scholarly journals 3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

2021 ◽  
Author(s):  
Ismail M. Meraz ◽  
Mourad Majidi ◽  
Bingliang Fang ◽  
Feng Meng ◽  
Lihui Gao ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Acquired Resistance ◽  
Selective Inhibition ◽  
Resistance Mechanisms ◽  
Humanized Mice ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Knock Out ◽  
Immunosuppressive Tumor Microenvironment ◽  
Phosphoinositide Dependent Kinase

AbstractOsimertinib sensitive and resistant NSCLC NCI-H1975 clones were used to model osimertinib acquired resistance in humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation were found in resistant clones. Resistant tumors in humanized mice were initially partially responsive to osimertinib, then aggressive tumor regrowth occurred accompanied by an immunosuppressive tumor microenvironment. 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitized resistant clones and a patient derived xenograft (PDX) with acquired resistance to osimertinib. PDK1 knock-out dysregulated PI3K/Akt/mTOR signaling, promoted cell cycle arrest at the G1 phase, and inhibited nuclear translocation of yes-associated protein (YAP). Higher expression of PDK1 was found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.

Novel resistance mechanisms to first-generation EGFR tyrosine kinase inhibitors: A perspective study in NSCLC patients using targeted next generation sequencing.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20576-e20576
Author(s):  
Ying Jin ◽  
Jianjun Zhang ◽  
Ming Chen ◽  
Yang Shao ◽  
Xun Shi ◽  
...  
Keyword(s):  
First Generation ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Targeted Next Generation Sequencing ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Nsclc Patients ◽  
Egfr T790m

e20576 Background:Patients with non-small-cell lung cancer (NSCLC) harboring sensitive epithelial growth factor receptor (EGFR) mutations invariably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Identification of actionable mutations conferring drug-resistance can be helpful for guiding the subsequent treatment decision. Currently, the known mechanisms of acquired resistance includes: the secondary gatekeeper EGFR-T790M mutation, activation of members of downstream signaling pathways such as PI3K/AKT/mTOR pathway, activation of bypass signaling such as MET, and changes in tumor histology. However, the mechanisms in the remaining patients are still unknown. Methods:In this prospective study, thirty-one advanced NSCLC patients initially carrying sensitive EGFR mutations and subsequently developing acquired resistance to the first-generation EGFR-TKIs were enrolled. Pre-treatment tumor samples as well as re-biopsies of tumor and plasma when the patients were diagnosed with EGFR-TKI resistance were acquired, followed by mutation profiling using targeted next generation sequencing (NGS) on 416 cancer-related genes. Results: In total, 55% of patients were identified to carry acquired secondary EGFR-T790M mutation. Three patients (~10%) harbor EGFR-T854A mutation, which has been reported as another TKI resistant mutation. 26% and 19% of cases accumulated TP53 and RB1 mutations, respectively. In T790M/T854A-negative cases, 30% of patients acquired MET amplification. Other potential acquired resistance mechanisms includes single nucleotide variants (SNVs) in genes such as SMAD4, DNMT3A, GNAS, ATM, KRAS, PIK3CA and TET2, and copy number variations (CNVs) in genes such as CDK4, MDM2, MYC, RICTOR and ERBB2. Conclusions:The study depicted the genetic landscapes comprehensively in matched pre- and post-EGFR-TKIs samples of NSCLC population resistant to first generation TKI treatments. Our analysis demonstrates new perspectives for further study of resistance and putting forward corresponding relevant tactics against the challenge of disease progression. Clinical trial information: NCT02804217.

scholarly journals Triple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC

2019 ◽  
Vol 12 (2) ◽  
pp. 625-630 ◽  
Author(s):  
Mike Ralki ◽  
Brigitte Maes ◽  
Karin Pat ◽  
Jokke Wynants ◽  
Kristof Cuppens
Keyword(s):  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Resistance Mechanisms ◽  
First Line ◽  
T790m Mutation ◽  
Her2 Mutation ◽  
Egfr Mutant ◽  
Egfr Tki

Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response.This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.

Blood-based genomic profiling of circulating cell-free tumor DNA (ctDNA) in 1397 patients (pts) with colorectal cancer (CRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 584-584
Author(s):  
John H. Strickler ◽  
Kimberly C. Banks ◽  
Rebecca J Nagy ◽  
Richard B. Lanman ◽  
AmirAli Talasaz ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Jak2 V617f ◽  
Resistance Mechanisms ◽  
The Body ◽  
Egfr Mutations ◽  
Genomic Alteration ◽  
Genomic Profiling ◽  
Single Nucleotide Variants ◽  
Genomic Alterations ◽  
Clinical Potential

584 Background: ctDNA is shed into the bloodstream by tumor cells throughout the body, offering a non-invasive means of genomic testing, and a way to detect heterogeneous, subclonal genomic alterations present in distinct tumor lesions within an individual pt. However, a broad comparison of mutation prevalence in CRC ctDNA versus CRC tumor tissue has not yet been performed. Methods: ctDNA from 1397 CRC pts was analyzed using a CLIA-certified digital sequencing assay (Guardant360, Guardant Health) capable of detecting single nucleotide variants (SNV) in up to 70 genes, as well as selected insertions/deletions, amplifications, and fusions. Subclonal mutations were defined as mutations with mutant allele fractions (MAF) ≤ 50% of the greatest somatic MAF in the sample. Frequencies of mutations detected were compared to two large tissue-based sequencing databases (TCGA and NHS/HPS). Results: 1500/1772 (85%) tests had at least one genomic alteration (1397 unique pts). The most common SNV mutations included TP53 (62%), APC (47%), KRAS (39%), PIK3CA (17%), EGFR (11%), SMAD4 (11%), and BRAF (11%); these frequencies were comparable to rates in TCGA and NHS/HPS. In contrast, EGFR extracellular domain (ECD) mutations (42 pts) and JAK2 V617F mutations (16 pts) detected in ctDNA were not seen in tissue sequencing, reflecting acquired resistance to EGFR antibodies and clonal hematopoiesis of indeterminate clinical potential, respectively. 88% of pts with ECD mutations had at least one additional non-ECD resistance alteration detected in ctDNA (range 1-9, median 2.6), including KRAS, NRAS, BRAF, MAP2K1, MET and ERBB2. EGFR mutations were most likely to be detected as subclonal (86%), while mutations most likely to be clonal included KRAS (71%), TP53 (65%), BRAF (65%), and APC(63%). In 84 pts with serial monitoring, 87% had either gain (61%) or loss (63%) of clones over time. Conclusions: Blood-based genomic profiling can effectively detect common genomic alterations in CRC at comparable frequencies as observed in tissue and provide novel insights into tumor clonality and clonal dynamics. Clinical trials to target EGFR ECD mutations may be limited by the multiplicity of resistance mechanisms in each pt.

Secondary T790M mutation and novel G796A mutation in exon20 of EGFR gene in patients with non-small cell lung cancer who show resistance to gefitinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7703-7703
Author(s):  
H. Uramoto ◽  
K. Sugio ◽  
T. Oyama ◽  
T. Iwata ◽  
T. Onizuka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Missense Mutation ◽  
Cell Lung Cancer ◽  
Acquired Resistance ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Egfr Gene

7703 Background: Somatically acquired mutations in the EGFR gene in non-small cell lung cancer are associated with a significant clinical response to a tyrosine kinase inhibitor (TKI). EGFR mutations occur predominantly in exon19 and/or exon21, namely, an in-frame deletion in exon19 or a missense mutation in exon21 (L858R), which have been found to be related to the sensitivity to TKI. However, most patients with such sensitive mutations in their tumor show progression during the TKI treatment. In such resistant tumors, a secondary threonine- to-methionine mutation at codon 790 (T790M) in exon20 has been reported to be related the resistance to either gefitinib or erlotinib. Methods: EGFR mutations in exons19–21 were examined by sequencing in 37 pretreatment tumors obtained from patients with NSCLC, who were treated by gefitinib. Of the 22 cases having sensitive EGFR mutations (19del or L858R), 15 showed CR/PR and 7 showed SD/PD. Of the 15 patients with CR/PR, 4 tumor samples (2 lung, 1 liver, and 1 pleural effusion) that became refractory to gefitinib, were obtained. In pretreatment tumor samples from 4 patients, an in-frame deletion of exon19 was observed in 3 tumors and a L858R mutation of exon21 was in 1 tumor. We next examined whether a secondary mutation occurred in a tumor with acquired resistance to gefitinib in 4 patients by the sequencing of exons 19–21, with informed consent. Results: Three of 4 tumor samples had a secondary T790M mutation, which was not detected in the pretreatment tumor samples. These 3 samples also had an in-frame deletion in exon19. There were no other novel secondary mutations in exons 19,20,21. In 7 cases showing resistance to gefitinib (SD/PD) in spite of the existence of sensitive mutations, 1 tumor demonstrated the co-existence of a missense mutation (G796A) in exon20. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to the cells carrying exon19 deletion. Conclusions: The T790M mutation is common in patients with acquired resistance to gefitinb. Our results suggest that screening tumor samples for a range of EGFR mutations may therefore improve our ability to identify the patients most likely to benefit from treatment with TKI. No significant financial relationships to disclose.

A static diagnostic biopsy in patients with mutated EGFR lung adenocarcinom to guide therapeutic decisions.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18039-e18039
Author(s):  
Giuseppe Altavilla ◽  
Mariacarmela Santarpia ◽  
Carmela Arrigo ◽  
Chiara Tomasello ◽  
Sara Benecchi ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chemotherapy Regimen ◽  
Acquired Resistance ◽  
Resistance Mutation ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Pik3ca Mutations ◽  
Met Amplification ◽  
Therapeutic Decisions ◽  
Tumor Biopsies

e18039 Background: Approximately 70% of the pts. whose lung cancers harbor EGFR mutations acquire drug resistence after a response to EGFR tyrosine kinase inhibitors (TKIs) treatment; this acquired resistance is mainly due to a secondary mutation in EGFR (T790 M) in about 50% of patients, amplification of MET in 15%, PIK3CA mutations in 5%, an unknown mechanism in almost 30%, and SCLC transformation in some patients. Furthermore, clinical experience revealed that cancers with acquired resistance can respond again to TKIs, after a drug-free interval. To aid in identification and treatment of these patients we examined a cohort of patients whose cancers were assessed with tumor biopsies at multiple times before and after their treatment with TKIs. Methods: 21 lung adenocarcinomas pts. (10 male, 11 female, median age 53 years) with EGFR mutations at 19 or 21 exons received TKIs, as first line of treatment. All showed a clinical response and all relapsed ( mTTP 10 months). At the time of relapse a new biopsy was performed, histologic samples were reviewed to re-confirm the diagnosis, EGFR and MET amplification were identified by FISH, while EGFR mutations have been tested by DNA sequencing. Results: At the time that drug resistence was acquired all pts. retained their original activating EGFR mutations, 9 pts. developed EGFR T790M resistance mutation with pronunced EGFR amplification in 3, 2 pts. developed MET amplification, 8 biopsies did not reveal any new mutations, two pts. were found to have a diagnosis of small cell lung cancer in their drug resistant tumor biopsies and responded well to conventional chemotherapy regimen.15 of 19 confirmed lung adenocarcinoma patient underwent to a cisplatin - pemetrexed chemotherapy regimen and at the time of progression 10 of them accepted to undergo a new biopsy. Three pts. ( after 4, 5 and 6 months break from treatment with TKIs ) lost T790M mutation and their disease responded to a second-line course of erlotinib. Conclusions: In our cohort of pts. with acquired EGFR resistence some patients lost acquired T790M mutation and become sensitive to EGFR inhibitor, in addition, two pts. underwent the histologic transformation from NSCLC to SCLC at the time of TKI resistence.

Erlotinib as a salvage treatment for patients with advanced non-small cell lung cancer after failure of gefitinib treatment: Is there a rationale for a clinical trial?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19099-e19099
Author(s):  
Nello Salesi ◽  
Barbara Di Cocco ◽  
Francesca Calabretta ◽  
Alida Armida Ciorra ◽  
Crescenzo Cirino ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Biologically Active ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Free Survival ◽  
Tki Resistance ◽  
Egfr Mutated

e19099 Background: Patients (pts) with advanced NSCLC and sensitizing EGFR mutations who initially respond to gefitinib or erlotinib eventually develop acquired resistance to the TKIs. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated pts resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. Methods: Retrospective review of 5 EGFR mutated (exon 19 deletions) patients that were given gefitinib and subsequently erlotinib. Results: All pts responded to gefitinib with median progression-free survival of 13 months (95% confidence interval, 4-16). After gefitinib resistance, 60% (3 of 5) of these pts displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). These pts acquired the T790M mutation. 2 gefitinib-resistant pts with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. In literature doesn’t exist a prospective study about the stratification of pts ordered by PS, age, gender, smoker/non-smoker, which could test the efficiency of the erlotinib after gefitinib in pts with different EGFR mutations. We only have at our disposal few studies control-case in non-selected pts which show a potential efficiency of erlotinib after the failure of the gefitinib, nevertheless, without an evident increase of the overall survival. Conclusions: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most pts. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.

SAVANNAH: A Phase II trial of osimertinib plus savolitinib for patients (pts) with EGFR-mutant, MET-driven (MET+), locally advanced or metastatic non-small cell lung cancer (NSCLC), following disease progression on osimertinib.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9119-TPS9119 ◽  
Author(s):  
Geoffrey R. Oxnard ◽  
Mireille Cantarini ◽  
Paul Frewer ◽  
George Hawkins ◽  
Jane Peters ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Acquired Resistance ◽  
Resistance Mechanisms ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Survival Duration ◽  
Common Mechanism ◽  
Egfr Mutant

TPS9119 Background: The toxicity profile of the third-generation EGFR-tyrosine kinase inhibitor (TKI) osimertinib makes it an attractive backbone for combination with other targeted agents, possibly overcoming acquired resistance mechanisms. Combination with a MET-inhibitor is an intuitive approach as MET-amplification was identified as the most common mechanism of resistance to osimertinib in preliminary ctDNA data from the Phase III FLAURA (15% of pts) and AURA3 (19% of pts) studies. Savolitinib (AZD6094, HMPL-504, volitinib) is an oral, potent and highly selective MET-TKI that had an acceptable safety profile when combined with osimertinib in the Phase Ib TATTON study, providing the basis for this Phase II SAVANNAH study (NCT03778229). Other mechanisms of acquired resistance to osimertinib, including secondary EGFR mutations (e.g. C797S), RAS/RAF activation, and oncogenic gene fusions, provide additional opportunities for developing osimertinib-based combinations. Methods: Eligible pts will have histologically/cytologically confirmed EGFR-mutant NSCLC, and MET+ disease by central FISH, central IHC, or local NGS (retrospectively confirmed by central FISH/IHC). Pts must have documented radiological progression following 1–3 lines of prior therapy (must include osimertinib). Pts will receive osimertinib 80 mg plus weight-based dosing with savolitinib 300 or 600 mg PO QD, in 28-day cycles. The primary objective is efficacy (RECIST 1.1) by overall response rate (ORR) in pts who are MET+ by central FISH. Secondary endpoints include: ORR ( MET+ by central IHC and all pts); progression-free survival, overall survival, duration of response, percent change in tumor size, HRQoL, and EGFR mutation ctDNA clearance ( MET+ by central FISH, central IHC, and all pts); safety, and pharmacokinetics (all pts). Based on the TATTON study, we anticipate enrolling ~172 MET+ pts to include ≥117 pts with MET+ disease by central FISH. Enrolment began in Q1 2019. Ongoing development of complementary trials targeting other osimertinib resistance mechanisms will also be discussed. Clinical trial information: NCT03778229.

scholarly journals Efficacy and acquired resistance for EGFR-TKI plus thoracic SBRT in patients with advanced EGFR-mutant non–small-cell lung cancer: a propensity-matched retrospective study

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Xia Wang ◽  
Zhimin Zeng ◽  
Jing Cai ◽  
Peng Xu ◽  
Pingan Liang ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
Control Group ◽  
Real World Data ◽  
Baseline Characteristics

Abstract Background This retrospective study aimed to evaluate the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with stereotactic body radiation therapy (SBRT) and to elucidate potential mechanisms of acquired resistance. Methods Patients with advanced NSCLC harboring positive EGFR mutations after initial TKI therapy for at least 8 weeks were eligible for SBRT between August 2016 and August 2019. Eligible patients were treated with thoracic SBRT, and TKI was continued after SBRT until it was considered ineffective. The control group was treated with TKIs monotherapy. Propensity score matching (PSM, ratio of 1:2) was used to account for differences in baseline characteristics. Overall survival (OS), progression-free survival (PFS), treatment safety and resistance mechanisms were evaluated. Results Three hundred eight patients were included in the study population. Among them, 262 patients received TKIs alone, and 46 patients received TKIs with SBRT. Baseline characteristics were not significantly different between the two cohorts after PSM. The median PFS was 19.4 months in the TKIs +SBRT group compared to 13.7 months in the TKIs group (p = 0.034). An influence on OS has not yet been shown (p = 0.557). Of the 135 patients evaluated after PSM, 28 and 71 patients in the TKIs and TKIs +SBRT cohorts, respectively, had plasma cell-free DNA (cfDNA) next-generation sequencing (NGS) performed at baseline and disease progression. In the TKIs +SBRT cohort, the NGS results showed that T790M mutations were detected in 64.3% (18/28) of patients. Patients in the TKIs cohort exhibited fewer T790M-positive mutations (40.8%, p = 0.035) compared to patients in the TKIs +SBRT cohort. Conclusion Real world data prove that TKIs plus thoracic SBRT significantly extend PFS with tolerable toxicity. The mutation ratio of T790M was increased in the TKIs +SBRT group compared to the TKIs only group. Further randomized studies are warranted.

Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients (p) with acquired resistance to erlotinib.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11010-11010 ◽  
Author(s):  
Jonathan S. Weissman ◽  
Petros Giannikopoulos ◽  
John St. John ◽  
Andrew V. Uzilov ◽  
Carlota Costa ◽  
...  
Keyword(s):  
Stem Cell ◽  
Transcriptome Sequencing ◽  
Acquired Resistance ◽  
Embryonic Stem ◽  
Genomic Analysis ◽  
Egfr Mutations ◽  
T790m Mutation ◽  
Tissue Samples ◽  
Whole Exome ◽  
Egfr Mutant

11010 Background: NSCLC p with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been performed. Methods: FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 11 EGFR mutant NSCLC p. DNA was extracted from all tumor and corresponding normal tissue samples and underwent whole exome sequencing using the Illumina HiSeq2500. RNA was extracted from all tumor samples and analyzed by whole transcriptome sequencing, also using the Illumina HiSeq2500. Results: Erlotinib resistant NSCLC specimens harbored upregulation of known resistance drivers including MET and AXL and novel alterations including upregulation of genes that are: 1) recurrently mutated in NSCLC, including ALK, STK11; 2) components of established embryonic stem cell signatures, including targets of Nanog, Oct4, Sox2, c-Myc, 3) neuronal lineage specific regulators, including NTRK3, NRCAM, ALK, LRP4. The analysis also revealed downregulation of several genes that are: 1) components of innate and acquired immunity, including HLA-A, -B, DQ, CD40; 2) phosphatases regulating survival signaling pathways, including PTEN, PTPRD, 3) proapoptotic components, including BNIP3L, IKIP. Conclusions: This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC p receiving targeted therapy. We identified known and novel molecular biomarkers of erlotinib acquired resistance in NSCLC p, and uncovered a previously unappreciated role for genetic events governing stem cell and neuronal phenotypes as well as immune evasion in erlotinib acquired resistance in NSCLC p. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC p.

Rebiopsy in TKI-resistance: A retrospective analysis.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8065-8065
Author(s):  
Justine Leonie Kuiper ◽  
Danielle Heideman ◽  
Erik Thunnissen ◽  
M A Paul ◽  
Egbert F. Smit
Keyword(s):  
Kras Mutation ◽  
Egfr Mutation ◽  
Objective Response ◽  
Acquired Resistance ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Second Primary ◽  
T790m Mutation ◽  
Tki Resistance ◽  
Tki Treatment

8065 Background: EGFR-TKI provides a clinical benefit in patients with EGFR-mutated NSCLC with median progression-free survival (PFS) of 12 months. Several resistance mechanisms (e.g. T790M mutation) have been described, however data are sparse. We analysed EGFR-mutation spectra in NSCLC patients with acquired resistance to TKI. Methods: Biopsies from patients with EGFR-mutation or TKI-response>24 weeks with both pre- and post TKI biopsy available were retrospectively analysed. Information was collected from the medical record. Response to TKI-treatment was assessed according to RECIST. PFS after TKI-treatment was calculated with a Kaplan-Meier curve. Results: 63 patients were included for analysis. Pre- and post TKI biopsy results are described in the Table. 32 patients received 1 (38%), 2 (10%) or 3 (3%) lines of chemotherapy before start of TKI and 18 patients received 1 (13%), 2 (11%), 3 (3%), or 5 (2%) lines of therapy after TKI treatment. Median PFS on TKI-treatment was 12,3 months (range: 1,4 – 43,2). Objective response rate was 61,9%. 47,6% of patients developed the T790M mutation. One patient developed transformation to SCLC with the original exon 19 deletion. One patient with pre-TKI an exon 18 + exon 21 mutation was found to have a KRAS-mutation post-TKI. Conclusions: In this cohort, frequency of development of T790M mutation was consistent with earlier reports. Transformation to SCLC occurred less than described earlier. Two patients did not retain their original mutation. Surprisingly, one patient developed a KRAS mutation: a second primary tumor is not excluded in this case. Rebiopsy in TKI-resistance provides important information on dynamic tumour characteristics and has management implications in certain patients. [Table: see text]

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