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In East Asia, epidermal growth receptor factor (EGFR) mutations are the most prevalent and important biomarkers for treating patients with advanced lung cancer. However, as L858R doublet mutations are rare, commercially available EGFR tests may yield false-negative results. To determine whether the L858R mutation of the L858R-K860I and L858R-L861F doublet mutations could be identified using different types of EGFR detection tests and to describe the clinical response of patients with lung cancer with L858R doublet mutations to EGFR tyrosine kinase inhibitors (TKI). Information and samples from four patients with L858R doublet mutations, including three with L858R-K860I and one with L858R-L861F, were retrospectively collected from the archives of our department. For each case, the clinical response to EGFR-TKI was retrieved from the medical records. Archived formalin-fixed paraffin-embedded blocks were subjected to Sanger sequencing, the cobas and Idylla EGFR tests, the IntelliPlex-LCP-DNA assay, and AmoyDx PLC panel. L858R mutations were all detected by Sanger sequencing and the Idylla EGFR test but missed by the cobas assay. The AmoyDx PLC detected L858R only in cases with L858R-K860I while the IntelliPlex-LCP-DNA assay detected L858R in the case with L858R-L861F. Additionally, three of the patients, who had measurable tumors, showed partial responses to afatinib and osimertinib. The L858R mutation associated with L858R-K860I and L858R-L861F doublet mutations could be detected using Idylla but not cobas EGFR tests. Using next-generation sequencing analysis should be considered after initial negative reports from the cobas test, because patients with L858R doublet mutations may benefit from EGFR-TKIs., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to disclose., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Introduction: Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup., Methods: Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC., Results: Twenty-eight heavily pretreated patients in the named patient use program had a documented ERBB2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF greater than 1 year. Objective response rate was 19% (3 of 16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11 of 16). Among 12 patients for whom type of ERBB2 mutation was specified, 10 had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib for more than 1 year. This subgroup had median TTF of 9.6 months, objective response rate of 33% (two of six), and disease control rate of 100% (six of six)., Conclusions: This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in ERBB2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with ErbB2-targeted treatment., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Osimertinib is approved for the treatment of non-small-cell lung cancer in patients who develop the EGFR Thr790Met mutation after treatment with epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs). We assessed outcomes in patients with non-small-cell lung cancer and the EGFR Thr790Met mutation who were treated with osimertinib, a third-generation EGFR TKI, after previous treatment failure with one or more other EGFR TKIs., Methods: Eligible patients had been enrolled at one centre in the AURA study, had shown resistance to a previous EGFR TKI, and had EGFR-activating mutations and acquired Thr790Met mutation detectable in tumour tissue or plasma. Patients took 20-240 mg osimertinib per day until disease progression or development of intolerable side-effects. Plasma samples were collected every 6 weeks and tumour tissue biopsy was done at study entry and was optional after disease progression. We tested samples for resistance mechanisms, including EGFR-activating, Thr790Met, and Cys797Ser mutations, and assessed associations with overall survival, progression-free survival, and survival after disease progression., Findings: Of 71 patients enrolled in AURA, 53 were eligible for this analysis. Median progression-free survival was 11·1 months (95% CI 8·4-13·9) and overall survival was 16·9 months (11·7-29·1). 47 patients had disease progression. Median overall survival after osimertinib progression was 5·4 months (95% CI 4·1-10·0). Plasma samples were available for 40 patients after disease progression. 12 (30%) of these had the Thr790Met mutation (four of whom also had Cys797Ser mutations). Patients without detectable EGFR-activating mutations in plasma before treatment had the best overall and post-progression survival (22·4 months, 95% CI 15·6-not reached, and 10·8 months, 7·2-not reached, respectively). Loss of the Thr790Met mutation but presence of EGFR-activating mutations in plasma were associated with the shortest progression-free survival (median 2·6 months, 95% CI 1·3-not reached). In 22 post-progression tumour samples, we found one squamous cell and two small-cell transformations. We detected Thr790Met in nine (50%) of 18 samples, Cys797Ser in two (17%) of 12, cMET amplification in five (50%) of ten, BRAF mutation in one (8%) of 13, and KRAS mutation in one (8%) of 13., Interpretation: Heterogeneous resistance mechanisms developed in patients receiving osimertinib. Differences in resistance mechanisms might dictate future development strategies for osimertinib in clinical trials., Funding: AstraZeneca, Taiwan Ministry of Science and Technology., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Introduction: AZD9291 (osimertinib) is designed for acquired T790M mutation after first- and second-generation EGFR) tyrosine kinase inhibitors have been used. Some of the resistance mechanisms that present after osimertinib treatment, including a newly acquired EGFR C797S mutation, have been identified. It is unclear, however, whether the bypass pathway is also a mechanism of resistance in patients after osimertinib treatment., Methods: Cells from malignant pleural effusion were collected and cultured at the time of progression in a patient being treated with osimertinib. Tumor genotyping was done by matrix-assisted laser desorption ionization-time of flight mass spectrometry. EGFR, AKT, MEK, and ERK phosphorylation were determined. An anchorage-dependent colony formation assay was used for drug sensitivity., Results: An acquired mutation, BRAF V600E, was found in the patient at the time of progression while being treated with osimertinib. Cells grown from malignant pleural effusion were sensitive to BRAF V600E inhibitor and were more vulnerable to a combination treatment with osimertinib., Conclusions: A potential mechanism of acquired resistance to osimertinib in patients with T790M is through the BRAF pathway. Simultaneous blockade of the BRAF and EGFR had a significant inhibitory effect., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Background: Acquired resistance occurs in most non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations experiencing a response to EGFR-tyrosine kinase inhibitor (TKI) initially. We investigated EGFR-TKI retreatment in patients who had previously received EGFR-TKI followed by chemotherapy., Materials and Methods: This was a retrospective multicenter study. Patients with locally advanced or metastatic adenocarcinoma or TTF-1 (+) NSCLC, positive EGFR sensitive mutation, and EGFR-TKI reuse after initial EGFR-TKI followed by chemotherapy were enrolled. The objectives were to assess the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) of EGFR TKI switched retreatment., Results: In total, 205 patients were enrolled, with a median age of 61.8 years (range 31.4-92.9). There was a larger proportion of females (62.9%) than males, and more never-smokers (73.2%) than ever-smokers. In the initial EGFR-TKI administration, 57.6% of patients showed a complete response (CR) or partial response (PR), and 34.6% had stable disease (SD); in the second-line chemotherapy, 13.7% had PR, and 58.0% had SD; in the EGFR-TKI retreatment, 7.3% had PR, and 37.1% had SD. The median PFS of first-line EGFR-TKI was 8.0 months (95% CI 7.3-8.2), and retreatment EGFR-TKI was 4.1 months (95% CI 2.7-4.6). The median OS since the start of the first-line EGFR-TKI therapy was 35.9 months (95% CI 28.8-50.9), and since the start of EGFR-TKI retreatment was 12.6 months (95% CI 10.4-20.9). In the univariable and multivariable regression analysis of factors associated with PFS of EGFR-TKI retreatment, time interval between the two EGFR TKIs equal to or more than 7 months was statistically significant (HR=0.62, 95% CI 0.44-0.86; HR=0.6, 95% CI 0.43-0.86), both p<0.01. Females with exon 21 mutation also showed a significant difference between the two groups (HR=0.51, 95% CI 0.30-0.86; HR=0.52 (0.31-0.88), both p<0.05)., Conclusions: EGFR-TKI retreatment was effective in prolonging survival, and was shown to be a worthwhile option for EGFR-mutated NSCLC patients after failure of first-line EGFR-TKI and chemotherapy. The survival benefit was especially pronounced in patients with longer drug holidays from the initial EGFR-TKI and in females with the exon 21 mutation., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: Previous studies have indicated that EGFR exon 19 deletions in non-small cell lung cancer (NSCLC) are associated with better outcomes to tyrosine kinase inhibitors (TKIs) than the L858R mutation. This study aimed to evaluate whether T790M, a resistant mutation, is more likely to coexist with L858R mutation than with exon 19 deletions in pretreatment NSCLC patients., Materials and Method: We searched MEDLINE and EMBASE up to Nov 30th, 2015 to identify randomized controlled trials (RCTs) and observational studies that reported pretreatment T790M and EGFR-activating mutation. A meta-analysis was performed using a random-effects model. The primary outcome was odds ratio (OR) of pretreatment T790M mutation in NSCLC co-existing with L858R mutation and exon 19 deletions. Stratified analysis was performed based on sensitivity of mutation detection methods for T790M., Results: We identified 15 observational studies and 3 RCTs for analysis. Pretreatment T790M was more frequent in L858R than in exon 19 mutated patients. The association of T790M and L858R was statistically significant in observational studies (OR, 1.65, 95% CI, 1.17-2.32), with less precision in RCTs (OR, 1.84, 95% CI, 0.96-3.52). In the stratified analysis based on the sensitivity of the mutation detection methods, the association was observed in the studies using intermediately (detection limit <5% and ≥ 0.1%; OR, 2.23, 95% CI, 1.19-4.17) and highly sensitive methods (detection limit <0.1%; OR, 1.74, 95% CI, 1.10-2.73), but not in those using low sensitivity methods (detection limit >5%; OR, 1.28, 95% CI, 0.74-2.23)., Conclusions: Pretreatment EGFR T790M mutation is more likely to coexist with L858R mutation than with exon 19 deletions in NSCLC. This association was observed only in studies using sensitive mutation detection methods (<5%)., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)