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T. Mitsudomi
Moderator of
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SC21 - Predictive Biomarkers for Outcome of Systemic Therapy in NSCLC (ID 345)
- Event: WCLC 2016
- Type: Science Session
- Track: Biology/Pathology
- Presentations: 5
- Moderators:K. Kerr, T. Mitsudomi
- Coordinates: 12/06/2016, 16:00 - 17:30, Hall C7
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SC21.01 - Predictive Biomarkers in NSCLC: The Impact of Tumor Heterogeneity (ID 6685)
16:00 - 17:30 | Author(s): Y. Yatabe
- Abstract
- Presentation
Abstract not provided
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SC21.02 - Predictive Biomarkers for Chemotherapy of NSCLC (ID 6686)
16:00 - 17:30 | Author(s): M. Filipits
- Abstract
- Presentation
Abstract not provided
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SC21.03 - Predictive Biomarkers for Immune Checkpoint Inhibitors in Lung Cancer (ID 6687)
16:00 - 17:30 | Author(s): F.R. Hirsch
- Abstract
- Presentation
Abstract not provided
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SC21.04 - Patient-Derived Xenografts for Guiding Therapy of Lung Cancer (ID 6688)
16:00 - 17:30 | Author(s): B.C. Cho
- Abstract
- Presentation
Abstract:
Preclinical drug screening and biomarker discovery in the NCI-60 cancer cell line panel as well as the xenograft developed by growing these cell lines subcutaneously in immunodeficient mice have repeatedly failed to predict clinical responses. In an attempt to circumvent the limited predictive values of conventional preclinical models, there has been increasing attention in the development and characterization of Patient-derived tumor xenograft (PDX) models. The PDX models, which were created by direct implantation of patient’s tumor in immunodeficient mice, have shown to reflect principal histologic and genetic characteristics of original patient tumors and retain tumor heterogeneity better than any other preclinical model. These models have been shown to be predictive of clinical outcomes and are being used for translational research, preclinical drug screening and biomarker identification and validation. The PDX model may also be used in the application of ‘co-clinical trial’ approach, in which it is developed from a patient enrolled in a clinical trial and treated with the same experimental agents to emulate clinical response. This strategy permits the assessment of drug response simultaneously in the patient and mouse model, providing an interesting platform to investigate resistance mechanism, predictive biomarkers and novel combination strategies in a real-time manner. I will present the utility of PDX models, which faithfully replicated the histologic, genomic and pharmacologic features observed in the original patients, and ‘co-clinical trial’ that mirror a phase II trial of agents targeting fibroblast growth factor receptor (FGFR) in non-small cell lung cancer.
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SC21.05 - Emerging Role of Liquid Biopsies in NSCLC (ID 6689)
16:00 - 17:30 | Author(s): P. Mack
- Abstract
- Presentation
Abstract not provided
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SH01 - WCLC 2016 Scientific Highlights - Prevention, Biology, Pathology (ID 483)
- Event: WCLC 2016
- Type: Scientific Highlights
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 3
- Moderators:M. Filipits, T. Mitsudomi
- Coordinates: 12/05/2016, 07:30 - 08:30, Hall C1
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SH01.01 - Prevention (ID 7116)
07:30 - 08:30 | Author(s): C. Dresler
- Abstract
- Presentation
Abstract not provided
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SH01.02 - Biology (ID 7118)
07:30 - 08:30 | Author(s): R. Govindan
- Abstract
- Presentation
Abstract not provided
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SH01.03 - Pathology (ID 7119)
07:30 - 08:30 | Author(s): K. Kerr
- Abstract
- Presentation
Abstract not provided
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Author of
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.03 - Alectinib (ALC) versus Crizotinib (CRZ) in ALK-Positive Non-Small Cell Lung Cancer (ALK+ NSCLC): Primary Results from Phase III Study (J-ALEX) (ID 5597)
11:00 - 12:30 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Background:
ALK inhibitors are the standard treatment for ALK+ NSCLC and the comparison between 2 ALK inhibitors will be valuable in determining therapeutic strategy for ALK+ NSCLC patients (pts). We conducted the randomized open-label Phase III trial designed to prove the superior PFS of ALC to CRZ in ALK-inhibitor naïve ALK+ NSCLC.
Methods:
ALK+ NSCLC pts were randomized 1:1 either to receive ALC (300 mg b.i.d.) or CRZ (250 mg b.i.d.) and stratified by ECOG PS (0/1 vs 2), treatment line (1[st] vs 2[nd]), and clinical stage (IIIB/IV vs recurrence). Primary endpoint was PFS according to the blinded independent review board. Secondary endpoints included overall survival, objective response rate, and safety. Under an assumption of expected hazard ratio (HR) of 0.643, 164 events were required to have 80% power with 2-sided alpha of 0.05. Three interim analyses (IA) for early stopping due to efficacy were planned after 33%, 50%, and 75% of required PFS events occurred.
Results:
207 pts were enrolled at 41 centers in Japan between November 2013 and August 2015. Independent data monitoring committee recommended the release of study data because the superiority in PFS had been demonstrated for ALC based on second IA. The PFS HR of ALC arm to CRZ arm was 0.34 (99.6826% CI: 0.17-0.70, stratified log-rank p<0.0001). Median PFS was not reached (95% CI: 20.3-Not Reached (NR)) in ALC arm while it was 10.2 months (95%CI: 8.2-12.0) in CRZ arm. ALC demonstrated favorable result of PFS in each sub-group for instance, treatment line (1[st] line: HR = 0.30, ALC: NR vs CRZ: 10.2 months, 2[nd] line: HR = 0.39, ALC: 20.3 months vs CRZ: 8.2 months), brain metastases at baseline (yes: HR = 0.08, ALC: NR vs CRZ: 10.2 months, no: HR = 0.39, ALC: 20.3 moths vs CRZ: 10.0 months) and clinical stage (stage IIIb/IV: HR = 0.31 ALC: 20.3 months vs CRZ: 8.3 months, recurrence: HR = 0.49, ALC: NR vs CRZ: 11.6 months). Grade 3-4 AEs (ALC: 26% vs CRZ: 52%), discontinuation of study drug due to AEs (ALC: 9% vs CRZ: 20%) and dose interruptions due to AEs (ALC: 29% vs CRZ: 74%) occurred with lower rate in the ALC arm. There were no treatment-related deaths in either arm.
Conclusion:
ALC demonstrated prolonged PFS compared with CRZ in all sub-groups with a favorable AE profile representing a potential new standard treatment for 1[st] line ALK+ NSCLC pts.
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MA15 - Immunotherapy Prediction (ID 400)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:O. Arrieta
- Coordinates: 12/07/2016, 14:20 - 15:50, Schubert 1
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MA15.11 - Acquired Resistance Mechanisms to EGFR Kinase Inhibitors Alter PD-L1 Expression Status in Lung Cancer (ID 4652)
14:20 - 15:50 | Author(s): T. Mitsudomi
- Abstract
Background:
Immunotherapies that target PD-1/PD-L1 exploit the primary roles of cytotoxic agents in lung cancers. However, tyrosine kinase inhibitors (TKIs) are still considered to be the first choice in lung cancer patients with EGFR mutations. Although immunotherapies may be applied as second line or later therapeutic approaches in these patients, after acquisition of resistance to EGFR-TKIs, it is unclear if acquired resistance mechanisms alter PD-L1 expression status that is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents.
Methods:
Lung cancer cell lines with EGFR mutations (HCC827, HCC4006, PC9, and H1975) and their isogenic descendants with acquired resistance to various EGFR-TKIs were examined in this study. The resistance mechanisms of descendants include T790M secondary mutation, MET gene amplification, epithelial to mesenchymal transition (EMT), and loss of amplified EGFR mutant allele. PD-L1 expression status was analyzed by immunohistochemistry (IHC) and immunoblotting. Effects of acquired resistance mechanisms on PD-L1 expression were also evaluated by shRNA mediated knockdown of candidate molecules, and co-localization analysis using fluorescent imaging. IFN-gamma was used to mimic immune cell attack. Published microarray data of cells with acquired resistance to EGFR-TKIs were also employed to evaluate our findings.
Results:
PD-L1 expression was upregulated in several resistant cells and correlated with EGFR activation. In addition, we found that the phosphorylation of EGFR tyrosine (Y) 992 site, but not Y845, Y1068, or Y1173, was correlated with increased expression of PD-L1. We also observed that TKI-resistant cells with marked E-cadherin downregulation (HCC4006 erlotinib resistant cells and H1975 osimertinib resistant cells), one of hallmarks of EMT, showed decreased expression of PD-L1. However, one cell line (853#10), displaying EMT-like phenotype but only slight E-cadherin downregulation, showed PD-L1 upregulation. Published microarray data from three TKI-resistant lines with EMT-like features also support the correlation of low E-cadherin and reduced PD-L1 expression. ShRNA mediated knockdown of E-cadherin decreased the expression of PD-L1 in parental cell lines. IFN-gamma treatment upregulated PD-L1 expression in both parental and in resistant cells with E-cadherin downregulation, however PD-L1 expression in resistant cells was still lower and localized mainly in the cytoplasm rather than the cell membrane.
Conclusion:
We observed a dramatic change of PD-L1 expression status in lung cancers with EGFR mutation after acquisition of resistance to EGFR-TKIs, depending on the resistance mechanisms. These results support the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the resistance mechanisms but also for the evaluation of PD-L1 expression status.
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)
14:20 - 15:50 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.
Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.
Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.
Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.
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P1.02 - Poster Session with Presenters Present (ID 454)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.02-047 - Effect of Dasatinib on EMT-Mediated-Mechanism of Resistance against EGFR Inhibitors in Lung Cancer Cells (ID 5809)
14:30 - 15:45 | Author(s): T. Mitsudomi
- Abstract
Background:
The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells. In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells harboring EGFR exon 19 deletion, which tend to acquire resistance to EGFR-TKIs via EMT in previous reports.The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells. In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells harboring EGFR exon 19 deletion, which tend to acquire resistance to EGFR-TKIs via EMT in previous reports.
Methods:
HCC4006ER cells with an EMT phenotype were previously established by chronic exposure to increasing concentrations of erlotinib. Sensitivity to dasatinib in parental HCC4006 and HCC4006ER cells was analyzed. Subsequently, HCC4006EDR cells were established by chronic treatment with combination of erlotinib and dasatinib. The expression of EMT markers of these cells and the mechanism of acquired resistance to this combination therapy were analyzed.
Results:
Short-term or long-term, ranging OOhours to XXXmonth, treatment with dasatinib did not reverse EMT in HCC4006ER. In contrast, HCC4006EDR cells maintained an epithelial phenotype, and the mechanism underlying resistance to erlotinib plus dasatinib combination therapy was attributable to a T790M secondary mutation. HCC4006EDR cells, but not HCC4006ER cells, were highly sensitive to a third-generation EGFR-TKI, osimertinib.
Conclusion:
Although dasatinib monotherapy did not reverse EMT in HCC4006ER cells, preemptive combination treatment with erlotinib and dasatinib prevented the emergence of acquired resistance via EMT, and led to the emergence of T790M. Our results indicate that preemptive combination therapy may be a promising strategy to prevent the emergence of EMT-mediated resistance.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-009 - Clinical Outcome of Node-Negative Oligometastatic Non-Small Cell Lung Cancer (ID 4357)
14:30 - 15:45 | Author(s): T. Mitsudomi
- Abstract
Background:
The concept of “oligometastasis” has emerged as a basis on which to identify patients with stage IV non–small cell lung cancer (NSCLC) who might be most amenable to curative treatment. Although such patients without regional lymph node metastases tend to have a longer overall survival (OS) than those with regional lymph node involvement, limited data have been available regarding the survival of patients with node-negative oligometastatic NSCLC. We have therefore now evaluated the clinical outcome of stage IV node-negative oligometastatic NSCLC.
Methods:
Consecutive patients with advanced NSCLC who attended Kindai University Hospital between January 2007 and January 2016 were recruited to this retrospective study. Patients with regional lymph node–negative disease and a limited number of metastatic lesions (≤5) per organ site and a limited number of affected organ sites (1 or 2) were eligible.
Results:
Eighteen patients were identified for analysis during the study period. The most frequent metastatic site was the central nervous system (CNS, 72%). Most patients (83%) received systemic chemotherapy, with only three (17%) undergoing aggressive surgery, for the primary lung tumor. The CNS failure sites for patients with CNS metastases were located outside of the surgery or radiosurgery field. The median OS for all patients was 15.9 months, with that for EGFR mutation–positive patients tending to be longer than that for EGFR mutation–negative patients.
Conclusion:
Our results indicate that a cure is difficult to achieve with current treatment strategies for NSCLC patients with synchronous oligometastases, although a few long-term survivors and a smaller number of patients alive at last follow-up were present among the study cohort. There is an urgent clinical need for prospective evaluation of surgical resection as a treatment for oligometastatic NSCLC negative for driver mutations.
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P2.08 - Poster Session with Presenters Present (ID 491)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Patient Support and Advocacy Groups
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.08-007 - Listen Advocate Voice - Web-Survey for the Japanese Model of Lung Cancer Advocacy by Society (ID 5651)
14:30 - 15:45 | Author(s): T. Mitsudomi
- Abstract
Background:
In Asian countries, the concept of cancer advocacy has not been sufficiently recognized. In Japan, Lung Cancer Society (JLCS) has led the lung cancer advocacy with a part of the NPO, and adopted the 2014 Kyoto Declaration. To evaluate the awareness and attitude of lung cancer advocacy activity among patients, medical workers, and the general population in Japan, web survey was planned for the perceptions of Kyoto declaration and JLCA (Japanese alliance for lung cancer advocacy) events which were carried out by JLCS in these 2 years.
Methods:
An internet survey using survey monkey was conducted which contained 6 closed-ended (selection one or free answers) and open-ended questions, depending on the JLCA network population in June 2016.
Results:
109 people of responded involving 36% of patients and their family, 25% of MD and medical worker, 19% of pharmaceutical company officials and 16% of news media. Perception of Kyoto declaration was 21% of attendee, 27% of well-known, 13% of partial known and 39% of non-awareness. Also the number of participants to the events of JLCA is, 49% of 0 times, 17% 0f 1-2 times, 24% of 3-4 times and 11% of more than 5 times. The most sympathy events ware voted to 1) lecture by a physician 57%, 2) lecture by survivor and the participants WCLC of cancer patients 46%, 3) information in the facebook and the web site 46% 4) citizen open lecture of lung cancer 39%, 5) Performance by society ambassador 38%, 6) advocacy program in annual meetings 26% and 7) Medical seminars around the country 26%. The proportion of respondents who have a certain reputation in the activities of JLCA was 76%. The requests to JLCA is, 1) is the most participation opportunities for information of new treatment and participation opportunities to clinical trial, followed by 2) wish to participate to all the programs in the Society.
Conclusion:
In Japan, awareness about the advocacy is improved, and it was found that the expect to Society for the diverse needs through the Internet survey.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-120 - EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib (ID 4818)
14:30 - 15:45 | Author(s): T. Mitsudomi
- Abstract
Background:
Afatinib is effective for lung cancers harboring common EGFR mutations, Del19 and L858R. We reported that tumors with exon 18 mutations are especially sensitive to afatinib compared with first generation (1G) EGFR- tyrosine kinase inhibitors (TKIs). However, data on the mechanisms of acquired resistance to afatinib are limited
Methods:
We established afatinib-resistant cells from Ba/F3 cells transfected with common or exon 18 (G719A and Del18) mutations and PC9 (del E746_A750), HCC4006 (del E746_A750), and 11_18 (L858R) cell lines by chronic exposure to increasing concentrations of afatinib. Separately, afatinib-resistant clones were established from above Ba/F3 cells by exposure to fixed concentrations of afatinib using N-ethyl-N-nitrosurea (ENU) mutagenesis. Re-biopsy samples from patients whose tumors acquired resistance to afatinib were collected. EGFR secondary mutations and bypass tracks were analyzed by Sanger sequence, western blot, and real time PCR.
Results:
Afatinib-resistant cells transfected with Del19, L858R, or G719A developed T790M, whereas those with Del18 acquired novel L792F mutation. ENU mutagenesis screening established 84 afatinib-resistant clones. All Del19 clones and most of the other clones acquired only T790M. However, C797S occurred in subsets of L858R, G719A, and Del18 clones. Additionally, subsets of Del18 clones acquired L792F. C797S-acquired cells were sensitive to erlotinib. L792F demonstrated intermediate resistance between T790M and C797S to both 1G and 3G-TKIs, whereas L792F was the least resistant to 2G-TKIs, particularly dacomitinib. Chronic exposure of Del18+L792F cells to dacomitinib induced additional T790M acquisition. T790M was detected in 1 of 4 clinical samples, whereas no EGFR secondary mutations were detected in afatinib-resistant PC9, HCC4006, or 11_18 cell lines. Regarding bypass tracks, IGF1R was over expressed in all of the three afatinib-resistant cell lines compared with parental cells, whereas expression of AXL and PTEN were not changed. Neither mutations in PIK3CA and BRAF nor amplification of MET and FGFR1 were detected in clinical samples and resistant cell lines.
Conclusion:
L792F and C797S, in addition to major T790M, can develop in afatinib-resistant cells, and these minor mutations appear to exhibit sensitivity to dacomitinib and erlotinib, respectively. These secondary mutations should be tested in clinical practice. Bypass track through IGF1R may be associated with acquired resistance to afatinib.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.04 - Discussant for PL03.02, PL03.03 (ID 7156)
08:35 - 10:25 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract not provided
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SC04 - EGFR Tyrosine Kinase Inhibitors: A Model for Successful Drug Development (ID 328)
- Event: WCLC 2016
- Type: Science Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
- Moderators:S. Thongprasert, O. Gautschi
- Coordinates: 12/05/2016, 11:00 - 12:30, Hall C7
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SC04.02 - Management of Resistance to EGFR Tyrosine Kinase Inhibitors (ID 6614)
11:00 - 12:30 | Author(s): T. Mitsudomi
- Abstract
- Presentation
Abstract:
Discovery of activating mutations of the EGFR gene in adenocarcinoma of the lung in 2004 opened the door to a new era for personalized therapy in thoracic oncology. Lung cancers with EGFR mutation are highly sensitive to EGFR-tyrosine kinase inhibitors (TKI) such as gefitinib, erlotinib, or afatinib, resulting in significantly prolonged progression free survival compared with those treated with platinum doublet chemotherapy. However, acquired resistance inevitably develops usually after a median of 10~12 months. The mechanisms for this resistance have been extensively studied and can be classified into 1) target gene alteration, 2) activation of bypass / accessory pathway, and 3) histologic transformation (Fig.).Figure 1 The most common (50~60%) mechanism for acquired resistance to the EGFR-TKI is a missense mutation at codon 790 of the EGFR gene resulting in substitution of threonine to methionine (T790M). This amino acid change reduces affinity between EGFR kinase and EGFR-TKI compared with that between EGFR-kinase and ATP, leading to reactivation of down-stream pathways. L747S, D761Y, and T854A are also known as secondary mutations that cause acquired resistance, but they are very rare. In these cases, cancer cells are still addicted to or dependent on EGFR pathway. Amplification of the MET gene which codes for a receptor of hepatocyte growth factor (HGF) was the first that was identified as a bypass track resistance mechanism against EGFR-TKI. Following this report, aberrant activation of other receptor tyrosine kinases such as HER2, HER3, AXL, IGF1R, have been reported. It is also shown that some ligands for the receptor tyrosine kinases such as HGF, FGF or IGF cause acquired resistance to EGFR-TKIs. Similarly, alteration of downstream molecule cause resistance. These molecules include BRAF, PTEN, JAK2, CRKL, DAPK, NF-kB, or PUMA. The third mechanism of acquired resistance is histologic transformation that includes small cell lung cancer transformation and epithelial-mesenchymal transition EMT). Exact mechanisms of these histologic changes are not fully understood. However, AXL, Notch-1, TGFb pathway activation as well as down regulation of MED12 ((Mediator Complex Subunit 12) have been proposed as mechanisms of EMT. Then, How are we able to cope with these resistance? For T790M gatekeeper mutations, the third generation EGFR inhibitors that selectively inhibit EGFR-T790M while sparing the wild-type EGFR are active. One of these drugs, osimertinib is already approved and gives a response rate of ~60% and progression free survival of ~11 months. Therefore, identification of T790M at the time of disease progression by rebiopsy is important. We have recently found that three other secondary EGFR mutations implicated in acquired resistance are also sensitive to osimertinib. Tumor resistance caused by activation of accessory pathways can be theoretically coped with by combination of the inhibitor of EGFR and involved molecules. However, because of rarity of each mechanism, there is no clear evidence whether these combination therapies will actually improve patient outcome In other cases, cytotoxic chemotherapy is still an important strategy. According to the IMPRESS study, median progression free survival for patients without T790M who received cisplatin plus pemetrexed was 5.4 months. Eeven with these strategies, cancer cells are smart enough to escape from the therapy using other mechanisms. Heterogeneities in terms of resistant mechanisms within a single patient become evident when specific therapeutic pressure persists. Therefore, we also need to have armamentarium that utilizes other mechanisms to cure lung cancer. Recent advances of immunotherapy targeting immune checkpoints appear attractive in this respect. These mechanism-driven therapeutic approaches will convert this fatal disease into a more chronic disorder, and eventually into a curable disease with the least patient burden.
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