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Zhihong Chen
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P1.14 - Targeted Therapy (ID 182)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.14-13 - EGFR Amplification Mediates Resistance to Third-Generation EGFR TKIs and in Vitro Validation of Combination Strategies to Overcome Resistance (Now Available) (ID 762)
09:45 - 18:00 | Author(s): Zhihong Chen
- Abstract
Background
As a concurrent genomic alteration in EGFR-mutant NSCLC, whether all detected EGFR amplification serve as a driver of resistance to third-generation EGFR-TKIs remains controversial. Furthermore, which subtype of EGFR amplification-mediated resistance is actionable has been poorly elucidated. Our study aims to investigate the driver role of EGFR amplification in mediating resistance to third-generation EGFR TKIs and potential strategy to overcome resistance mediated by EGFR amplification.
Method
44 resistance samples from 32 patients who experienced disease progression from to a third-generation EGFR TKI abivertinib in Guangdong Lung Cancer Institute underwent NGS-based genomic profiling (data cutoff: october 30, 2018). FISH analysis of tissue samples from patients with EGFR amplification detected by NGS was performed. Different alleles of EGFR over-expressed PC9GR cell line models was established. Cell proliferation assay and western blot were performed to determine the sensitivity of these cell lines to third-generation EGFR TKI abivertinib and osimertinib, and to screen for potential strategies to overcome resistance mediated by EGFR amplification.
Result
Upon abivertinib progression, 27 patients provided plasma samples (six patients also provided paired samples from the progression sites) and five patients only provided samples from the progression sites for NGS. A heterogeneous landscape of resistance to abivertinib was observed with EGFR amplification being the most frequent, observed in 11 (34%) patients (Figure 1) , and considered a putative resistance mechanism in seven (22%) patients. FISH analysis of 3 patients who had available tissue samples further confirmed the presence of EGFR amplification detected by NGS. We established 3 different EGFR-overexpressed PC9GR cell lines by lentivirus transfection of Del 19 EGFR, Del19/T790M EGFR and wild-type EGFR. Among them, introduction of wild-type EGFR resulted in significantly loss of cellular sensitivity to abivertinib and osimertinib under EGF stimulation, but retains sensitivity to combination treatment of abivertinib and afatinib. In addition, abivertinib plus nimotuzumab also demonstrated preliminary inhibitory effect on phosphorylation of EGFR downstream pathway in wild-type EGFR overexpressed PC9GR. Finally, abivertinib plus nimotuzumab or afatinib in is effective and tolerable in treating 2 patients who developed EGFR amplification-mediated resistance to abivertinib. One of them experienced a long-term benefit from the combination treatments with an overall progression-free survival of 23 months.
Conclusion
Wild-type EGFR amplification mediates resistance to third-generation EGFR TKIs and could be overcome by combination treatments. Future studies need to more precisely determine the presence of wild-type EGFR amplification in third-generation EGFR TKIs resistant setting.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-49 - Molecular Characteristics of HER2 Mutations in Non-Small Cell Lung Cancer (Now Available) (ID 2859)
10:15 - 18:15 | Author(s): Zhihong Chen
- Abstract
Background
Earlier clinical trials targeting on HER2 exon 20 mutations show promising results. However, target therapy also had shown a favorable effect on non-tyrosine kinase domain (non-TKD) mutations in preliminary studies and case report, while no systemic study was reported about non-TKD mutations in HER2. Hence, The study aims to comprehensively outline the mutation landscape of HER2 in NSCLC.
Method
HER2 profile data (patients, N=5,222) from thirteen NSCLC studies in the cBioPortal for Cancer Genomics was screened. Finally, after excluding duplicated data (n=2,725) and no HER2 profile data (n=563), 1,934 individuals were enrolled in the analysis. The mutation subtype, mutation type, mutation region, biological effect of mutations referred to OncoKB, and HER2 copy number variation were described.
Result
4.3% (84/1934) of NSCLC patients were detected with HER2 mutation, and three patients carried double HER2 mutations, totally eighty-seven HER2 mutations were identified in the study. Fifty-three HER2 mutation subtypes were identified, and the most common mutation subtypes were Y772_A775dup (24%, 21/87), S310F (6%, 5/87), G776delinsVC (5%, 4/87) and G778_P780dup (5%, 4/87) respectively. HER2 fusion was identified in 8% (7/87) of mutations with a tendency to concurrent with HER2 copy number increased (5 amplification, 2 copy number gain). As for mutation region, 43% (37/87) of mutations occurred in TKD, while biological effect was not validated in 16% (6/37) of TKD mutations. Notably, biological effect of 56% mutations was inclusive or unknown. In gain of function subset, 82% (31/38) of mutations located at TKD, 13% (5/38) and 5% (2/38) were located at furin-like cysteine rich region and transmembrane domain.
Conclusion
Mutation subtypes were diverse in HER2. Though accounting for more than half of HER2 mutations, the effect of non-TKD mutations was fewly understood rather than TKD mutations. Biological effect and clinical implication of non-TKD mutations need to be further investigated in the near future.
