Osimertinib as a Potential Targeted Therapy for Non-Small Cell Lung Carcinoma (NSCLC) Patients with EGFR Exon 20 T790M (original) (raw)
Osimertinib As First-Line Treatment of EGFR Mutation-Positive Advanced Non-Small-Cell Lung Cancer
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2017
Purpose The Osimertinib First Time in Patients Ascending Dose (AURA) study ( ClinicalTrials.gov identifier: NCT01802632) included two cohorts of treatment-naïve patients to examine clinical activity and safety of osimertinib (an epidermal growth factor receptor [EGFR] -tyrosine kinase inhibitor selective for EGFR-tyrosine kinase inhibitor sensitizing [ EGFRm] and EGFR T790M resistance mutations) as first-line treatment of EGFR-mutated advanced non-small-cell lung cancer (NSCLC). Patients and Methods Sixty treatment-naïve patients with locally advanced or metastatic EGFRm NSCLC received osimertinib 80 or 160 mg once daily (30 patients per cohort). End points included investigator-assessed objective response rate (ORR), progression-free survival (PFS), and safety evaluation. Plasma samples were collected at or after patients experienced disease progression, as defined by Response Evaluation Criteria in Solid Tumors (RECIST), to investigate osimertinib resistance mechanisms. Results At...
Current Oncology
Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and the leading cause of cancer-related mortality worldwide. It is responsible for 80–85% of lung cancer cases. NSCLC can be divided into several groups, led by adenocarcinoma (ADC)–40–50% and squamous cell carcinoma (SCC)–20–30%. The development of new molecular therapies targeting particular abnormalities such as mutations in the EGFR (Epidermal Growth Factor Receptor) gene or ROS1 or ALK genes rearrangements resolved in novel strategies in advanced NSCLC management. EGFR mutation occurs mostly in patients with ADC and those patients are mostly females with no or light smoking history. The hereby presented patient fitted the ADC characteristics, while they were diagnosed with SCC. The unusual diagnosis implied further genetic testing, which established the occurrence of L858R substitution in exon 21 in the EGFR gene. A 63-year-old female was admitted to the unit due to a dry cough, pain in the right chest ar...
Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer
The New England journal of medicine, 2017
Background Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Methods In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. Results The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression...
Cancers, 2019
Osimertinib is a mutant-selective EGFR inhibitor that is effective against non-small cell lung cancer (NSCLC) in patients with the EGFR-T790M mutation, who are resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the factors affecting response to osimertinib treatment are unknown. In this retrospective study, 27 NSCLC patients with the EGFR-T790M mutation were enrolled at five institutions in Japan. Among several parameters tested, the progression-free survival (PFS) associated with the initial EGFR-TKIs was positively correlated with the PFS after osimertinib treatment (p = 0.021). The median PFS following osimertinib treatment and the overall survival (OS) were longer in patients who responded to osimertinib than in those who did not (17.7 months versus 3.5 months, p = 0.009 and 24.2 months versus 13.5 months, p = 0.021, respectively). A multivariate analysis demonstrated that the PFS with initial EGFR-TKIs was significantly related to the PFS with osimertinib treatm...
Journal of Cancer Research and Clinical Oncology, 2023
Purpose EGFR tyrosine kinase inhibitor (TKI) therapy in EGFR-mutated lung cancer is limited by acquired resistance. In half of the patients treated with first/second-generation (1st/2nd gen) TKI, resistance is associated with EGFR p.T790M mutation. Sequential treatment with osimertinib is highly active in such patients. Currently, there is no approved targeted second-line option for patients receiving first-line osimertinib, which thus may not be the best choice for all patients. The present study aimed to evaluate the feasibility and efficacy of a sequential TKI treatment with 1st/2nd gen TKI, followed by osimertinib in a real-world setting. Methods Patients with EGFR-mutated lung cancer treated at two major comprehensive cancer centers were retrospectively analyzed by the Kaplan-Meier method and log rank test. Results A cohort of 150 patients, of which 133 received first-line treatment with a first/second gen EGFR TKI, and 17 received first-line osimertinib, was included. Median age was 63.9 years, 55% had ECOG performance score of ≥ 1. Firstline osimertinib was associated with prolonged progression-free survival (P = 0.038). Since the approval of osimertinib (February 2016), 91 patients were under treatment with a 1st/2nd gen TKI. Median overall survival (OS) of this cohort was 39.3 months. At data cutoff, 87% had progressed. Of those, 92% underwent new biomarker analyses, revealing EGFR p.T790M in 51%. Overall, 91% of progressing patients received second-line therapy, which was osimertinib in 46%. Median OS with sequenced osimertinib was 50 months. Median OS of patients with p.T790M-negative progression was 23.4 months. Conclusion Real-world survival outcomes of patients with EGFR-mutated lung cancer may be superior with a sequenced TKI strategy. Predictors of p.T790M-associated resistance are needed to personalize first-line treatment decisions.
Osimertinib in EGFR-Mutated Lung Cancer: A Review of the Existing and Emerging Clinical Data
OncoTargets and Therapy, 2021
The use of epidermal growth factor receptor (EGFR) inhibitors such as osimertinib has improved outcomes and quality of life for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Osimertinib has become the preferred EGFR tyrosine kinase inhibitor (TKIs) for patients with these mutations after demonstrating superior efficacy compared to first generation EGFR TKIs, such as erlotinib and gefitinib. More recently osimertinib has also shown to be beneficial in patients with resectable NSCLC harboring EGFR mutations irrespective of whether they received adjuvant chemotherapy or not. The drug is now FDA approved in this setting. With osimertinib being used more commonly in earlier stage and front-line settings, we are more likely to see patients who develop resistance to this drug. The aim of this review is to provide a comprehensive review of the data with osimertinib in EGFR mutation positive NSCLC, potential resistance mechanisms and an overview of key ongoing clinical trials.
Molecular and clinical oncology, 2018
Osimertinib, a third-generation epithelial growth factor receptor (EGFR) tyrosine kinase inhibitor, has been demonstrated to be effective for treating patients with T790M-positive advanced non-small cell lung cancer (NSCLC) with a relatively good performance status (grade 0-1). Reports of therapeutic response to osimertinib in advanced NSCLC patients with poor performance status are infrequent. The present case report discusses a patient with advanced lung adenocarcinoma harboring EGFR exon 19 deletion and T790M mutation with central nervous system involvement and poor performance status. The patient had a past history of partial lung resection due to lung adenocarcinoma, positive genetic test for EGFR exon 19 deletion in post-surgical tumor specimens, and therapy with erlotinib and onartuzumab for the appearance of a lung metastatic tumor during the post-surgical follow-up. The combined therapy was continued until the discovery of metastatic tumors in bones and the central nervous ...
Cancer science, 2018
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with EGFR mutant non-small-cell lung cancer (NSCLC). However, most patients become resistant to these drugs, so their disease progresses. Osimertinib, a third-generation EGFR-TKI that can inhibit the kinase even when the common resistance-conferring Thr790Met (T790M) mutation is present, is a promising therapeutic option for patients whose disease has progressed after first-line EGFR-TKI treatment. AURA3 was a randomized (2:1), open-label, phase III study comparing the efficacy of osimertinib (80 mg/d) with platinum-based therapy plus pemetrexed (500 mg/m ) in 419 patients with advanced NSCLC with the EGFR T790M mutation in whom disease had progressed after first-line EGFR-TKI treatment. This subanalysis evaluated the safety and efficacy of osimertinib specifically in 63 Japanese patients enrolled in AURA3. The primary end-point was progression-free survival (PFS) base...
Cancer Science, 2018
Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for EGFR-TKI sensitizing (EGFRm) and T790M resistance mutations. The primary objective of the cytology cohort in the AURA study was to investigate safety and efficacy of osimertinib in pretreated Japanese patients with EGFR T790M mutation-positive non-small cell lung cancer (NSCLC), with screening EGFR T790M mutation status determined from cytology samples. The cytology cohort was included in the Phase I dose expansion component of the AURA study. Patients were enrolled based on a positive result of T790M by using cytology samples, and received osimertinib 80 mg in tablet form once daily until disease progression or until clinical benefit was no longer observed at the discretion of the investigator. Primary endpoint for efficacy was objective response rate (ORR) by investigator assessment. Twenty-eight Japanese patients were enrolled into the cytology cohort. At data cut-off (February 1, 2016), 12 (43%) were on treatment. Investigator-assessed ORR was 75% (95% confidence interval [CI] 55, 89) and median duration of response was 9.7 months (95% CI 3.8, not calculable [NC]). Median progression-free survival was 8.3 months (95% CI 4.2, NC) and disease control rate was 96% (95% CI 82, 100). The most common all-causality adverse events were paronychia (46%), dry skin (46%), diarrhea (36%) and rash (36%). Osimertinib provided clinical benefit with a manageable safety profile in patients with pretreated EGFR T790M mutation-positive NSCLC whose screening EGFR T790M mutationpositive status was determined from cytology samples. (ClinicalTrials.gov number NCT01802632).