Mutation and treatment profiles of patients with concurrent EGFR and ALK actionable mutations (muts).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3138-3138
Author(s):  
Jun Zhao ◽  
Caixia Liu ◽  
Hui Liu ◽  
Yong He ◽  
Liqiang Rao ◽  
...  
Keyword(s):  
First Generation ◽  
Low Frequency ◽  
Resistance Mechanisms ◽  
The Other ◽  
Kaplan Meier ◽  
Tki Resistance ◽  
Treatment Naïve ◽  
Alk Positive ◽  
Egfr Tki ◽  
Egfr Tkis

3138 Background: Actionable muts in EGFR and ALK define two molecular subtypes sensitive to EGFR-TKIs and ALK-TKIs, respectively. Although generally mutually exclusive, they did co-exist in some cases. However, when and how do they co-exist are not well understood. Methods: Pts with concurrent actionable muts in ALK and EGFR were selected from our database. Their mutation profiles and treatment histories were analyzed. PFS was estimated using Kaplan-Meier method. Results: Among 341 ALK-positive ( ALK-pos) and 3804 EGFR-positive ( EGFR-pos) pts, 9 (2.6% of ALK-pos, 0.2% of EGFR-pos) had concurrent EGFR and ALK actionable muts, including 3 EX19Indel + EML4-ALK, 2 EX19Indel + STRN-ALK, 2 L858R + L1152R, 1 L858R + EML4-ALK, and 1 G719C + S768I + STRN-ALK. All 9 pts had lung cancer. One pt with EX19Indel + EML4-ALK was treatment naïve. The other 8 pts have taken ≥ 1 EGFR-TKIs. The mPFS of these pts on first-generation EGFR-TKIs was 22 mo (95% CI: 11 - NR). Except for 1 pt who progressed on Gefitinib and subsequently on Osimertinib had a T790M+C797G, the other 7 EGFR-TKI resistance pts had no common known resistance muts. 3 pts ordered NGS tests before taking EGFR-TKIs. None of them had ALK muts at that time. Later, 1 pt (19Indel) gained an STRN-ALK after 15 mo on Osimertinib, 1 pt (L858R) gained an EML4-ALK after 5 mo on Gefitinib, and 1 pt (L858R) gained an L1152R after 10 mo on Afatinib. Therefore, ALK muts were likely developed as resistance mechanisms during EGFR-TKIs therapies in these 3 pts. Unfortunately, with no information on ALK status before EGFR-TKI therapies, we can not tell if the ALK muts were also developed during and conferred resistance to EGFR-TKI therapies in the other 5 pts. Both STRN-ALK and ALK L1152R were recorded 4 times in our database, and they concurred with EGFR actionable muts in 3 and 2 of the 4 records, respectively. Conclusions: ALK and EGFR actionable muts concurred at a relatively low frequency in our pts. In some cases, ALK muts were developed during EGFR-TKI therapies. Developed either together or sequentially, some combinations of EGFR and ALK muts, such as L858R with L1152R and EX19Indel with ALK fusion, may form more easily or may be preferable than other combinations for the development or evoluation of tumors.

scholarly journals Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance

2020 ◽  
Author(s):  
Xu Zhang ◽  
Tapan K. Maity ◽  
Karen E. Ross ◽  
Yue Qi ◽  
Constance M. Cultraro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Egfr Mutations ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Resistant Cells

AbstractLung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative mass spectrometry dataset to uncover alterations in signaling pathways, reveal a proteomic signature of epithelial mesenchymal transition (EMT) and identify kinases and phosphatases with altered expression and phosphorylation in TKI resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition resulting in inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified dactolisib, a PI3K/mTOR inhibitor, which in combination with osimertinib overcomes resistance both in vitro and in vivo.One Sentence SummaryGlobal quantitative proteome and phosphoproteome analyses to examine altered signaling pathways in isogenic 3rd generation EGFR TKI sensitive and resistant cells.

scholarly journals Effect of β-Blocker in Treatment-Naïve Patients With Advanced Lung Adenocarcinoma Receiving First-Generation EGFR-TKIs

2020 ◽  
Vol 10 ◽  
Author(s):  
Chia-Hao Chang ◽  
Chih-Hsin Lee ◽  
Jen-Chung Ko ◽  
Lih-Yu Chang ◽  
Ming-Chia Lee ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
First Generation ◽  
Treatment Naïve ◽  
Β Blocker ◽  
Egfr Tkis

scholarly journals EGFR-TKI resistance promotes immune escape in lung cancer via increased PD-L1 expression

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Shunli Peng ◽  
Rong Wang ◽  
Xiaojuan Zhang ◽  
Yueyun Ma ◽  
Longhui Zhong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune Escape ◽  
Objective Response ◽  
Tki Resistance ◽  
Before And After ◽  
Cytotoxicity Of Lymphocytes ◽  
Egfr Tki ◽  
Egfr T790m ◽  
Egfr Tkis

Abstract Background The ATLANTIC trial reported that higher PD-L1 expression in tumors was involved in a higher objective response in patients with EGFR+/ALK+ non-small cell lung cancer (NSCLC), indicating the possibility of anti-PD-1/PD-L1 therapy as a third-line (or later) treatment for advanced NSCLC. Therefore, the determination of status and regulatory mechanisms of PD-L1 in EGFR mutant NSCLC before and after acquired EGFR-TKIs resistance are meaningful. Methods The correlation among PD-L1, c-MET, and HGF was analyzed based on TCGA datasheets and paired NSCLC specimens before and after acquired EGFR-TKI resistance. EGFR-TKI resistant NSCLC cells with three well-known mechanisms, c-MET amplification, hepatocyte growth factor (HGF), and EGFR-T790M, were investigated to determinate PD-L1 expression status and immune escape ability. PD-L1-deleted EGFR-TKIs sensitive and resistant cells were used to evaluate the immune escape ability of tumors in mice xenograft models. Results Positive correlations were found among PD-L1, c-MET, and HGF, based on TCGA datasheets and paired NSCLC specimens. Moreover, the above three resistant mechanisms increased PD-L1 expression and attenuated activation and cytotoxicity of lymphocytes in vitro and in vivo, and downregulation of PD-L1 partially restored the cytotoxicity of lymphocytes. Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression. Conclusions HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.

ctDNA resistance landscape of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9601-9601
Author(s):  
Ji-Youn Han ◽  
Myung-Ju Ahn ◽  
Sang-We Kim ◽  
Ki Hyeong Lee ◽  
Eun Kyung Cho ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Resistance Mechanisms ◽  
Third Generation ◽  
Egfr Amplification ◽  
Phase 2 Trial ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
In Cis ◽  
Egfr Tki ◽  
Egfr Tkis

9601 Background: While EGFR mutant ( EGFRm) non-small cell lung cancer (NSCLC) patients usually experience improved clinical benefit with EGFR TKIs, most eventually progress. Understanding mechanisms of resistance (MoR) may allow for more personalized treatment. Lazertinib is an irreversible third generation EGFR TKI for which MoR are unknown. Obtaining sufficient tumor tissue for genotyping at progression is often difficult. Therefore, we utilized plasma ctDNA from patients treated with lazertinib to explore MoR. Methods: Plasma samples from 47 NSCLC patients in the phase 2 trial of lazertinib (NCT03046992) were collected at screening and progressive disease (PD) and underwent ctDNA NGS of 74 genes using Guarant360. All patients were positive for an EGFR Ex19del or L858R ( EGFRm) and T790M by tissue testing at screening. Acquired, nonsynonymous, characterized mutations detected in a PD sample but not in the screening sample from the respective patient were considered putative MoR, excluding aneuploidy. Patients with detectable plasma EGFRm and/or T790M at screening were evaluable. Results: ctDNA was detected in 47 (100%) screening samples and 43/45 (96%) PD samples (two failed sequencing). An EGFRm was detected in 85% of patients at screening (n = 40), 38 of which had PD ctDNA results and were included in analysis. T790M was detected in 30 patients at screening and subsequently not detected at PD in 21 of these patients, 55% of all 38 included patients. Among the ten patients with T790M detected at PD, on-target MoR were detected in 7 (18% of all included patients) including EGFR C797S (n = 3, 8%), EGFR amplification (n = 3, 8%), and EGFR T854A (n = 1, 3%). All C797S were in cis with T790M. No on-target MoR were detected in patients without T790M detected at PD. Off-target MoR were seen in 34% of patients (13/38) including mutations in PIK3CA (13%; 2 E545K, 2 E542K, 1 E81K), ERBB2 (5%; 1 D769H, 1 V777L), KRAS (3%; 1 G12C), and BRAF (3%; 1 G469A). Gene amplifications were detected in CCND1 (n = 1, 3%) , CCNE1 (n = 2, 5%) , ERBB2 (n = 1, 3%) , FGFR1 (n = 1, 3%) , MET (n = 4, 11%) , and PIK3CA (n = 1, 3%), with some patients having multiple MoR. Conclusions: The spectrum of MoR identified in this cohort of patients treated with lazertinib is similar to that reported in other third generation EGFR TKIs, but with some differences in frequencies. The most common resistance mechanisms are T790M loss and PIK3CA alterations which may address the mechanism of action. Our findings suggest putative MoR of lazertinib and show that ctDNA NGS is an effective way to identify MoR in patients progressing on targeted therapy. Clinical trial information: NCT03046992 .

scholarly journals Reduced PHLPP Expression Leads to EGFR-TKI Resistance in Lung Cancer by Activating PI3K-AKT and MAPK-ERK Dual Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Wei Wang ◽  
Xinhang Xia ◽  
Kuifei Chen ◽  
Meng Chen ◽  
Yinnan Meng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Cell Lines ◽  
Nsclc Cell ◽  
Erk Pathway ◽  
Tki Resistance ◽  
Pre Treatment ◽  
Gefitinib Resistance ◽  
Egfr Tki ◽  
Egfr Tkis

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective in advanced EGFR-mutation non-small cell lung cancer (NSCLC) but the magnitude of tumor regression varies, and drug resistance is unavoidable. The pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) levels are reduced or lost and acts as a tumor suppressor in many cancers. Here, we hypothesized that PHLPP is a key regulator of EGFR-TKI sensitivity and a potential treatment target for overcoming resistance to EGFR-TKI in lung cancer.MethodsCell proliferation and growth inhibition were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assay. PHLPP- knockdown stable cell lines were generated by lentivirus-mediated delivery of PHLPP shRNAs. The expression of PHLPP mRNA and protein levels was detected by real-time quantitative polymerase chain reaction (qPCR) and Western blotting. Immunohistochemical (IHC) staining was performed to detect the PHLPP expression in clinical patient tissue samples. A transcriptomic assay of genome-wide RNA expressions of PHLPP in NSCLC cell lines according to gefitinib sensitivity was obtained from Gene Expression Omnibus (GEO) database. Murine xenograft model was established to verify the function of PHLPP in gefitinib resistance in vivo.ResultsPHLPP highly expressed in gefitinib-sensitive NSCLC cell lines than gefitinib-resistant NSCLC cell lines. In gefitinib-acquired resistance cell line HCC827-GR, PHLPP expression even dramatically reduced. Knockdown of PHLPP in NSCLC cells decreased cell death induced by the EGFR-TKI, while overexpression PHLPP in gefitinib-resistance NSCLC cells can enhance or restore EGFR-TKIs sensitivity. Mechanism study indicated that PHLPP downregulation attenuates the effect of EGFR-TKI on the both AKT and ERK pathway, thereby decreasing the cell death sensitivity to EGFR inhibitors. In xenograft mice, knockdown of PHLPP decreased tumor response to gefitinib and advanced tumor cells re-growth after gefitinib treatment. In clinical, PHLPP expression were reduced in the post-relapse tumor compared to that of pre-treatment, and lower pre-treatment PHLPP levels were significantly correlated with shorter progression-free survival (PFS) in patients with EGFR-mutant lung adenocarcinoma whom treated with EGFR-TKI.ConclusionsOur data strongly demonstrated that loss of PHLPP function was a key factor of EGFR-TKI resistance in NSCLC. Downregulated PHLPP expression activated PI3K-AKT and MAPK-ERK pathway which strengthened cell survival to EGFR-TKI. Therefore, PHLPP expression level was not only a potential biomarker to predict EGFR-TKIs sensitivity but also as a therapeutic target in EGFR-TKIs therapy, enhancing PHLPP expression may be a valuable strategy for delaying or overcoming EGFR-TKIs drug resistance.

scholarly journals Patients Harboring Uncommon EGFR Exon 19 Deletion-insertion Mutations Respond Well to First-generation EGFR Inhibitors and Osimeritinib Upon Acquisition of T790M

2021 ◽  
Author(s):  
Yurong Wang ◽  
Ruipan Zheng ◽  
Peizhu Hu ◽  
Ziheng Zhang ◽  
Shujing Shen ◽  
...  
Keyword(s):  
First Generation ◽  
Resistance Mutation ◽  
Resistance Mechanisms ◽  
First Line ◽  
T790m Mutation ◽  
Similar Treatment ◽  
Significant Difference ◽  
Exon 19 Deletion ◽  
Egfr Tkis ◽  
Exon 19

Abstract Background: This study is to investigate the effects and resistance mechanisms of first-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in non-small cell lung cancer (NSCLC) patients carrying rare EGFR exon 19 deletion-insertion (19delins) mutations. Methods: The next generation sequencing (NGS) data of 1783 patients diagnosed as advanced NSCLC from November 2017 to September 2020 were successively and retrospectively reviewed. 41 patients with EGFR 19delins and 41 patients with EGFR exon 19 deletion (19del) were enrolled in this study, who were given first generation EGFR TKIs as first-line therapy. Results: 17 mutation types of EGFR 19delins were identified in this study, L747_P753delinsS (10/41) and L747_A750delinsP (9/41) were the most frequent mutation types, followed by L747_T751delinsP (6/41) and E746_S752delinsV (3/41). Under the same baseline characteristics, median progression-free survival (mPFS) was similar in patients with EGFR 19delins to those with EGFR 19del (10.4 months vs. 13.1 months, p=0.1076). Interestingly, patients with L747_T751delinsP had a better mPFS than those with other variants (18.7 months vs. 13.1 months, p=0.035). No significant difference in mPFS was found among the three groups of gefitinib, icotinib, and erlotinb with 14.7 months, 10.9 months, and 13.1 months (p>0.05). After progression from first-line EGFR TKIs, both EGFR 19delins and EGFR 19del had similar rates of developing resistance mechanisms including EGFR T790M mutation (45.8% vs. 57.8%). Patients acquiring T790M mutation received osimeritinib as second-line treatment, and the mPFS was similar between the groups of EGFR 19delins (n=8) and EGFR 19del (n=10): 12.0 months vs. 12.2 months (p=0.97). Conclusion: Our results indicate that patients with uncommon EGFR 19delins can also benefit from first-generation EGFR TKIs treatment, having similar treatment responses and survival outcomes to those with EGFR 19del, even similar clinical outcomes from osimeritinib upon acquiring T790M resistance mutation.

scholarly journals Efficacy of EGFR-TKI Plus Chemotherapy or Monotherapy as First-Line Treatment for Advanced EGFR-Mutant Lung Adenocarcinoma Patients With Co-Mutations

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhengyu Yang ◽  
Ya Chen ◽  
Yanan Wang ◽  
Shuyuan Wang ◽  
Minjuan Hu ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
First Generation ◽  
Progression Free Survival ◽  
Poor Response ◽  
Time To Progression ◽  
Free Survival ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Generation Sequencing ◽  
Egfr Tkis

BackgroundCo-mutations was associated with poor response to EGFR-TKIs. First-generation EGFR-TKIs combined with chemotherapy was reported to be more effective than TKIs alone in advanced lung adenocarcinoma patients.ObjectiveThis retrospective study aimed to explore whether EGFR-mutant patients with co-mutations can benefit from EGFR-TKIs plus chemotherapy.Patients and MethodsWe retrospectively collected data of 137 EGFR-mutant patients with advanced lung adenocarcinoma who underwent next-generation sequencing in our hospital in 2018. Among them, 96 were treated with EGFR–TKIs alone and 41 received EGFR–TKIs plus chemotherapy. We analyzed the progression-free survival (PFS) of patients with co-mutations using different treatments.ResultsConcurrent TP53 mutations, especially exon 4 and 6, were associated with a markedly shorter time to progression on EGFR-TKI monotherapy (11.4 months vs. 16.6 months, P=0.003), while EGFR–TKIs plus chemotherapy would benefit those patients more (with TP53: 11.4 months vs. 19.1 months, P=0.001, HR=0.407; without TP53: 16.6 months vs. 18.9 months, P=0.379, HR=0.706). The incidence of T790M after resistance was equal in patients treated with different treatments (53% vs. 53%, P=0.985).ConclusionsIn our study, concurrent TP53 mutations were found to be risk factors for EGFR-TKI monotherapy, but TKI combined with chemotherapy could eliminate this heterogeneity.

scholarly journals Hypothesis generative head-to-head study comparing efficacy of afatinib and osimertinib based on immunological biomarkers in Japanese NSCLC patients with EGFR mutations (Heat on Beat study)

2020 ◽  
Vol 12 ◽  
pp. 175883592096725
Author(s):  
Kei Morikawa ◽  
Hisashi Tanaka ◽  
Hidetoshi Itani ◽  
Saori Takata ◽  
Satoshi Watanabe ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Immune Checkpoint ◽  
Japanese Patients ◽  
Advanced Lung Cancer ◽  
Treatment Naïve ◽  
Egfr Mutant ◽  
Nsclc Patients ◽  
Egfr Tki ◽  
Egfr Tkis

Background: In the FLAURA trial, superiority of osimertinib over the standard of care (SOC) was not demonstrated in Asian patients; SOC seemed favorable among Japanese patients (hazard ratio 1.39, 95% confidence interval 0.82–2.33). Three reasons are suggested: since rechallenge with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is covered by health insurance in Japan, EGFR-TKI rechallenge rate was higher in SOC than in the osimertinib group, which resulted in a long-term sequential administration of EGFR-TKIs; treatment discontinuation rate was high in the osimertinib group due to adverse events such as interstitial pneumonia among Japanese patients. EGFR-TKIs enhance tumor antigen-specific cytotoxicity of T cells, especially first- and second-generation EGFR-TKIs, which are more active against various cells with wild-type EGFR, including regulatory T cells. Consequently, subsequent immune checkpoint inhibitor therapy seemed more promising in the SOC group. Therefore, optimal first-line EGFR-TKI for EGFR-mutant advanced lung cancer may not have been identified in Japanese patients. Methods: The Heat on Beat study is a randomized, open-label, multicenter, phase II study to compare OS between initial treatment with afatinib and osimertinib in treatment-naïve patients with advanced or recurrent EGFR-mutant NSCLC. Exploration of immunomonitoring through peripheral blood mononuclear cells will also be performed, before, during, and after treatment. Treatment-naïve EGFR mutation-positive non-small cell lung cancer (NSCLC) patients ( N = 100) will be randomized to two groups in a 1:1 ratio. The co-primary endpoints are 3-year survival rate and characterization of immune environment associated with response to afatinib, osimertinib, or immune checkpoint inhibitors. Enrollment will start in May 2020 at 28 sites in Japan and continue for 1 year, with 3-year follow-up. Discussion: Because there is no clinical trial comparing second- with third-generation EGFR-TKI for advanced EGFR-mutant NSCLC, our study would provide a major impact on clinical practice. Trial registration Japan Registry of Clinical Trials, jRCTs031190221, registered date: 25 February 2020, https://jrct.niph.go.jp/en-latest-detail/jRCTs031190221

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