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Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis: A observational study.

ABSTRACT: Epidermal growth factor receptor (EGFR) mutations for EGFR-tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients are with clinical benefits. Nevertheless, eventual resistance to EGFR-TKI is almost inevitable. In about 50% patients, EGFR-TKI develops a secondary mutation, which is often the T790?M mutation. We aimed to investigate the relationship between EGFR gene status in the peripheral blood and prognosis (progression-free survival [PFS] and overall survival [OS]) in advanced lung adenocarcinoma patients and the 20 exon 790 site mutation (T790?M) and acquired resistance to EGFR-TKI.A total of 49 patients with EGFR-TKI resistance and advanced lung cancer who visited the Shihezi University School of Medicine between 12/2013 and 12/2014 were enrolled in this study. Peripheral blood plasma DNA was isolated after EGFR-TKI resistance and the EGFR exon 20 T790?M mutation was detected using the probe amplification refractory mutation system method.The T790?M mutation rate was 30.6% (15/49). There was no association between T790?M mutation and age, gender, smoking, clinical stage, Eastern Cooperative Oncology Group rating, initial EGFR mutation, and EGFR-TKI drugs, but EGFR-TKI resistance was associated with progression (P?=?.009). Median progression-free survival (PFS) of patients with T790?M mutation was 9.6 months and median overall survival (OS) was 17.6 months, compared to 6.8 and 12.7 months in controls (P?=?.018 and P?=?.027). Multivariate analysis showed that T790?M mutations independently affected the PFS (risk ratio, RR?=?0.653, 95% confidence interval, CI: 0.069-0.886, P?=?.032) and OS (RR?=?0.847, 95% CI: 0.208-2.696, P?=?.008).T790?M mutation and EGFR-TKI resistance are independent factors to affect PFS and OS of non-small cell lung cancer patients.

SUBMITTER: Wang Y

PROVIDER: S-EPMC6076133 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis: A observational study.

Wang Yuli Y Wei Yuan Y Ma Xiaoping X Ma Xinyu X Gong Ping P

Medicine 20180701 28

Epidermal growth factor receptor (EGFR) mutations for EGFR-tyrosine kinase inhibitors (EGFR-TKI) in non-small cell lung cancer (NSCLC) patients are with clinical benefits. Nevertheless, eventual resistance to EGFR-TKI is almost inevitable. In about 50% patients, EGFR-TKI develops a secondary mutation, which is often the T790 M mutation. We aimed to investigate the relationship between EGFR gene status in the peripheral blood and prognosis (progression-free survival [PFS] and overall survival [OS ...[more]

PMID: 29995771

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Project description:PurposeWe aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations.Materials and methodsThis multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint.ResultsThe overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment.ConclusionEGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Project description:BackgroundHER2 (or ERBB2) amplification is an important mechanism for acquired resistance to EGFR tyrosine kinase inhibitors (TKI). The benefits of HER2-targeted therapy have been limited. Herein, we investigated the molecular and clinical patterns of HER2 amplification in non-small cell lung cancer (NSCLC) patients during progression on EGFR-TKIs and the potential of combining EGFR-TKI and pyrotinib to overcome resistance.MethodsIn this study, 1,637 NSCLC cases from Geneseeq after progression of EGFR-TKIs were screened and analyzed by next generation sequencing (NGS), in which 48 patients with HER2 amplification were eligible and enrolled. A total of 403 patients from Sun Yat-sen University Cancer Center (SYSUCC) were screened and five patients with concomitant EGFR mutations and HER2 amplification were retrospectively collected to assess the effect of afatinib or combination of EGFR-TKI and pyrotinib.ResultsIn the 48 patients from the Geneseeq cohort, 27 (56.2%) patients suffered from resistance of 1st/2nd generation EGFR-TKI, and 21 (43.8%) patients from 3rd generation. As for the five patients forming the SYSUCC cohort, three patients were treated with afatinib, one achieved partial response (PR) with progression-free survival (PFS) of 6 months and two quickly developed disease progression. Two patients were treated with EGFR-TKIs plus pyrotinib, one receiving gefitinib plus pyrotinib achieved PR with PFS of 8 months and benefited from osimertinib plus pyrotinib for 3 months till data-off; one receiving osimertinib plus pyrotinib achieved SD for 4 months till data-off. The most common co-occurring alteration was TP53 (91.7%) in the mutation profile of the 48 patients from the Geneseeq cohort, and four patients had TP53 co-mutations of the five patients from the SYSUCC cohort.ConclusionIn this study, we detected 7% HER2 amplification present in EGFR-TKIs resistance. Patients with concomitant EGFR mutation and HER2 amplification may derive clinical benefit from therapies that target both EGFR and HER2.

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.

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Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis: A observational study.

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Association between advanced NSCLC T790 M EGFR-TKI secondary resistance and prognosis: A observational study.

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