutant ERBB1 (L858R; L858R T790M; exon 19 deletion). Neratinib rapidly reduced KRASG12V and RAC1G12V nanoclustering which was followed by KRASG12V, but not RAC1G12V, being extensively mislocalized away from the plasma membrane. This correlated with reduced levels of, and reorganized membrane localization of phosphatidylserine and cholesterol. Reduced nanoclustering was not associated with inactivation of ERBB1, Merlin or Ezrin. The drug combination killed cells expressing mutant KRAS, NRAS or mutant ERBB1 proteins. Afatinib or osimertinib resistant cells were killed with a similar efficacy to non-resistant cells. Compared to osimertinib-resistant cells, sensitive cells had less ERBB2 Y1248 phosphorylation. In osimertinib resistant H1975 cells, the drug combination was less capable of inactivating AKT, mTOR, STAT3, STAT5, ERK1/2 whereas it gained the ability to inactivate ERBB3. In resistant H1650 cells, the drug combination was less capable of inactivating JAK2 and STAT5. Sensitive cells exhibited elevated basal phosphorylation of YAP and TAZ. In resistant cells, portions of YAP and TAZ were localized in the nucleus. [Neratinib + pemetrexed] increased phosphorylation of YAP and TAZ, caused their nuclear exit, and enhanced ERBB2 degradation. Thus, neratinib targets an unidentified protein whose functional inhibition directly results in RAS inactivation and tumor cell killing. Our data prove that, albeit indirectly, oncogenic RAS proteins are druggable by neratinib.

Topics: Acrylamides; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Lung Neoplasms; Pemetrexed; Quinolines; Receptor, ErbB-2; Transcription Factors; Transcriptional Coactivator with PDZ-Binding Motif Proteins; YAP-Signaling Proteins

Osimertinib is the standard therapy for epidermal-growth-factor-receptor (EGFR)-mutant lung cancers. We herein report a case of osimertinib-induced interstitial lung disease (OsiILD) with an organizing pneumonia (OP) pattern and provide a literature-based review. Six months after osimertinib administration, a 75-year-old woman with right pleural carcinomatosis developed ILD with an OP pattern. After salvage chemotherapy, osimertinib with corticosteroid was successfully re-administered. A literature review suggested that 1) OsiILD with an OP pattern was rare but should be recognized, and 2) re-administration of osimertinib in OsiILD was successful in select patients. A criterion that determines whether a patient would benefit from re-administration is warranted.

Topics: Acrylamides; Adenocarcinoma; Aged; Aniline Compounds; Antineoplastic Agents; ErbB Receptors; Female; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Pneumonia; Protein Kinase Inhibitors; Salvage Therapy

Topics: Acrylamides; Adenocarcinoma; Aged; Aniline Compounds; Diagnosis, Differential; Hepatitis B; Hepatitis B virus; Humans; Lung Neoplasms; Male; Recurrence; Virus Activation

NSCLC patients with EGFR mutation were at a higher incidence of developing brain metastasis (BM). Patients with BM are associated with high mortality. Reducing BM incidence becomes increasingly significant for NSCLC patients to achieve prolonged survival. The aim of the study was to explore the possible risk factors of developing metachronous BM during EGFR-TKIs treatment, and to identify the potential candidates for prophylactic cranial irradiation (PCI) or the first-line Osimertinib treatment.. A total of 157 consecutive EGFR-mutated advanced NSCLC patients without BM at initial diagnosis in our institution from 2012 and 2018 were retrospectively reviewed. Comparisons of OS were performed based on BM status. The cumulative incidence of metachronous BM was calculated by the Kaplan-Meier method, and the independent risk factors of metachronous BM were investigated by multivariate analysis.. Patients developing metachronous BM had worse survival (mOS: 22.1 months) than patients not-developing BM (mOS: 44.8 months). Moreover, the multivariate analysis indicated that age ≤ 49 years (P = 0.035), number of extracranial metastases (P = 0.013), and malignant pleural effusion (P = 0.002) were independent risk factors of metachronous BM. Furthermore, the 1-year actuarial incidence of developing metachronous BM in patients with no risk factor (n = 101), 1 risk factor (n = 46), and 2 risk factors (n = 10) were 7.01, 14.61, and 43.75%, respectively (P < 0.001).. Patients developing metachronous BM during EGFR-TKIs treatment have worse outcomes. Our results suggested that EGFR-mutated advanced NSCLC patients with ≥1 risk factors were candidates for PCI or the first-line Osimertinib treatment.

Topics: Acrylamides; Adenocarcinoma; Adult; Age Factors; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Cranial Irradiation; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Prognosis; Protein Kinase Inhibitors; Retrospective Studies; Risk Factors

The clinical efficacy of osimertinib for patients with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) exon 20 insertion mutations is unclear. Few case reports exist on the successful treatment of such tumors with osimertinib. We report a case wherein osimertinib administration had no effect in a patient with EGFR exon 20 insertion-positive lung adenocarcinoma.. A 48-year-old never-smoking woman was referred to our hospital for chronic cough. Computed tomography (CT) and positron emission tomography-CT revealed a nodule in the right middle lobe, consolidation in the right upper lobe, multiple lymph node metastases, liver metastasis, and multiple bone metastases.. On the basis of further examination using transbronchial lung biopsy, the patient was diagnosed with cT1N3M1 stage IVB lung adenocarcinoma. An EGFR exon 20 insertion, without any additional mutations, was identified.. Daily oral administration of 80 mg osimertinib was initiated to treat the EGFR exon 20 insertion-positive lung adenocarcinoma.. Although the disease appeared to be stable 2.5 months after the administration of osimertinib, the tumor started to grow 3 months after administration, and carcinoembryonic antigen levels became higher than those before treatment. Thus, osimertinib was discontinued, and treatment with carboplatin as well as pemetrexed and bevacizumab was started, which the patient responded to.. EGFR exon 20 insertion mutations must be classified in more detail to assess the efficacy of EGFR tyrosine kinase inhibitors. Osimertinib doses that provide favorable therapeutic windows should be considered. Further clinical research is required to clarify the efficacy of osimertinib and other drugs for exon 20 insertion mutations.

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Antineoplastic Agents; Female; Genes, erbB-1; Humans; Lung Neoplasms; Middle Aged; Treatment Failure

The cervix is a rare site of metastasis from advanced lung adenocarcinoma. Driven gene detection is particularly important for the treatment of advanced lung adenocarcinoma.. A 49-year-old Chinese female was sent to our hospital because of lumbago and sacroiliac joint pain; she was unable to walk and had vaginal bleeding. The following examinations were performed: imaging, colposcopy, bronchoscopy, immunohistochemistry and next-generation sequencing.. According to the clinical manifestations and the examination results, the diagnosis was lung adenocarcinoma with cervical, brain, adrenal gland and bone metastases. More importantly, EGFR gene mutations (del19) were detected in both the primary lung lesion and uterine cervical biopsy specimen.. Osimertinib was chosen as the first-line treatment.. Lumbago and sacroiliac joint pain were significantly relieved. The levels of tumor markers decreased. Primary injuries and metastatic sites were significantly reduced.. Physicians should be alert to the signals of vaginal bleeding and consider that primary lung adenocarcinoma may metastasize to the uterine cervix.

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Antineoplastic Agents; Female; Genes, erbB-1; Humans; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Sequence Deletion; Uterine Neoplasms

Osimertinib yields significant tumor responses and durations of progression-free survival (PFS) in patients with acquired T790M mutations. However, the evidence supporting liquid biopsy-guided treatment is still limited. This study examined the real-world benefits of osimertinib in patients with tissue or plasma T790M mutations.. From January 2016 to June 2018, a total of 183 non-small-cell lung cancer patients were enrolled. The presence of the T790M mutation was assessed by either tissue or plasma. The PFS, overall survival, and tumor response rates of the patients were calculated and compared with those of previous clinical trials.. T790M mutations were detected in 51.5% of the patients, including 64 of 140 (45.7%) who underwent liquid biopsies and 23 of 29 (79.3%) who underwent tumor biopsies. After excluding those in clinical trials, 46 patients received osimertinib, including 33 with positive plasma and 13 with positive tissue results for T790M mutations. The median PFS was 11.3 months (interquartile range: 5.2-NR) in all the T790M-positive patients and 10.1 months (interquartile range: 5.9-NR) in the plasma T790M-positive patients. The overall survival, meanwhile, was not reached, whereas the one-year survival rate was 66.1% in all the patients and 61.4% in those who were plasma T790M-positive. The objective response rate and disease control rate were 37.8% and 91.9% in all the patients and 34.6% and 92.3% in the plasma T790M-positive group, respectively. Using a Cox proportional hazards regression, we determined that male gender was a poor prognostic factor for PFS.. In this retrospective real-world analysis, it was determined that both tissue and plasma T790M mutations can be used to guide treatment with osimertinib. Similar disease control rates and survival durations were observed in comparison to those of phase 3 clinical trials.

Topics: Acrylamides; Adenocarcinoma; Aged; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; ErbB Receptors; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Progression-Free Survival; Protein Kinase Inhibitors

Topics: Acrylamides; Adenocarcinoma; Aged, 80 and over; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Crizotinib; Disease Progression; DNA, Neoplasm; ErbB Receptors; Erlotinib Hydrochloride; Fatal Outcome; Humans; Lung Neoplasms; Male; Oncogene Fusion; Phosphoproteins; Proto-Oncogene Proteins c-met

Next generation sequencing (NGS)-based tumor profiling identified an overwhelming number of uncharacterized somatic mutations, also known as variants of unknown significance (VUS). The therapeutic significance of

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Genes, erbB-1; Humans; Lung Neoplasms; Middle Aged; Molecular Dynamics Simulation; Mutation; Pharmacogenomic Testing; Prospective Studies; Protein-Tyrosine Kinases

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

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; Adaptor Proteins, Signal Transducing; Adenocarcinoma; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Carrier Proteins; Crizotinib; Drug Resistance, Neoplasm; Female; Gene Rearrangement; Golgi Matrix Proteins; Humans; Lung Neoplasms; Membrane Proteins; Membrane Transport Proteins; Middle Aged; Prognosis; Protein-Tyrosine Kinases; Proto-Oncogene Proteins

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; Aged; Aniline Compounds; Crizotinib; Erlotinib Hydrochloride; Female; Humans; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors

Several ultra-sensitive methods for T790M in plasma cell-free DNA (cfDNA) have been developed for lung cancer. The correlation between mutation-allele frequency (MAF) cut-off, drug responsiveness, and outcome prediction is an unmet needs and not fully addressed. An innovative combination of peptide nucleic acid (PNA) and Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) was used to proof of concept for monitoring cfDNA T790M in EGFR-mutant patients. Mutant enrichment by PNA was optimized and the detection limit was evaluated through serial dilutions. The cut-off value was identified by receiver-operating-characteristic (ROC) curve analysis utilizing serial sampled plasmas of patients from EGFR-tyrosine kinase inhibitor (TKI) pretreatment to progressive-disease (PD). Results, comparisons, and objective response rate (ORR) were analyzed in 103 patients' tumor and cfDNA T790M, with 20 of them receiving an additional COBAS test. The detection limit was 0.1% MAF. The cut-off for PD and imminent PD was 15% and 5% with an ROC area under the curve (AUC) of 0.96 and 0.82 in 2 ml plasma. Detection sensitivity of cfDNA T790M was 67.4% and overall concordance was 78.6%. ORR was similar in T790M-positive cfDNA (69.6%) and tumor samples (70.6%) treated with osimertinib. Among 65 T790M-positive tumors, 15 were negative in cfDNA (23.1%). Seven of 38 T790M-positive cfDNA samples were negative in the tumors (18.4%). PNA-MALDI-TOF MS had a higher detection rate than COBAS. In conclusion, identification of T790M cut-off value in cfDNA improves cancer managements. We provide a strategy for optimizing testing utility, flexibility, quality, and cost in the clinical practice.

Topics: Acrylamides; Adenocarcinoma; Adult; Aged; Aged, 80 and over; Aniline Compounds; Cell-Free Nucleic Acids; Disease-Free Survival; ErbB Receptors; Female; Humans; Limit of Detection; Lung Neoplasms; Male; Middle Aged; Mutation; Peptide Nucleic Acids; Piperazines; Protein Kinase Inhibitors; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Treatment Outcome

We reported a case of relapsing immune-related colitis (initially caused by nivolumab) following osimertinib therapy for lung adenocarcinoma. A 45-year-old female who had never smoked was diagnosed with adenocarcinoma of the lung and underwent surgical resection. Four years after surgical resection, she was diagnosed with recurrent disease and was eventually treated with nivolumab as third-line therapy. One month after the completion of nivolumab therapy, the patient reported abdominal pain and frequent diarrhea. We diagnosed immune-related colitis and started oral prednisolone. However, the steroid therapy was ineffective, so the patient was administered infliximab and an increased dose of prednisolone. Her symptoms subsequently resolved, and her mucosal lesions improved. Six months after the last administration of nivolumab, osimertinib was initiated as fourth-line therapy, but 3 days later, the patient developed blood in the stool and frequent diarrhea. Osimertinib treatment was discontinued, given the possibility that it had reactivated the patient's immune-related colitis. We subsequently re-administered oral prednisolone (2 mg/kg/day), and the colitis resolved within a few weeks.

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Colitis; Female; Humans; Lung Neoplasms; Middle Aged; Piperazines; Prognosis; Programmed Cell Death 1 Receptor

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

AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment.. Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib. Tumor genotyping was done by matrix-assisted laser desorption ionization-time of flight mass spectrometry. EGFR, AKT, MEK, and ERK phosphorylation were determined. An anchorage-dependent colony formation assay was used for drug sensitivity.. An acquired mutation, BRAF V600E, was found in the patient at the time of progression while being treated with osimertinib. Cells grown from malignant pleural effusion were sensitive to BRAF V600E inhibitor and were more vulnerable to a combination treatment with osimertinib.. A potential mechanism of acquired resistance to osimertinib in patients with T790M is through the BRAF pathway. Simultaneous blockade of the BRAF and EGFR had a significant inhibitory effect.

Topics: Acrylamides; Adenocarcinoma; Adult; Aniline Compounds; Bone Neoplasms; Drug Resistance, Neoplasm; Humans; Lung Neoplasms; Male; Mutation; Neoplasm Staging; Phosphorylation; Piperazines; Pleural Effusion, Malignant; Prognosis; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf

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

Tyrosine kinase inhibitors (TKIs) have been developed to treat patients with EGFR-mutant lung cancers. However, the therapeutic efficacy of TKIs in patients with uncommon EGFR mutations remains unclear.. Next-generation sequencing was performed on a patient's lung adenocarcinoma tumor sample, revealing rare combined in cis (on the same allele) EGFR mutations. Stable Ba/F3 and NIH-3T3 cell lines harboring the mutations were established to investigate the effect of first-, second-, and third-generation EGFR TKIs on cell proliferation by MTS assay and EGFR phosphorylation by Western blotting.. EGFR L858M/L861Q mutations in cis were detected in the tumor of a patient with NSCLC. The patient demonstrated primary resistance to erlotinib and was subsequently treated with afatinib, which caused tumor regression. In in vitro studies, first- and third-generation TKIs exhibited a decreased capacity to prevent EGFR phosphorylation and inhibit cell proliferation in EGFR L858M/L861Q cells compared with cells harboring the common EGFR L858R point mutation. In contrast, afatinib treatment reduced proliferation and inhibited EGFR phosphorylation in L858M/L861Q- and L858R-mutant cells at similar concentrations.. Afatinib may be a beneficial therapeutic option for a subset of patients with lung cancer who harbor rare EGFR mutations in their tumors. Understanding how uncommon mutations affect protein structure and TKI binding will be important for identifying effective targeted therapies for these patients.

Topics: Acrylamides; Adenocarcinoma; Afatinib; Alleles; Aniline Compounds; Animals; Antineoplastic Agents; Cell Proliferation; ErbB Receptors; Erlotinib Hydrochloride; Female; Gefitinib; Humans; Lung Neoplasms; Mice; Middle Aged; NIH 3T3 Cells; Phosphorylation; Piperazines; Point Mutation; Protein Kinase Inhibitors; Quinazolines; Tumor Cells, Cultured

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

Leptomeningeal carcinomatosis (LMC) remarkably decreases the quality of life of EGFR-mutant lung cancer patients. In contrast to the lesions outside the central nervous system (CNS), molecular mechanisms of EGFR tyrosine kinase inhibitor (TKI) resistance in CNS lesions including LMC are largely unknown. In this study, we established an in vivo imaging model for LMC with EGFR mutant lung cancer cell lines harboring an exon 19 deletion in EGFR and evaluated the effect of first generation EGFR-TKIs, erlotinib, second generation afatinib, and third generation AZD9291. In PC-9/ffluc model, erlotinib treatment slowed the development of LMC. Importantly, treatment with afatinib or AZD9291 apparently delayed the development of LMC. Moreover, treatment with a higher dose of AZD9291, also associated with inhibited phosphorylation of EGFR downstream molecule S6, regressed LMC refractory to the aforementioned EGFR-TKI treatments. These observations suggest that the third generation EGFR-TKI AZD9291 may be an effective treatment for first or second generation EGFR-TKI resistant LMC caused by EGFR-mutant lung cancer.

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Animals; Apoptosis; Blotting, Western; Cell Proliferation; Disease Models, Animal; Drug Resistance, Neoplasm; ErbB Receptors; Female; Fluorescent Antibody Technique; Humans; Immunoenzyme Techniques; Lung Neoplasms; Meningeal Carcinomatosis; Mice; Mice, SCID; Mutation; Phosphorylation; Protein Kinase Inhibitors; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

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

Topics: Acrylamides; Adenocarcinoma; Aniline Compounds; Antineoplastic Agents; Biopsy; Drug Resistance, Neoplasm; ErbB Receptors; High-Throughput Nucleotide Sequencing; Humans; Lung Neoplasms; Male; Middle Aged; Mutation; Piperazines; Pleural Neoplasms

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

Osimertinib (AZD9291, Tagrisso) is a potent, irreversible third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI).. Our report demonstrates that osimertinib is able to inhibit the growth of a radiotherapy- and surgery-refractory EGFR T790M-positive brain metastasis in a patient with lung adenocarcinoma.. These data show that re-biopsy in EGFR-mutated non-small cell lung cancer patients with acquired TKI resistance should be performed.

Topics: Acrylamides; Adenocarcinoma; Adult; Aniline Compounds; Antineoplastic Agents; Brain Neoplasms; ErbB Receptors; Female; Humans; Lung Neoplasms; Piperazines; Point Mutation; Protein Kinase Inhibitors; Treatment Outcome

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