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Y. Xu
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P2.03 - Chemotherapy/Targeted Therapy (ID 704)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P2.03-013 - Uncommon Mutation Types of EGFR and Response to EGFR Tyrosine Kinase Inhibitors in Chinese Non-Small Cell Lung Cancer Patients (ID 8076)
09:30 - 09:30 | Author(s): Y. Xu
- Abstract
Background:
Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined.
Method:
Seven hundred and fifty-five non-small cell lung cancer (NSCLC) patients with EGFR mutation analyses for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis.
Result:
Rare sensitive mutations (G719X, L861Q, S768I), primary resistant mutation (Ex20 ins), and complex mutations (G719X + L861Q, G719X+S768I, 19 del+T790M, 19 del+L858R, L858R+S768I, and L858R+T790M) of EGFR were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) patients, respectively. TKI treatment in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Importantly, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins (8.6 versus 4.1 versus 3.1 months; p=0.041). Furthermore, complex EGFR mutations were independent predictors of increased overall survival in NSCLC patients (Hazard Ratios=0.31; 95% confidence intervals: 0.11-0.90; p=0.031). Among them, patients harboring Del-19 compound L858R mutations showed a tendency to have higher response rate and improved median PFS than those regarding patients with other complex mutations patterns (66.7% verse14.3%, p=0.021; 10.1 verse 8.6 months, p=0.232).
Conclusion:
Personalized treatment should be evolving in different types of uncommon EGFR mutations. And complex mutations of EGFR may benefit more from EGFR-TKIs than other uncommon mutations in Chinese NSCLC patients.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-030 - TP53 Alteration, a Potential Primary Cause of Early Progression in EGFR-Mutated NSCLC Patients Treated with First-Line TKIs (ID 9426)
09:30 - 09:30 | Author(s): Y. Xu
- Abstract
Background:
EGFR-TKIs are recommended first-line treatment for patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). Most patients develop resistance after an average of approximately 12 months. Among various mechanisms, about half are acquired with T790M in EGFR exon 20. Little is known about the mechanisms in patients progressed within 6 months after first-line treatment of EGFR-TKIs. Therefore, we prospectively designed this study to investigate the possible mechanisms of resistance in this group of patients.
Method:
NSCLC patients with sensitive EGFR mutations who treated with first-line EGFR-TKI in Zhejiang Cancer Hospital from Jun 2014 to Jan 2017 were screened prospectively. Tissue samples pre-TKI and after disease progression (RECIST1.1) were collected. Blood samples were collected after disease progression. The study was approved by hospital research ethics committees. Of the total 50 patients enrolled for the study, 21 patients were included and further divided into two groups: patients suffered disease progression within six months after taking EGFR-TKI were classified as Group A (rapid progress group, n=13); patients took EGFR-TKI more than two years were classified as Group B (long term survival group, n=8). Patients with a PFS between 6 months to two years were excluded. We performed NGS of ~416 cancer related genes from the primary cancer samples collected before TKI treatment. Differences of gene alterations between two groups were analyzed.
Result:
The median age was 55 years old (range: 34-75 years). There were 47.6% female and 53.8% non-smokers. All patients in Group A carried TP53 mutation before treatment, none was found in Group B. The average cancer-related genetic mutations is 6.46 (range 3-16, 6 in Group A, 5.6 in Group B, P>0.05). There was enrichment for co-alterations in TP53 (100%), RB1 (38%), NKX2-1 (31%), BIM (30.8%) in pre-treated tissues from Group A. ERCC2 (38%), JAK3 (38%), BRCA2 (25%) were enriched in pre-treated tissues from Group B. Mutation rate of EGFR T790M after resistance was lower in Group A (2/13,15.4%) than in Group B (2/5, 40%). Three patients (3/8) are still benefit from first-line EGFR-TKI without disease progression in Group B. The median PFS was 3 months for Group A (range 1-5 months) and 26.5 months for Group B (range 24-52 months).
Conclusion:
This data highlights a model of genetic collectives as potential mechanisms of rapid progression in first-line EGFR-TKIs treatment. TP53 mutation reduced responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, contributing to rapid disease progression. EGFR T790M mutation seems uncommon in rapid progression patients.
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P3.03-031 - Response to Crizotinib Can Occur in C-MET Overexpression NSCLC Independent of MET exon14 Alterations After First-Line EGFR-TKI Resistance (ID 9463)
09:30 - 09:30 | Author(s): Y. Xu
- Abstract
Background:
Although non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations are responsive to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), drug resistances are always inevitable. Concurrent multiple mutations and bypass mechanisms both can contribute to development of resistance to EGFR-TKIs. Preclinical and clinical evidences suggest a role for MET activation as a secondary driver of resistance to targeted therapy. Activation of the MET pathway can occur through a diverse set of mechanisms including MET amplification, MET exon 14 alterations, MET overexpression. As partial overlap of these biomarkers occurs, whether one is purely a surrogate for the other, or if both can represent true oncogenic driver states continues to be explored. Cases of MET inhibitor sensitive NSCLC harboring exon 14 alterations without co-incident amplification have already been described. But concurrent EGFR-mutation and MET overexpression in one case is rare. Whether MET overexpression can be served as a driver alteration in NSCLC and its cut-off value need to be explored.
Method:
A NSCLC patient with EGFR mutation who took first line EGFR-TKI therapy was described in this report. The chest enhanced CT examination, whole-body PET/CT, coarse needle biopsy on right clavicle and bronchoscopy were taken to assess the disease condition before treatment. ARMS, IHC, FISH, ddPCR and NGS were used to detect gene alterations including gene mutation, overexpression and amplification, in cancer tissue samples obtained before TKI and after disease progression.
Result:
In this case, we described a 56-year-old male NSCLC patient with EGFR Ex21 L858R mutation who underwent refractory after first line EGFR-TKI therapy and was confirmed having concurrent c-MET overexpression (ICH: +++, 95%) before treatment. Disease progression was occurred after taking first-line EGFR-TKI for 4 months. Patient was then further confirmed having c-MET overexpression (ICH: +++, 90%) but without EGFR T790M mutation, c-MET amplification and MET exon 14 alterations in progressed cancer samples. Crizotinib was added to the treatment from Aug 8, 2016 after disease progression. And the recent chest enhanced CT examination on May 5, 2017 confirmed complete response (CR) to crizotinib in this patient.
Conclusion:
Our case report uncovered the underling mechanism of c-MET overexpression in EGFR-TKI resistance, and crizotinib may assist to overcome this resistance to EGFR-TKI. In this case, MET overexpression and EGFR mutation were concurrent before treatment. Thus, whether simultaneously applied EGFR-TKI and MET inhibitor in first-line treatment could result a better outcome was needed to be further demonstrated. The ideal cut-off value of MET overexpression is also waiting for determination.
