Treatment strategies after failure to reversible tyrosine kinase inhibitors (rTKI) in EGFR mutant (mut) non-small cell lung cancer (NSCLC) patients (p): A retrospective analysis of 41 Spanish p.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19089-e19089
Author(s):  
Jordi Remon ◽  
Teresa Moran ◽  
Diego Alcaraz ◽  
Laia Capdevila ◽  
Rut Porta ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Treatment Strategies ◽  
Local Therapy ◽  
Stage Iv ◽  
Standard Of Care ◽  
Therapeutic Strategies ◽  
Egfr Mutations ◽  
First Line Therapy ◽  
Egfr Mutant

e19089 Background: Different therapeutic approaches have been used in the clinical setting in NSCLC p harbouring EGFR mutations progressing to rTKI, although the standard of care in this situation is still not well established. Methods: A multi-institutional database from four different centers in Spain was review to identify EGFR mut p with acquired resistance to rTKI in order to evaluate the therapeutic strategies after rTKI failure and the effect on the post-progression survival (PPS) of these treatments. Results: 41 p with acquired resistance to rTKI were identified: 63% female; median (m) age 62 ±11 yrs; 95% Caucasian; del19 76%, never or light former smokers 100%; 90.2% adenocarcinomas; 51 % received TKI as first line therapy; 85% were initial stage IV .mPFS for the rTKI was 8.4 months (mo) and mOS was 29.7 mo for the entire population. P were treated with a median of 2 therapeutic strategies after the rTKI failure. 6 therapeutic strategies have been identified. As immediate approach, 16 p were switched to chemotherapy (CT) with a mPPS of 3 mo. 9 p were switched to an irreversible TKI obtaining a mPPS of 3.9 mo. rTKI plus other drug was maintained in 11 p: rTKI plus CT in 9 p with a mPPS of 4 mo and rTKI plus other drug different to CT in 2 with a mPPS of 2 mo. Despite the progression, rTKI was maintained in 2 p considered slow progressors and local therapy, in addition to the rTKI, was administered in 3 p with oligoM1progressive disease obtaining a mPPS of 1.4 and 36 mo, respectively. 8 p were treated sequentially with ≥5 strategies. These p attained a mOS of 27.7 mo. Conclusions: The combination of different strategies when treating EGFR mut p after rTKI failure may impact the survival especially when p are candidates to receive some of this treatments sequentially. These strategies may reflect different subsets of EGFR mut disease.

Oncogenic alterations detected by droplet digital PCR in patients with metastatic colorectal cancer resistant to cetuximab.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 575-575
Author(s):  
Rujiao Liu ◽  
Zhi-Yu Chen ◽  
Weijian Guo ◽  
Xiaodong Zhu ◽  
Mingzhu Huang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Acquired Resistance ◽  
Standard Of Care ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Egfr Mutations ◽  
Exon 2 ◽  
First Line Therapy ◽  
Line Setting

575 Background: Anti-EGFR therapy is the standard of care for metastatic colorectal cancer (mCRC) patients with RAS and BRAF genes wild type (wt). Secondary alterations of several genes have been identified as possibly resistant mechanisms to EGFR blockade, these including mutations of KRAS, NRAS, BRAF, MEK and EGFR ectodomain, as well as amplifications of HER2 and c-MET. In this study, we investigated alterations of these targeted genes for mCRC patients with acquired resistance to cetuximab treatment by using non-invasive droplet digital PCR (ddPCR) method within circulating DNA. Methods: We enrolled 38 RAS and BRAF wt patients, who progressed after failure of cetuximab contained regimens between Jul 2015 and Jan 2018. Plasma samples from all 38 patients were collected and detected for seven candidates (mutation of KRAS, NRAS, EGFR, BRAF, MEK, amplification of HER2, c-MET) by using ddPCR at the time of baseline, each evaluation by interval of 2 months and documented progression. All clinical parameters were collected simultaneously. Results: A total of 23 secondary alterations were found in 17 (17/38,44.7%) cetuximab resistant patients. The targeted gene alterations were detected as follows: 9 (9/23,39%) RAS mutations, 5 (22%) HER2 amplifications, 5 (22%) EGFR mutations, 2 (9%) c-MET amplifications, 1 (4%) BRAF and 1 MEK mutation. Among 17 patients, 6 patients had multiple alterations, including 2 patients with KRAS+EGFR mutations, 2 patients with HER2+c-MET co-amplifications and 2 patients with KRAS gene exon 2 and 3 multiple mutations. Primary sites were 15 left sides and 2 right sides, descending colon (12 cases) was the most common origins. Eleven patients were synchronous disease. Twelve patients received cetuximab as first line therapy, whereas 5 patients in the ≥ 2nd line setting. All of these 17 patients, plasma levels of oncogenic alterations detected by ddPCR were showed dynamic changing and good agreement with tumor responding status. Conclusions: Oncogenic alterations detected by ddPCR were found in almost half mCRC patients resistant to cetuximab. Dynamic changes of specific alteration may facilitate making decisions for selection of anti-EGFR mAb during the treatment course.

Incidence, characteristics, and survival of patients with EGFR-mutant lung cancers with EGFR T790M at diagnosis identified in the lung cancer mutation consortium (LCMC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8085-8085
Author(s):  
Mark G. Kris ◽  
Geoffrey R. Oxnard ◽  
Bruce E. Johnson ◽  
Lynne D Berry ◽  
Heidi Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Egfr Mutation ◽  
Acquired Resistance ◽  
Stage Iv ◽  
Egfr Mutations ◽  
Lung Cancers ◽  
Exon 20 ◽  
Egfr Mutant ◽  
Egfr T790m ◽  
Exon 19

8085 Background: Somatic T790M mutations are detected in 62% of EGFR-mutant lung cancers with acquired resistance to EGFR TKIs, and have rarely been identified in the tumor at diagnosis and/or within the germline DNA. Multiplexed genotyping by the LCMC permitted us to evaluate the incidence of T790M at diagnosis, co-mutations, and survival of patients with this driver. Methods: The 14 member LCMC prospectively tested tumors of patients with lung adenocarcinomas in CLIA laboratories for mutations in EGFR and 9 other genes. We assayed T790Mby Sequenom, Snapshot, or Sanger sequencing. Germline DNA was not collected. Results: In the 987 tumors tested, 209 had mutations in EGFR alone: 25 T790M (2.5%) , 157 sensitizing EGFR mutations (exon 19 del, L858R, L861Q, G719X) without T790M, 23 exon 20 ins, 4 other mutations. 13 additional cases harbored mutations in EGFR and another driver; 2 with both T790M and PIK3CA. In each of the 27 EGFR-mutant cases with T790M, a coincident EGFR mutation was detected (18 exon 19 del, 9 L858R, 1 exon 20 ins). EGFR T790M was found more often than EGFR exon 20 ins or mutations in HER2 (1.9%), BRAF (1.6%), or PIK3CA (0.7%). Patients with T790M: 77% women, 81% never smokers, median age 55 (range 38-79), stage IV at diagnosis 81%, PS 0/1 100%. Characteristics did not differ from persons with sensitizing mutations and no T790M. Median survival from the diagnosis of metastatic disease for patients with EGFR-mutant lung cancers was 3.5 yrs with T790Mand 4.0 yrs without (p=0.926). Conclusions: T790M mutations were detected at diagnosis in 3% of adenocarcinomas and always coincident with another EGFR mutation. Cases with T790M represent 13% of all cases of EGFR- mutant lung cancer. Characteristics and survival for patients with EGFR- mutant lung cancers with T790M at diagnosis were similar to individuals with sensitizing mutations and no T790M. The observed incidence of T790M exceeded that of the other actionable targets HER2, BRAF, and PIK3CA. Trials should study this unique population identified by routine multiplexed genotyping. Supported by 1RC2CA148394-01 and the National Lung Cancer Partnership. Clinical trial information: NCT01014286.

Characterizing Acquired Resistance to TKIs in EGFR Mutant Lung Adenocarcinoma Cell Lines

2013 ◽  
Vol 9 ◽  
Author(s):  
Jing Sun
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Resistant Cell ◽  
Egfr Mutations ◽  
Mesenchymal Transition ◽  
Major Mechanism ◽  
Egfr Mutant

Traditional treatments for non-small cell lung adenocarcinomas do produce impressive improvements in patient health. Newly developed biologically based treatments exploit the drug-sensitivity conferred by mutations in the epidermal growth factor receptor (EGFR). In adenocarcinomas, cell proliferation and survival depend on mutant EGFR activity. For patients with certain EGFR mutations, treatment with tyrosine kinase inhibitors (TKIs) rather than chemotherapy improves patient survival. However, almost every patient acquires resistance to TKI treatment. About 50% of acquired resistance is because of a secondary mutation in EGFR. MET gene amplification, which allows cells to use MET to activate downstream signals, is another established mechanism. A third known mechanism is epithelial to mesenchymal transition (EMT). About 30% of all resistance mechanisms still remain unknown. This semester, the HCC2279 EGFR-mutant human adenocarcinoma line was characterized in hopes of discovering new models of resistance. Growth inhibition assays and immunoblotting were used to analyze the effects of treatments and to examine the status of signaling molecules. The HCC2279 resistant line appeared to have an EGFR-independent mechanism and did not seem to use MET as a major mechanism of resistance. The resistant cells continued to grow in the presence of TKI and TKI plus MET inhibitor, and immunoblotting showed that TKIs were capable of completely inhibiting the activation and phosphorylation of EGFR and MET. Signs of EMT were detected via immunoblotting due to a loss of E-cadherin and gain of vimentin, and EMT was corroborated by histological changes such as a loss in resistant cell polarity.

Radiographic assessment and therapeutic decisions at RECIST progression in EGFR-mutant NSCLC treated with EGFR tyrosine kinase inhibitors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7553-7553
Author(s):  
Mizuki Nishino ◽  
Stephanie Heon ◽  
Suzanne Eleanor Dahlberg ◽  
David Michael Jackman ◽  
Nikhil H. Ramaiya ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Advanced Nsclc ◽  
Cox Model ◽  
Acquired Resistance ◽  
Initial Response ◽  
Patient Characteristics ◽  
Egfr Mutations ◽  
First Line ◽  
Therapeutic Decisions ◽  
Egfr Mutant

7553 Background: EGFR mutated advanced NSCLC treated with EGFR TKIs typically progresses after initial response due to acquired resistance. TKI therapy is often continued beyond RECIST progression (PD). We investigated the frequency of this practice and patterns of RECIST PD via imaging findings, as well as the association between patient characteristics and discontinuation of TKI among patients (pts) who progressed while on TKI. Methods: Among a cohort of 101 advanced NSCLC pts with sensitizing EGFR mutations treated with first-line erlotinib or gefitinib at DFCI, 70 pts treated between 2002 and 2010 had at least two CT scans for retrospective radiographic assessments using RECIST1.1; 56 pts had experienced PD by the data closure date of June 2011. Results: Among 56 pts experiencing PD, 46 (82%) were female, median age was 63 (range 35-79), 28 (50%) were never-smokers, 32 (57%) had distant mets, 32(57%) had exon 19 deletion, and 50 (89%) received erlotinib. 49 pts (88%) continued TKI therapy for at least 2 mos beyond retrospectively assessed PD. 31/32 (97%) pts who progressed by increase of target lesions continued TKI. 13/16 (81%) pts who progressed by new lesion remained on TKI. Two pts with PD in non-target lesions discontinued therapy at PD. 5/6 (83%) pts with both increase of target lesions and new lesion at PD continued TKI. In 49 continuing pts, the median time from RECIST PD to termination of TKI was 10.1 mos (range: 2.2-64.2 mos). 15/49 (31%) pts who continued TKI received additional chemo compared to 0/7 pts who discontinued (Fisher’s p=0.17). Pts who discontinued therapy (n=7) were significantly younger (median 48 yrs) than those who continued TKI at PD (median 64 yrs, Wilcoxon p=0.003). Median OS beyond RECIST PD among those who continued TKI was 31.8 mos (95% CI 15.9- not reached) and though underpowered, this did not appear to be impacted by TTP when adjusted in a Cox model (p=0.84). Conclusions: 88% of EFGR-mutant NSCLC pts who progressed on first-line TKI continued therapy beyond RECIST PD, which is not the single determining factor for terminating TKI in EGFR-mutant NSCLC pts. Additional progression criteria specific to this population are needed to better guide therapeutic decision making.

scholarly journals Better Progression-Free Survival in Elderly Patients with Stage IV Lung Adenocarcinoma Harboring Uncommon Epidermal Growth Factor Receptor Mutations Treated with the First-line Tyrosine Kinase Inhibitors

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 434 ◽  
Author(s):  
Ming-Ju Tsai ◽  
Jen-Yu Hung ◽  
Mei-Hsuan Lee ◽  
Chia-Yu Kuo ◽  
Yu-Chen Tsai ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Egfr Mutations ◽  
First Line ◽  
Free Survival ◽  
Younger Patients ◽  
Epidermal Growth

Patients with lung adenocarcinoma harboring common epidermal growth factor receptor (EGFR) mutations usually have a good response rate (RR) and longer progression-free survival (PFS) to EGFR tyrosine kinase inhibitors (TKIs). However, the treatment efficacy to uncommon EGFR mutations remains controversial. We, therefore, performed a retrospective study, screening 2958 patients. A total of 67 patients with lung adenocarcinoma harboring uncommon EGFR mutations were enrolled and 57 patients with stage IV diseases receiving a first-line EGFR TKI were included for further analyses. The patients were classified into 27 (47%) “a single sensitizing uncommon mutation”, 7 (12%) “multiple sensitizing mutations”, 5 (9%) “a sensitizing mutation and a resistant uncommon mutation”, and 18 (32%) “other resistant uncommon mutations”. No significant difference was noted in PFS or overall survival (OS) between groups. Patients receiving different first-line EGFR TKIs had similar PFS and OS. The elder patients had a significantly poorer performance status than the younger patients but a significantly longer PFS than the younger patients (median PFS: 10.5 vs. 5.5 months, p = 0.0320). In conclusion, this is the first study to identify that elderly patients with stage IV lung adenocarcinoma harboring uncommon EGFR mutation might have a longer PFS. Large-scale prospective studies are mandatory to prove our findings.

scholarly journals Understanding the Mechanisms of Resistance in EGFR-Positive NSCLC: From Tissue to Liquid Biopsy to Guide Treatment Strategy

2019 ◽  
Vol 20 (16) ◽  
pp. 3951 ◽  
Author(s):  
Marzia Del Re ◽  
Stefania Crucitta ◽  
Giulia Gianfilippo ◽  
Antonio Passaro ◽  
Iacopo Petrini ◽  
...  
Keyword(s):  
Treatment Strategy ◽  
Liquid Biopsy ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Phosphatidyl Inositol ◽  
Egfr Mutations ◽  
Mechanisms Of Resistance ◽  
Alternative Source ◽  
Egfr Mutant

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [MET] gene amplification, Kirsten Rat Sarcoma [KRAS], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [PI3KCA], and RAF murine sarcoma viral oncogene homolog B1 [BRAF] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR-mutant NSCLC.

Lung Cancer in 2013: State of the Art Therapy for Metastatic Disease

2013 ◽  
pp. 339-346
Author(s):  
Frances A. Shepherd ◽  
Paul A. Bunn ◽  
Luis Paz-Ares
Keyword(s):  
Lung Cancer ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Stage Iv ◽  
Poor Performance ◽  
Initial Therapy ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Molecular Features ◽  
Platinum Doublet

Lung cancer is the leading worldwide cause of cancer death and the majority of patients present with metastatic stage IV disease. At diagnosis, clinical, histologic, and molecular features must be considered in therapeutic decision-making for systemic therapy. Molecular testing for at least epidermal growth factor receptor ( EGFR) and ALK should be performed in all patients before therapy. Platinum doublet chemotherapy may be considered for “fit” patients who do not have a molecular driver genetic abnormality. Bevacizumab can be considered for addition to the doublet in patients with nonsquamous cancers who have no contraindications. A pemetrexed combination is considered only in nonsquamous histology. Patients with EGFR mutations or ALK fusions should be treated with erlotinib or crizotinib, respectively, even in patients with tumor-related poor performance. The tyrosine-kinase inhibitors (TKIs) may be continued until multisite, symptomatic progression. For patients initially treated with a platinum doublet, maintenance chemotherapy with pemetrexed, erlotinib, gemcitabine, or possibly docetaxel is an option with selection based on clinical features, histology, type of initial therapy, and response to first-line therapy.

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