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The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma.

ABSTRACT: PURPOSE:The main objective of this study was to investigate the relationship among the clinical characteristics and the frequency of T790M mutation in advanced epidermal growth factor receptor (EGFR)‒mutant lung adenocarcinoma patients with acquired resistance after firstline EGFR‒tyrosine kinase inhibitor (TKI) treatment. Materials and Methods:We enrolled EGFR-mutant stage IIIB-IV lung adenocarcinoma patients, who had progressed to prior EGFR-TKI therapy, and evaluated their rebiopsy EGFR mutation status. RESULTS:A total of 205 patients were enrolled for analysis. The overall T790M mutation rate of rebiopsy was 46.3%. The T790M mutation rates among patients with exon 19 deletion mutation, exon 21 L858R point mutation, and other mutations were 55.0%, 37.3%, and 27.3%, respectively. Baseline exon 19 deletion was associated with a significantly higher frequency of T790M mutation (adjusted odds ratio, 2.14; 95% confidence interval [CI], 1.20 to 3.83; p=0.010). In the exon 19 deletion subgroup, there was a greater prevalence of T790M mutation than other exon 19 deletion subtypes in patients with the Del E746-A750 mutation (61.6% vs. 40.6%; odds ratio, 2.35; 95% CI, 1.01 to 5.49; p=0.049). The progression-free survival (PFS) of first-line TKI treatment > 11 months was also associated with a higher T790M mutation rate (54.1% vs. 39.3%; adjusted odds ratio, 1.82; 95% CI, 1.02 to 3.25; p=0.044). Patients who underwent rebiopsy at metastatic sites had more chance to harbor T790M mutation (52.6% vs. 33.8%; adjusted odds ratio, 1.97; 95% CI, 1.06 to 3.67; p=0.032). CONCLUSION:PFS of first-line EGFR-TKI, rebiopsy site, EGFR exon 19 deletion and its subtype Del E746- A750 mutation are associated with the frequency of T790M mutation.

SUBMITTER: Huang YH

PROVIDER: S-EPMC6192936 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn this open-label, international phase 2 study, the authors assessed the efficacy and safety of olmutinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who had a confirmed T790M mutation and disease progression on previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.MethodsPatients aged ≥20 years received once-daily oral olmutinib 800 mg continuously in 21-day cycles. The primary endpoint was the objective response rate (patients who had a confirmed best overall response of a complete or partial response), assessed by central review. Secondary endpoints included the disease control rate, the duration of objective response, progression-free survival, and overall survival. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 4.03).ResultsOverall, 162 patients (median age, 63 years; women, >60%) were enrolled from 68 sites in 9 countries. At the time of database cutoff, 23.5% of enrolled patients remained on treatment. The median treatment duration was 6.5 months (range, 0.03-21.68 months). Overall, 46.3% of patients (95% CI, 38.4%-54.3%) had a confirmed objective response (all partial responses). The best overall response (the objective response rate regardless of confirmation) was 51.9% (84 patients; 95% CI, 43.9%-59.8%). The confirmed disease control rate for all patients was 86.4% (95% CI, 80.2%-91.3%). The median duration of objective response was 12.7 months (95% CI, 8.3-15.4 months). Estimated median progression-free survival was 9.4 months (95% CI, 6.9-12.3 months), and estimated median overall survival was 19.7 months (95% CI, 15.1 months to not reached). All patients experienced treatment-emergent adverse events, and 71.6% of patients had grade ≥3 treatment-emergent adverse events.ConclusionsOlmutinib has meaningful clinical activity and a manageable safety profile in patients with T790M-positive non-small cell lung cancer who received previous epidermal growth factor receptor-tyrosine kinase inhibitor therapy.

Project description:BackgroundA subset of lung adenocarcinoma with EGFR-tyrosine kinase inhibitor sensitizing mutations (mEGFR) is common in non-smokers and women, suggesting that mutational stressors other than smoking are involved.MethodsTargeted sequencing using a custom panel containing 70 cancer-related genes were performed from 73 cases of lung adenocarcinoma with mEGFR (study cohort). In parallel, publicly available data of 47 TCGA-LUAD cases with mEGFR (LUAD cohort) were extracted from the GDC data portal and analyzed by non-negative matrix factorization using the Maftools package.ResultsIn the study cohort, the C?>?A transversions accounted for 12.9% of all single nucleotide variations (SNVs), comprising the second smallest proportion among SNVs. The E19del-subgroup had a significantly lower mutational burden with significantly higher Ti/Tv ratio than the SNV-subgroup, which includes cases with L858R and other EGFR-TKI sensitizing SNVs. (P?=?0.0326 and 0.0002, respectively, Mann-Whitney U test). In the LUAD cohort, the mutational burden was substantially lower than in other TCGA cancer cohorts, and the frequency of C?>?A transversions was 30.3%, occupying the second frequency. The E19del-subgroup had a lower mutational burden overall and a higher Ti/Tv ratio than the SNV-subgroup (P?=?0.0497 and P?=?0.0055, respectively, Mann-Whitney U test). Smoking-related signature 4 was observed only in the L858R-subgroup, while ignature 30 and 5 was observed in both groups.ConclusionsLung adenocarcinoma with mEGFR(+) has a lower mutational burden and does not show a characteristic mutation pattern influenced by smoking. E19del and L858R, which are representative subtypes of mEGFR(+) lung adenocarcinoma, differ in terms of mutational spectrum, as the E19del-subgroup has a lower mutation burden and a higher Ti/Tv ratio than the SNV-subgroup. These findings could help explain the differences in the responses to EGFR-TKIs and in the clinical courses between the two lung adenocarcinoma subgroups.

Project description:ObjectiveTo explore the potential of CT radiomics in detecting acquired T790M mutation and predicting prognosis in patients with advanced lung adenocarcinoma with progression after first- or second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.Materials and methodsContrast-enhanced thoracic CT was collected from 250 lung adenocarcinoma patients (with acquired T790M mutation, n = 146, without mutation, n = 104) after progression on first- or second-generation TKIs. Radiomic features were extracted from each volume of interest. The maximum relevance minimum redundancy and the least absolute shrinkage and selection operator (LASSO) regression method were used to select the optimized features in detecting acquired T790M mutation. Univariate Cox regression and LASSO Cox regression were used to establish the radiomics model to predict the progression-free survival of osimertinib treatment. Finally, nomograms (which) combined clinical factors with radscore to predict the acquired T790M mutation and prognosis were built separately. In addition, the two nomograms were validated by the concordance index (C-index), decision curve analysis (DCA), and calibration curve analysis where appropriate.ResultsClinical factors including the progression-free survival of first-line EGFR TKIs, EGFR mutation, and N stage and 12 radiomic features were useful in predicting the acquired T790M mutation. The area under the receiver operating characteristic curves (AUC) of clinical, radiomics, and nomogram models were 0.70, 0.74, and 0.78 in the training set and 0.71, 0.71, and 0.76 in the validation set, respectively. The DCA and calibration curve analysis demonstrated a good performance of the nomogram model. Clinical factors including age and first-generation EGFR TKIs and 12 radiomic features were useful in patients' outcome prediction. The C-index of the combined nomogram was 0.686 in the training set and 0.630 in the validation set, respectively. Calibration curves demonstrated a relatively poor performance of the nomogram model.ConclusionNomogram combined clinical factors with radiomic features might be helpful to detect whether patients developed acquired T790M mutation or not after progression on first- or second-generation EGFR TKIs. Nomogram prognostic model combined clinical factors with radiomic features might have a limited value in predicting the survival of patients harboring acquired T790M mutation treated with osimertinib.

Project description:AIM:To identify non-quinazoline kinase inhibitors effective against drug resistant mutants of epidermal growth factor receptor (EGFR). METHODS:A kinase inhibitor library was subjected to screening for specific inhibition pertaining to the in vitro kinase activation of EGFR with the gatekeeper mutation T790M, which is resistant to small molecular weight tyrosine kinase inhibitors (TKIs) for EGFR in non-small cell lung cancers (NSCLCs). This inhibitory effect was confirmed by measuring autophosphorylation of EGFR T790M/L858R in NCI-H1975 cells, an NSCLC cell line harboring the gatekeeper mutation. The effects of a candidate compound, Janus kinase 3 (JAK3) inhibitor VI, on cell proliferation were evaluated using the MTT assay and were compared between T790M-positive and -negative lung cancer cell lines. JAK3 inhibitor VI was modeled into the ATP-binding pocket of EGFR T790M/L858R. Potential physical interactions between the compound and kinase domains of wild-type (WT) or mutant EGFRs or JAK3 were estimated by calculating binding energy. The gatekeeper residues of EGFRs and JAKs were aligned to discuss the similarities among EGFR T790M and JAKs. RESULTS:We found that JAK3 inhibitor VI, a known inhibitor for JAK3 tyrosine kinase, selectively inhibits EGFR T790M/L858R, but has weaker inhibitory effects on the WT EGFR in vitro. JAK3 inhibitor VI also specifically reduced autophosphorylation of EGFR T790M/L858R in NCI-H1975 cells upon EGF stimulation, but did not show the inhibitory effect on WT EGFR in A431 cells. Furthermore, JAK3 inhibitor VI suppressed the proliferation of NCI-H1975 cells, but showed limited inhibitory effects on the WT EGFR-expressing cell lines A431 and A549. A docking simulation between JAK3 inhibitor VI and the ATP-binding pocket of EGFR T790M/L858R predicted a potential binding status with hydrogen bonds. Estimated binding energy of JAK3 inhibitor VI to EGFR T790M/L858R was more stable than its binding energy to the WT EGFR. Amino acid sequence alignments revealed that the gatekeeper residues of JAK family kinases are methionine in WT, similar to EGFR T790M, suggesting that TKIs for JAKs may also be effective for EGFR T790M. CONCLUSION:Our findings demonstrate that JAK3 inhibitor VI is a gatekeeper mutant selective TKI and offer a strategy to search for new EGFR T790M inhibitors.

Dataset Information

The Association of Acquired T790M Mutation with Clinical Characteristics after Resistance to First-Line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Lung Adenocarcinoma.

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