osimertinib and Liver-Neoplasms

A phase I, open-label study (NCT02197234) assessed the effects of osimertinib on simvastatin exposure in patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer and disease progression post-EGFR tyrosine kinase inhibitor treatment. Here, we report on a retrospective analysis of two patients (patients 1 and 2) who had liver metastases and high simvastatin exposure prior to osimertinib treatment, which changed following treatment. Patients received single oral doses of simvastatin 40 mg on day (D) 1 and D31, and osimertinib 80 mg once daily on D3-32. At baseline, both patients had abnormal liver function tests (LFTs; Child-Pugh scores of 6 and 8, respectively), significant liver metastasis, and, after a single simvastatin dose, had higher (~ 10-fold) exposure compared with all other patients. Following 31 days of continuous osimertinib treatment, simvastatin exposures (area under the plasma concentration-time curve from zero to infinity (AUC) and maximum plasma concentration (C

Topics: Acrylamides; Administration, Oral; Adult; Aged; Aged, 80 and over; Aniline Compounds; Antineoplastic Combined Chemotherapy Protocols; Area Under Curve; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Drug Interactions; Female; Follow-Up Studies; Humans; Liver; Liver Function Tests; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Retrospective Studies; Simvastatin; Tomography, X-Ray Computed; Treatment Outcome; Tumor Burden; Young Adult

To investigate the effects of osimertinib on hepatocellular carcinoma (HCC) and angiogenesis, and its combinatory effects with venetoclax in HCC.. Viability was assessed by flow cytometry of Annexin V in multiple HCC cell lines after drug treatment. In vitro angiogenesis assay was performed using primary human liver tumor associated endothelial cell (HLTEC). HCC-bearing model was generated by subcutaneous implantation of Hep3B cells to investigate the efficacy of osimertinib alone and its combination with venetoclax.. Osimertinib significantly induced apoptosis in a panel of HCC cell lines regardless of EGFR expression level. It inhibited capillary network formation and induced apoptosis in HLTEC. Using HCC xenograft mouse model, we further showed that osimertinib at non-toxic dose inhibited tumor growth by ~ 50% and remarkably decreased blood vessel in tumor. Mechanism studies demonstrated that osimertinib acted on HCC cells in an EGFR-independent manner. It decreased level of VEGF and Mcl-1 in HCC cells via suppressed phosphorylation of eIF4E, thus leading to inhibition of eIF4E-mediated translation. Mcl-1 overexpression reversed pro-apoptotic effect of osimertinib, suggesting an important role of Mcl-1 in osimertinib's action in HCC cells. Of note, the combination of osimertinib and venetoclax achieved approximately complete HCC cell death and tumor growth in mice.. We provide pre-clinical evidence that osimertinib is a promising candidate for the treatment of HCC via targeting tumor cells and angiogenesis. The combination of osimertinib and venetoclax is synergistic in inhibiting HCC.

Topics: Animals; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; ErbB Receptors; Eukaryotic Initiation Factor-4E; Humans; Liver Neoplasms; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Xenograft Model Antitumor Assays

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

Osimertinib-the third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-has been widely used as a first-line treatment for patients with metastatic EGFR-mutant non-small cell lung cancer (NSCLC). Osimertinib demonstrated central nervous system activity in patients with brain metastasis; however, its efficacy against other distant metastatic organs, including bone and liver, remains unclear. Therefore, we retrospectively analyzed the clinical efficacy of osimertinib in these patients in comparison to other EGFR-TKIs.. Clinical data of patients with advanced NSCLC receiving gefitinib/erlotinib (n = 183), afatinib (n = 55), or osimertinib (n = 150) at five medical institutions were retrospectively assessed for progression-free survival (PFS), overall survival (OS), and best overall response rate (ORR).. In univariate and multivariate analyses, most distant metastases, including the brain and bone, were unrelated to the therapeutic efficacy of osimertinib, although liver metastasis and L858R mutation were independently associated with shorter PFS. PFS and OS in patients with liver metastases were significantly shorter than those in patients without liver metastases (PFS: 7.4 vs. 19.7 months, OS: 12.1 months vs. not reached, respectively). Osimertinib provided significantly longer PFS in patients with brain or bone metastasis and exon 19 deletion than the other EGFR-TKIs. The PFS of patients with liver metastases was not significantly different among the three EGFR-TKI groups. Furthermore, the ORR of osimertinib in patients with liver metastases was significantly attenuated, and the effectiveness was similar to 1. Osimertinib provided better clinical benefits than 1

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Mutation; Neoplasm Metastasis; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Treatment Outcome

Osimertinib is a third generation EGFR-TKI inhibitor approved in the first-line setting for patients with advanced non-small cell lung cancer (NSCLC). Additionally, it represents the treatment of choice in patients who present with T790M mutations and evidence of relapse of the disease. Effectiveness and safety of this drug have been studied in multiple clinical trials and observational studies, however, information regarding outcomes among Hispanic patients treated with Osimertinib is scarce. The objective of this study was to examine real-world effectiveness and safety of first-line Osimertinib in a cohort of Hispanic patients with NSCLC, emphasizing post-progression outcomes.. This is a multicenter, multinational, retrospective cohort study of Hispanic patients treated with Osimertinib as first-line for EGFR-mutated NSCLC. Patients with a confirmed diagnosis of metastatic EGFR-mutated NSCLC who received Osimertinib (80mg/day until evidence of disease progression or presence of intolerable adverse effects) were identified and included. NGS was performed in tumor samples or liquid biopsies among patients who had disease progression. The primary outcome was progression-free survival, and the secondary outcome was post-progression survival.. A total of 94 patients from Mexico, Argentina, Costa Rica, Colombia, Panama, Chile and the USA were included, with a median age of 59 years. Identified mutations included EGFR Exon 19 deletions and EGFR pL858R point mutations. Median progression-free survival (PFS) was 14.4 months (95%CI 12.4-18.2 months). Lung/pleura and lymph nodes were the most common sites of progression. Median post-progression survival was 7.73 months (95%CI 4.07 months-Not reached). Factors which negatively affected PFS included presence of liver metastases at diagnosis and a tumor mutational burden > 5 mut/Mb.. Treatment with first line osimertinib represents an effective and safe option for Hispanic patients with metastatic NSCLC. Liver metastases and a higher tumor mutation burden were associated with a lower PFS. Despite effectiveness, different mechanisms of resistance were identified among the patients in this cohort, including mutations which can be targeted by other therapeutic options.

Topics: Acrylamides; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Hispanic or Latino; Humans; Indoles; Liver Neoplasms; Lung Neoplasms; Middle Aged; Mutation; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies

A 63-year-old woman underwent right lower lobectomy and mediastinal dissection for lung cancer. At 5 years and 5 months after surgery, chest computed tomography revealed multiple liver metastasis. EGFR gene mutations of L858R and T790M were detected in both the primary lung cancer lesion and the liver metastasis specimen. Gefitinib was initiated as the first-line treatment, but the tumors increased in size. Osimertinib, as second-line treatment, was remarkably effective against the liver metastatic lesions and it maintained a partial response for approximately 1 year. Thus, osimertinib was effective for liver metastasis of lung cancer with EGFR mutations of L858R and T790M.

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

Although non-small cell lung cancers (NSCLCs) harboring EGFR mutations initially respond well to EGFR-tyrosine kinase inhibitors (TKIs), they typically progress after approximately one year. The EGFR T790M mutation is the most common resistance mechanism. NSCLCs with T790M respond well to osimertinib; however, the heterogeneity of NSCLCs may limit the efficacy. Some patients exhibit a mixed response (MR), in which some lesions shrink and others progress, but little is known of the incidence and characteristics of such a response. We sought to determine the frequency and clinical course in MR patients.. We retrospectively reviewed the records of patients who had received osimertinib for NSCLC with EGFR T790M.. Between April and December 2016, 48 patients were administered osimertinib. Seven patients (15%) exhibited one of two MR types: (i) progressive lesions that did not include the re-biopsy site (5 patients), and (ii) progressive lesions that included the re-biopsy site (2 patients). The most frequent progressive sites were liver and lung metastases (4 patients). Three patients continued osimertinib following an MR, one of whom had received local therapy for liver metastasis and achieved disease control on osimertinib for an additional four months.. An MR was detected in 15% of NSCLC patients with T790M. This finding suggests that several different resistance mechanisms are active within a single patient who develops resistance to EGFR-TKIs. Osimertinib is basically effective for tumors that acquire resistance to EGFR-TKIs as a result of T790M mutation. Therefore, additional local therapy may be beneficial for patients who develop an MR to osimertinib.

Topics: Acrylamides; Adenoma, Pleomorphic; Adult; Aged; Aged, 80 and over; Aniline Compounds; Carcinoma, Non-Small-Cell Lung; Disease Progression; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Protein Kinase Inhibitors; Retrospective Studies; Survival Analysis; Treatment Outcome

Topics: Acrylamides; Aged; Aged, 80 and over; Aniline Compounds; Brain Neoplasms; Carcinoma, Adenosquamous; Disease Progression; ErbB Receptors; Humans; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Mutation; Piperazines; Pneumonia; Protein Kinase Inhibitors; Steroids