Dataset Information

First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments.

ABSTRACT:

Background

Although the clinical application of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been a new step forward in the first-line treatment of non-small cell lung cancer (NSCLC), an increasing number of patients with progression on osimertinib represents a great challenge clinically. The patterns of resistance mechanisms and subsequent treatment strategies after first-line osimertinib resistance are not well established.

Methods

Between January 1, 2016 and October 31, 2020, a consecutive of 56 EGFR-mutant lung cancer patients treated with osimertinib as first-line therapy at Daping Hospital (Chongqing, China) were retrospective screened. The samples of pre-osimertinib and osimertinib-resistance were all detected by next-generation sequencing (NGS) panels. Statistical analyses were carried out using SPSS 23.0 software. Survival analyses were performed using the Kaplan-Meier method and compared using a log-rank test between groups.

Results

Among 47 patients with osimertinib effectiveness analysis, the median progression free survival (mPFS) was 15.4 months (95% confidence interval [CI]: 12.2-24.9 months), and median overall survival (mOS) was 35.5 months (95% CI: 23.9 months -NA). A total of 21 patients underwent repeated NGS tests upon osimertinib resistance. MET amplification was the most common resistance mechanism (6/21, 28.6%), followed by C797S mutation (5/21, 23.8%). A total of 15 patients received subsequent treatments, with mPFS of 7.3 months (95% CI 5.0 months -NA). Among them, 7 patients with EGFR C797 S or/and MET amplification received subsequent second-line targeted therapy, achieving mPFS of 7.3 months (95% CI 4.5 months -NA). Of note, 3 patients received immunotherapy as second- or third-line treatment after osimertinib resistance, achieving median clinical benefit of 37.3 months.

Conclusions

MET amplification and C797S mutation are main resistance mechanisms, which could be targeted by crizotinib and gefitinib, respectively. More than 50% patients could receive subsequent anticancer targetable therapies after first-line osimertinib resistance. Immunotherapy may also be an acceptable choice after osimertinib resistance.

SUBMITTER: Nie N

PROVIDER: S-EPMC9661557 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments.

Nie Naifu N Li Jianghua J Zhang Jian J Dai Jie J Liu Zhulin Z Ding Zhenyu Z Wang Yubo Y Zhu Mengxiao M Hu Chen C Han Rui R Tang Huan H Li Li L He Yong Y

Clinical Medicine Insights. Oncology 20221111

<h4>Background</h4>Although the clinical application of osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has been a new step forward in the first-line treatment of non-small cell lung cancer (NSCLC), an increasing number of patients with progression on osimertinib represents a great challenge clinically. The patterns of resistance mechanisms and subsequent treatment strategies after first-line osimertinib resistance are not well established.< ...[more]

PMID: 36387609

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Project description:Importance:The survival of patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) gene mutations has improved substantially in the last decade with the development of targeted tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation TKI that is approved by the US Food and Drug Administration for the treatment of patients who develop EGFR T790M mutations, has recently shown improved clinical outcomes compared with gefitinib and erlotinib for treatment-naive patients. Objective:The aim of this study was to assess the cost-effectiveness of osimertinib for the first-line treatment of patients with EGFR-mutated NSCLC. Design, Setting, and Participants:For this cost-effectiveness analysis, we extracted individual patient data from the FLAURA randomized clinical trial and used findings of our earlier meta-analysis to develop a decision-analytic model and determine the cost-effectiveness of osimertinib (AZD9291) compared with first- and second-generation EGFR-TKIs over a 10-year time horizon. All direct costs were based on US and Brazilian payer perspectives. Main Outcomes and Measures:The main outcome of this study was the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained by using osimertinib compared with first- or second-generation EGFR-TKIs in previously untreated EGFR-mutated NSCLC. Results:In the base case using the data as reported in the FLAURA trial, the incremental QALY for osimertinib was 0.594 compared with the first- and second-generation EGFR-TKIs. In the United States, the osimertinib ICERs were $226?527 vs erlotinib, $231?123 vs gefitinib, and $219?874 vs afatinib. In Brazil, the ICERs were $162?329, $180?804, and $175?432, respectively. The overall survival (95% CI) reported in the FLAURA trial (hazard ratio, 0.63; 95% CI, 0.45-0.88) had the strongest association with the ICER (ranging from $84?342 to $859?771). Osimertinib price adjustments to the FLAURA trial data improved cost-effectiveness. For example, a discount of 10% on osimertinib acquisition cost was associated with a 20% decreased ICER compared with the base case ICER, and a discount of 20% on osimertinib acquisition cost was associated with a 40% decreased ICER compared with the base case ICER. Conclusions and Relevance:At current costs, by World Health Organization cost-effectiveness threshold criteria, osimertinib is not cost-effective for first-line therapy of EGFR-mutated NSCLC in either the United States or Brazil.

Project description:BackgroundIn the global FLAURA study, first-line osimertinib, a third-generation irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR), significantly improved progression-free survival (PFS) and overall survival (OS) versus comparator EGFR TKIs in patients with EGFR mutation-positive (EGFRm) advanced non-small-cell lung cancer (NSCLC).ObjectiveThe FLAURA China study assessed first-line osimertinib in Chinese patients with EGFRm advanced NSCLC (NCT02296125).MethodsFLAURA China was a double-blind, randomized, phase III study. Adults from mainland China with previously untreated EGFRm (Exon 19 deletion or L858R) advanced NSCLC were enrolled in the global study or a China-only study under the same protocol; 136 patients were randomized to osimertinib (80 mg once daily [od]; n = 71) or comparator EGFR TKI (gefitinib or erlotinib; all sites selected gefitinib 250 mg od; n = 65). Patients were randomized and allocated to treatment groups by a central computer system. Treatment continued until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed PFS; OS was a secondary endpoint.ResultsAll 136 randomized patients were analyzed. Osimertinib extended median PFS by 8.0 months versus comparator EGFR TKI (17.8 vs. 9.8 months; hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.37-0.85). Median OS was 33.1 months in the osimertinib group versus 25.7 months in the comparator group (HR 0.85; 95% CI 0.56-1.29). At 3 years, 20% of patients on osimertinib and 8% on the comparator remained on randomized treatment. Grade 3 or higher adverse events (AEs) were reported in 54 and 28% of patients in the osimertinib and comparator groups, respectively, driven by increased local reporting of laboratory- and disease-related AEs. No new safety signals were identified.ConclusionsFirst-line osimertinib treatment resulted in a clinically meaningful PFS and OS benefit versus comparator EGFR TKI in Chinese patients with EGFRm advanced NSCLC. Safety data were consistent with the known safety profile of osimertinib.Clinical trial registrationClinicalTrials.gov NCT02296125, registered 20 November 2014.

Project description:BackgroundLung cancer is imposing significant pressure on the national health insurance system worldwide, especially under the COVID-19 pandemic. However, the cost-effectiveness of all available first-line treatments for patients with advanced epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) is still uncertain. The aim of this study was to evaluate the cost-effectiveness of 12 first-line treatments for patients with advanced EGFR mutated NSCLC from the perspective of the United Kingdom (UK) National Health Service and Chinese health care system.MethodsWe used a Markov model to estimate the cost-effectiveness of 12 treatments, including 6 EGFR tyrosine kinase inhibitors, 4 combination treatments and 2 chemotherapies. The key clinical efficacy and safety data were from a network meta-analysis. The cost and health preference were mainly collected from the literature. The most cost-effective treatment was inferred through a sequential analysis. Uncertainty was tested with one-way sensitivity analyses, scenario analyses, and probabilistic sensitivity analyses. Quality-adjusted life years (QALYs), direct medical costs, and incremental cost-effectiveness ratio (ICER) were estimated, at willingness-to-pay thresholds of £20000 to £50000 and £8000 to £24000 per QALY in the UK and China respectively.ResultsFor clinical effectiveness, osimertinib and gefitinib plus pemetrexed based chemotherapy (PbCT) yielded the highest QALYs, while two chemotherapy treatments gained the lowest QALYs. For costs, gefitinib treatment was the cheapest option in both countries (£24529 in the UK and £12961 in China). For cost-effectiveness, 4 treatments including gefitinib, gefitinib plus pemetrexed, gefitinib plus PbCT, and osimertinib formed the cost-effectiveness frontier in both countries. Gefitinib alone (70.7% and 80.0% under the threshold of £20000 and £8000 per QALY in the UK and China, respectively) and gefitinib plus PbCT (62.3% and 71.2% under the threshold of £50000 and £24000 per QALY in the UK and China, respectively) were most likely to be cost-effective compared with other first-line treatments.ConclusionsGefitinib and gefitinib plus PbCT were likely to be cost-effective for patients with advanced EGFR mutated NSCLC in both countries.

Project description:BackgroundThe FLAURA trial demonstrated improved overall survival (OS) with first-line osimertinib for patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). We studied the efficacy and safety of osimertinib in a cohort treated during the coronavirus disease 2019 (COVID-19) pandemic.MethodsPatients diagnosed with EGFR-mutated advanced NSCLC between 11 March 2020 to 31 December 2021 who received first-line osimertinib in British Columbia, Canada were identified retrospectively. Kaplan-Meier curves of OS and progression-free survival (PFS) from the start of osimertinib were plotted. The associations of baseline characteristics with PFS, and development of pneumonitis or dose reductions due to toxicity with OS were evaluated with hazard ratios estimated using univariable and multivariable Cox models.ResultsThe cohort comprised 231 individuals. 58.7% of patients with de novo advanced NSCLC were initially diagnosed after presentation to the Emergency Room. At osimertinib initiation, 31.6% were aged ≥75 years and 45.5% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Median PFS and OS were 18.0 months [95% confidence interval (CI): 16.1-26.2] and 25.4 months (95% CI: 20.3-not reached), respectively. On multivariable analysis, age ≥75 years (vs. <75), ECOG PS 2/3 (vs. 0/1), ECOG PS 4 (vs. 0/1), current smokers (vs. never smokers), programmed death ligand 1 (PD-L1) expression ≥50% (vs. <1%), and L858R mutation (vs. exon 19 deletion) were associated with shorter PFS. Among 110 patients who progressed, 33.6% received subsequent therapy. A proportion of 16.5% of the cohort developed grade ≥3 adverse events. Pneumonitis from osimertinib (3.9% incidence) was weakly associated with shorter OS (hazard ratio: 2.59, 95% CI: 0.94-7.12, P=0.066); dose reductions were not associated with worse OS. 10.8% of patients developed COVID-19.ConclusionsIn a cohort receiving first-line osimertinib during the COVID-19 pandemic, ECOG PS ≥2 was observed in nearly half of patients at treatment initiation contributing to a median OS shorter than in FLAURA. The incidence of severe adverse events was low and dose reduction for drug toxicity did not impact OS. Identifying and reducing barriers to the diagnosis of NSCLC during the COVID-19 pandemic are required.

Dataset Information

First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments.

Background

Methods

Results

Conclusions

Publications

First-Line Osimertinib in Patients With EGFR-Mutated Non-Small Cell Lung Cancer: Effectiveness, Resistance Mechanisms, and Prognosis of Different Subsequent Treatments.

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