Impact of coexisting gene mutations in EGFR-mutated non-small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs.

The T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation-positive non-small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment. A total of 57 EGFR mutation-positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software. Progression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P =  0.049). Coexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.

Takeda M ，Sakai K ，Hayashi H ，Tanaka K ，Haratani K ，Takahama T ，Kato R ，Yonesaka K ，Nishio K ，Nakagawa K ... -  《-》

Independent prognostic value of ultra-sensitive quantification of tumor pre-treatment T790M subclones in EGFR mutated non-small cell lung cancer (NSCLC) treated by first/second generation TKI, depends on variant allele frequency (VAF): Results of the Fren

T790M mutations inEGFR-mutated non-small cell lung cancer (NSCLC) account for nearly 50% of acquired resistance mechanisms to EGFR-TKIs. Earlier studies suggested that tumor T790M could also be detected in TKI-naïve EGFR-mutated NSCLC. The aim of the study is to assess the prevalence and clinical significance of quantification of tumor pre-treatment T790M subclones. We analyzed 366 EGFR-mutated NSCLC patients of the real-life IFCT Biomarkers France study with available pre-treatment formalin-fixed paraffin-embedded (FFPE) tumor DNA before treatment by first/second-generation EGFR-TKI. We used ultra-sensitive Droplet Digital Polymerase Chain Reaction (ddPCR) QX200 (BIO-RAD®, Hercules, CA, USA). All samples were tested in duplicate. ddPCR identified T790M in 19/240 specimens (8%). T790M-positive and T790M-negative populations were not different for clinical baseline characteristics. T790M Variant Allele Frequency (VAF) was > 0.01% <0.1%, > 0.1% <1%, > 1% <10%, and >10% in five (26.3%), six (31.6%), six (31.6%), and two (10.5%) patients, respectively. T790M VAF was >0.1% in 11/13 (84%) patients with rapid (<3 months) or usual progression (3-20 months) compared to 0/3 with low progression (>20 months) (p = 0.02). In a Cox model, T790M mutation positivity was correlated with overall survival (OS) and progression-free survival (PFS) for 10% > VAF >1% (hazard ratio [HR] = 2.83, 95% confidence interval [CI] 1.13-7.07, p = 0.03; HR=3.62, 95%CI 1.43-4.92, p = 0.007, respectively) and for VAF >10% (HR = 19.14, 95%CI 4.35-84.26, p < 0.001; HR = 17.89, 95%CI 2.21-144.86, p = 0.007, respectively). Ultra-sensitive detection of tumor T790M mutation concerned 8% of EGFR-mutated TKI-naïve NSCLC patients and has a negative prognostic value only for T790M VAF over 1%.

Beau-Faller M ，Pencreach E ，Leduc C ，Blons H ，Merlio JP ，Bringuier PP ，de Fraipont F ，Escande F ，Lemoine A ，Ouafik L ，Denis M ，Hofman P ，Lacave R ，Melaabi S ，Langlais A ，Missy P ，Morin F ，Moro-Sibilot D ，Barlesi F ，Cadranel J ，French Cooperative Thoracic Intergroup (IFCT) ... -  《-》

Detection of EGFR-Activating and T790M Mutations Using Liquid Biopsy in Patients With EGFR-Mutated Non-Small-Cell Lung Cancer Whose Disease Has Progressed During Treatment With First- and Second-Generation Tyrosine Kinase Inhibitors: A Multicenter Real-Li

In advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients whose disease has progressed during treatment with first- and second-generation tyrosine kinase inhibitors (TKIs), liquid biopsy (LB) is routinely used to evaluate the presence of EGFR T790M as an acquired resistance mechanism. The objective of this study was to assess a real-life picture of EGFR T790M detection in LB. Liquid biopsies performed between June 2016 and October 2018 for advanced EGFR-mutated NSCLC at disease progression during treatment with first- and second-generation TKIs were retrospectively evaluated in 5 Italian centers. Circulating tumor DNA was extracted from plasma and tested with different commercial kits. The detection rate in LBs and the patients' characteristics were correlated. We enrolled 120 consecutive patients. The overall T790M detection rate observed using LB was 25.8%. Fifty-four of 89 (60.7%) patients with negative LB results underwent tissue rebiopsy, and 56% were positive for T790M. The overall rate of T790M positivity in the study cohort was 49.2%. LB performed before formal tumor progression according to Response Evaluation Criteria In Solid Tumors criteria was negative for T790M in all patients (n = 21; P = .012). T790M positivity was statistically significantly higher in cases of disease progression at extrathoracic metastatic sites (P = .008) and, specifically, in the case of worsening bone disease (P = .003). Our study shows that the detection of T790M-positive patients whose disease progressed during treatment with first- and second-generation TKIs in real life was according to the literature. However, this result was obtained with a specific clinical course (repeat LBs and tissue rebiopsy), thus implying the necessity for multidisciplinary management.

Minari R ，Mazzaschi G ，Bordi P ，Gnetti L ，Alberti G ，Altimari A ，Gruppioni E ，Sperandi F ，Parisi C ，Guaitoli G ，Bettelli S ，Longo L ，Bertolini F ，Pagano M ，Bonelli C ，Tagliavini E ，Nicoli D ，Ubiali A ，Zangrandi A ，Trubini S ，Proietto M ，Fiorentino M ，Tiseo M ，DETECTION Study Group ... -  《-》

Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib.

Hochmair MJ ，Buder A ，Schwab S ，Burghuber OC ，Prosch H ，Hilbe W ，Cseh A ，Fritz R ，Filipits M ... -  《-》

Uncommon EGFR mutations associate with lower incidence of T790M mutation after EGFR-TKI treatment in patients with advanced NSCLC.

Advanced non-small cell lung cancer (NSCLC) patients harboring non-resistant uncommon epidermal growth factor receptor (EGFR) mutations have stepped into the era of targeted therapy. This study aimed to investigate the incidence of acquired T790M mutation and their outcome to subsequent osimertinib in patients of advanced NSCLC harboring uncommon EGFR mutations. Patients with EGFR mutation and performed re-biopsy after progression on prior EGFR-tyrosine kinase inhibitors (TKIs) were reviewed and analyzed. Those with T790M mutation and received subsequent osimertinib treatment were further collected for survival analysis. Finally, 754 patients, including 48 with uncommon mutation, 362 with 19del and 344 with L858R were enrolled. T790M mutation was identified in 341 patients (341/754, 45.2 %). The incidence of T790M mutation was 27.1 % in patients harboring uncommon mutations, significantly lower than 55.2 % and 37.2 % of 19del and L858R (p < 0.001). Logistic regression analysis further found uncommon mutation associated with significantly lower probability of developing T790M (odds ratio [OR] = 0.32, 95 % confidence interval [CI] 0.16-0.64). Among 236 patients received subsequent osimertinib treatment (including 12 uncommon mutation, 145 19del and 79 L858R), patients harboring uncommon mutations showed significantly shorter progression free survival (PFS) (median: 4.6 vs. 11.6 vs. 12.1 months, p < 0.001) and overall survival (OS) (median: 8.1 vs. 35.4 vs. 24.9 months, p = 0.001) compared with 19del and L858R, also associated with numerically lower objective response rate (ORR) (p = 0.085) and lower disease control rate (DCR) (p = 0.074). Multivariate analysis further found that uncommon mutation was the only one significantly associated with both PFS (hazard ratio [HR] = 3.44, 95 %CI 1.79-6.58) and OS (HR = 3.64, 95 %CI 1.66-7.99). Uncommon EGFR mutation showed a significantly lower incidence of acquired T790M mutation and benefited significantly less from subsequent osimertinib treatment than common EGFR mutations in patients with advanced NSCLC.

Yang S ，Mao S ，Li X ，Zhao C ，Liu Q ，Yu X ，Wang Y ，Liu Y ，Pan Y ，Wang C ，Gao G ，Li W ，Xiong A ，Chen B ，Sun H ，He Y ，Wu F ，Chen X ，Su C ，Ren S ，Zhou C ... -  《-》