Investigation of efficacy and acquired resistance for EGFR-TKI plus bevacizumab as first-line treatment in patients with EGFR sensitive mutant non-small cell lung cancer in a Real world population.

We aimed to investigate the clinical efficacy of EGFR tyrosine kinase inhibitor (TKI, T) plus bevacizumab (an antiangiogenic therapy, A) in a real-world population and to provide insights into their mechanism of resistance. This study included 256 NSCLC patients harboring EGFR sensitizing mutations (EGFR 19del and L858R) who underwent nextgeneration sequencing (NGS) with 168-gene panel prior to treatment between Jan 2015 to Aug 2018. Cohort A included 60 patients treated with A + T; while cohort B consisted of 120 patients treated with EGFR-TKI monotherapy with the patients identified using Propensity Score Matching (Ratio of 1:2). Clinical outcomes and potential resistance mechanism were evaluated. Baseline clinical characteristics were not significantly different between Cohort A and B. Compared with cohort B, cohort A had significantly better overall response rate (95% vs 74.2%, p = 0.001) and longer median progression-free survival (PFS, 16.5m vs.12.0 m, HR = 0.7, p = 0.001). Until Jan 2019, 31 and 103 patients in cohort A and B, respectively, were evaluated with progressive disease and underwent tissue re-biopsy and NGS profiling with 168-gene panel. In cohort B, T790M was the predominant acquired resistance mechanism, detected in 51.5% (53/103) of progressive tumors, followed by amplifications in EGFR (15.5%, 16/103) and MET (6.8%, 7/103). Contrastingly, cohort A had a significantly lower rate of T790 M mutation (35.5%, 11/31, p = 0.0003), followed by mutations in TP53 (29.0%, 9/31), RB1 (9.7%, 3/31), SMAD4 (3.2%, 1/31) and EGFR V834 L (3.2%, 1/31) and amplifications in EGFR (9.7%, 3/31), and MET(6.5%, 2/31). Treatment with first-line A + T significantly extends the time to progression and increases the response rate with acceptable safety profile. T790 M was the most common acquired resistance mechanism but it was less common in patients who received A + T.

Zeng L ，Xiao L ，Jiang W ，Yang H ，Hu D ，Xia C ，Li Y ，Zhou C ，Xiong Y ，Liu L ，Liao D ，Guan R ，Li K ，Wang J ，Zhang Y ，Yang N ，Mansfield AS ... -  《-》

EGFR-TKI rechallenge with bevacizumab in EGFR-mutant non-small cell lung cancer.

Otsuka K ，Hata A ，Takeshita J ，Okuda C ，Kaji R ，Masago K ，Fujita S ，Katakami N ... -  《-》

Clinicopathologic Characteristics, Treatment Outcomes, and Acquired Resistance Patterns of Atypical EGFR Mutations and HER2 Alterations in Stage IV Non-Small-Cell Lung Cancer.

The clinicopathologic characteristics, acquired resistance patterns, and outcomes among patients with atypical EGFR mutations and HER2 alterations remain underexplored. A single-center retrospective review was conducted. Oncogenes assessed include typical EGFR (t-EGFR; exon 19 del and L858R), atypical EGFR (a-EGFR; G719X, exon 20, L861Q), HER2 (exon 19, exon 20, amplifications), gene fusions (ALK, ROS1, RET), RAS (KRAS, NRAS), and RAF (BRAF V600E). Progression-free survival (PFS), overall survival (OS), disease control rate, and objective response rate (Response Evaluation Criteria in Solid Tumors 1.1) were collected. Among 570 patients, we found 55 a-EGFR mutations (13 G719X, 38 exon 20, 4 L861Q) and 31 HER2 alterations (2 exon 19 mutations, 27 exon 20 insertions, 2 amplifications). Patients with EGFR and HER2 alterations had increased lung and bone metastases relative to patients with gene fusions, RAS/RAF mutations, and no identified driver oncogenes (P < .001). Patients with EGFR exon 20 insertions had a median PFS to EGFR tyrosine kinase inhibitors (TKIs) of 5 months and an OS of 16 months-significantly worse than exon 19 del and L858R (Bonferroni correction; P < .001), but not G719X or L861Q. Relative to t-EGFR mutations, T790M and MET amplification occurred less frequently as acquired resistance mechanisms among a-EGFR samples (P < .001). Ten patients with a-EGFR mutations and HER2 alterations received single-agent immune checkpoint inhibitors (ICIs) with no radiographic responses and a median PFS of 2 months. EGFR and HER2-mutated NSCLC have a high rate of synchronous lung and bone metastases. Patients with a-EGFR mutations have inferior responses to EGFR-directed therapies with lower rates of acquired T790M and MET amplification. Responses to ICIs are uniformly poor. Novel therapeutic approaches are needed.

Patil T ，Mushtaq R ，Marsh S ，Azelby C ，Pujara M ，Davies KD ，Aisner DL ，Purcell WT ，Schenk EL ，Pacheco JM ，Bunn PA ，Camidge DR ，Doebele RC ... -  《-》

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 ... -  《-》

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 ... -  《-》