T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients

Li, Wei; Ren, Shengxiang; Li, Jiayu; Li, Aiwu; Fan, Lihong; Li, Xuefei; Zhao, Chuanliang; He, Yayi; Gao, Guanghui; Chen, Xiaoxia; Li, Shuai; Shi, Jingyun; Zhou, Caicun; Fei, Ke; Schmid-Bindert, Gerald

doi:10.1016/j.lungcan.2014.03.011

Cited by 86 publications

(85 citation statements)

References 32 publications

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“…This could be explained because a longer exposure to a TKI confers the time to develop a resistance mutation. Following this observation, previous studies have shown slower cell growth and favorable outcomes in patients with acquired resistance to EGFR-TKI associated to T790M mutations (32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 68%

Characteristics of progression to tyrosine kinase inhibitors predict overall survival in patients with advanced non-small cell lung cancer harboring an EGFR mutation

Barrón

Cardona²,

Corrales³

et al. 2018

J. Thorac. Dis.

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Background: Non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations has a distinct biology and heterogeneous clinical behavior. We evaluated the characteristics to progression such as clinical patterns of progression (dramatic, gradual, and local) with the prognosis of NSCLC patients treated with tyrosine kinase inhibitors (TKIs). Methods: We reviewed 123 advanced-NSCLC patients with an EGFR-sensitizing mutation treated with TKIs (gefitinib, erlotinib and afatinib). We assessed patients according to clinical factors and progression pattern to TKIs at three centers. Results: For all patients, 58.5%, 31.7% and 9.8% harbored exon19 deletion, exon21 L858R mutation and other-sensitivity mutations, respectively. Median progression-free survival (PFS) was 8.8 months (95% CI: 7.9-9.7). Sixty percent of patients were asymptomatic. Dramatic-progression was the most frequent pattern (50.4%), followed by gradual-progression (32.5%), and local-progression (17.1%). Median overall survival (OS) was 23.1 months (95% CI: 17.4-28.9). In the univariate analysis, factors associated to a longer OS included pattern [gradual-progression (32.1), dramatic (19.5) and local (18.8 months), P=0.008], and the time to progression to TKI [>12 months (38.5), 6-12 months (19.1), <6 months (9.6), P<0.001]. Multivariate analysis showed that only time to progression to TKI was independently associated to OS and PFS. Conclusions: Factors at TKI progression associated to a longer OS can define a subset of patients who may benefit from continued TKI therapy, as well as from local-ablative therapy in progression sites, especially in patients without T790M or who lack access to third-generation TKI.

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Section: Discussionmentioning

confidence: 68%

Characteristics of progression to tyrosine kinase inhibitors predict overall survival in patients with advanced non-small cell lung cancer harboring an EGFR mutation

Barrón

Cardona²,

Corrales³

et al. 2018

J. Thorac. Dis.

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“…To date, no satisfying biomarkers have been found to indicate which patients may receive benefit from the continuation of first-generation TKI therapy. One study found that T790M positive patients had better prognosis with both longer PFS and OS than those without the mutation, and, therefore, claimed patients with acquired T790M mutation at the time of progression may benefit more from TKI re-challenge (30). But another study reported that survival outcomes of secondary TKIs did not differ significantly between T790M-positive and T790M-negative groups; this indicated that T790M might not predict the clinical outcomes in first-generation TKI re-challenge (16).…”

Section: Discussionmentioning

confidence: 99%

The alteration of T790M between 19 del and L858R in NSCLC in the course of EGFR-TKIs therapy: a literature-based pooled analysis

et al. 2018

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Background: Treatment-naive epidermal growth factor receptor (EGFR) T790M mutation is more inclined to coexist with L858R than with 19 del in non-small cell lung cancer (NSCLC) patients. However, EGFRtyrosine kinase inhibitors (EGFR-TKIs) might alter this status. We sought to compare the prevalence of T790M upon acquired resistance to EGFR-TKIs between 19 del and L858R by assembling all existing data.Methods: Electronic databases were comprehensively searched for eligible studies. The primary endpoint was the odds ratio (OR) of T790M mutation in NSCLC co-existing with L858R mutation and 19 del upon resistance to first-generation EGFR-TKIs. A random effects model was used. Stratified analysis was performed based on study type (retrospective and prospective), race (Asians and Caucasians) and sample type (tissue and plasma). Results: A total of 25 studies involving 1,770 patients were included. The overall T790M existent rate was 45.25%. Post-resistance T790M was more frequent in 19 del than in L858R mutated patients (53% vs. 36%; OR 1.87; P<0.001). All outcomes of subgroup and overall analyses were similar. In contrast, we re-analyzed the previous meta-analysis, finding that the pooled rate of pretreatment T790M was 14% and 22% in 19 del and L858R respectively (OR 0.59; P<0.001). The increase of T790M rate was 2.79-fold in 19 del and only 0.63-fold in L858R in the course of EGFR-TKIs therapy.Conclusions: Opposite to the situation of de novo T790M, it was observed that T790M was more frequent in exon 19 deletion than in L858R among patients with acquired resistance to EGFR-TKIs. The difference in T790M alteration between 19 del and L858R encourages development of detection or treatment strategies for the specific resistance mechanism.

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“…Tumors of most patients treated first-line with a currently approved EGFR-TKI develop resistance, however, leading to disease progression (Kobayashi et al, 2005;Pao et al, 2005;Sequist et al, 2011). The EGFR T790M mutation is found in approximately 60% of cases that have developed resistance to EGFR-TKIs Oxnard et al, 2011;Yu et al, 2013;Kuiper et al, 2014;Li et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

Dickinson

Cantarini

Collier

et al. 2016

Drug Metabolism and Disposition

107

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Preclinical and clinical studies were conducted to determine the metabolism and pharmacokinetics of osimertinib and key metabolites AZ5104 and AZ7550. Osimertinib was designed to covalently bind to epidermal growth factor receptors, allowing it to achieve nanomolar cellular potency . Covalent binding was observed in incubations of radiolabeled osimertinib with human and rat hepatocytes, human and rat plasma, and human serum albumin. Osimertinib, AZ5104, and AZ7550 were predominantly metabolized by CYP3A. Seven metabolites were detected in human hepatocytes, also observed in rat or dog hepatocytes at similar or higher levels. After oral administration of radiolabeled osimertinib to rats, drug-related material was widely distributed, with the highest radioactivity concentrations measured at 6 hours postdose in most tissues; radioactivity was detectable in 42% of tissues 60 days postdose. Concentrations of [ 14 C]-radioactivity in blood were lower than in most tissues. After the administration of a single oral dose of 20 mg of radiolabeled osimertinib to healthy male volunteers, ∼19% of the dose was recovered by 3 days postdose. At 84 days postdose, mean total radioactivity recovery was 14.2% and 67.8% of the dose in urine and feces. The most abundant metabolite identified in feces was AZ5104 (∼6% of dose). Osimertinib accounted for ∼1% of total radioactivity in the plasma of non-small cell lung cancer patients after 22 days of 80-mg osimertinib once-daily treatment; the most abundant circulatory metabolites were AZ7550 and AZ5104 (<10% of total osimertinibrelated material). Osimertinib is extensively distributed and metabolized in humans and is eliminated primarily via the fecal route.

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T790M mutation is associated with better efficacy of treatment beyond progression with EGFR-TKI in advanced NSCLC patients

Cited by 86 publications

References 32 publications

Characteristics of progression to tyrosine kinase inhibitors predict overall survival in patients with advanced non-small cell lung cancer harboring an EGFR mutation

Characteristics of progression to tyrosine kinase inhibitors predict overall survival in patients with advanced non-small cell lung cancer harboring an EGFR mutation

The alteration of T790M between 19 del and L858R in NSCLC in the course of EGFR-TKIs therapy: a literature-based pooled analysis

Metabolic Disposition of Osimertinib in Rats, Dogs, and Humans: Insights into a Drug Designed to Bind Covalently to a Cysteine Residue of Epidermal Growth Factor Receptor

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