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Yuan Chen
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OA10 - Right Patient, Right Target & Right Drug - Novel Treatments and Research Partnerships (ID 910)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 10:30 - 12:00, Room 106
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OA10.07 - Resistance Mechanisms of Osimertinib in Chinese Non-Small Cell Lung Cancer Patients: Analysis from AURA17 Trial (ID 12693)
11:35 - 11:45 | Author(s): Yuan Chen
- Abstract
- Presentation
Background
Osimertinib is approved for metastatic NSCLC patients with EGFR T790M mutation after progression from TKI therapy. Despite impressive tumor responses, drug resistance usually develops. The resistance mechanisms of osimertinib are emerging but studies with large cohorts of Chinese patients and association with clinical outcomes are lacking. Here we report a biomarker study of osimertinib using plasma samples from 107 Chinese patients who had progressed by 24 months after LSFD (Oct. 2017) of AURA17 (NCT02442349), the 2nd-line pivotal trial in China.
a9ded1e5ce5d75814730bb4caaf49419 Method
Serial plasma cell-free DNA (cfDNA) were collected from baseline until progressive disease (PD) by investigator assessment. Capture-based 75-gene NGS panel with unique molecular index (UMI) system was used to identify resistance mechanisms to osimertinib by comparing paired cfDNA at baseline and PD. Droplet digital PCR (ddPCR) was used to dynamically monitor EGFR mutation changes (L858R, Ex19Del, T790M and C797S) during treatment course. Association of cfDNA biomarkers based on valid test results with objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) from DCO3 (Mar. 20, 2018) was analyzed.
4c3880bb027f159e801041b1021e88e8 Result
The 107 patients were with ORR of 68.2%, median PFS of 8.2 months, and median OS of 21.5 months. Eight-two had detectable EGFR sensitizing mutations (L858R or Ex19Del) in their PD cfDNA samples. Among them, 15 had acquired EGFR C797S, all in cis with T790M, and with no enrichment for L858R or Ex19Del (6 and 9, respectively). The median time of C797S detection from plasma was 2.8 (1.2-8.4) months prior to PD. EGFR L718Q, I744T, C775Y, G796S/D, T854I mutations, or amplification were found in 11 patients. Aberrations in bypass tracks including AKT2, ALK, DDR2, ERBB2/3, HRAS, JAK1/2, KRAS, MET, NTRK1, PIK3CA, RIT1, etc. were observed in 45 patients.
Clearance of EGFR sensitizing mutations at weeks 3 of treatment was associated with favorable ORR (78.7% vs. 33.3%), PFS (9.6 vs. 4.0 months, p<0.001) and OS (21.5 vs. 11.7 months, p<0.001). Clearance of EGFR sensitizing mutations at weeks 6 of treatment was also associated with favorable ORR (80.0% vs. 36.8%) and PFS (8.3 vs. 4.2 months, p<0.001). Presence of T790M at PD was correlated with longer PFS (12.3 vs. 5.5 months, p<0.001) and OS (21.3 vs. 13.2 months, p=0.045). Acquired or enriched TP53 alterations at PD were associated with worse PFS (4.2 vs. 8.3 months, p=0.008).
8eea62084ca7e541d918e823422bd82e Conclusion
Our study revealed diverse resistance mechanisms to osimertinib in Chinese NSCLC patients and urged for new drug discovery or combination strategies to overcome this clinical challenge.
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-14 - mTORC1 Regulates the Radiosensitivity of NSCLC Cells with Wildtype PI3KCA and KRAS Genes by Affecting EMT (ID 13125)
12:00 - 13:30 | Presenting Author(s): Yuan Chen
- Abstract
Background
Resistance to radiotherapy has been shown to be a key cause of treatment failure in NSCLC and associates with local recurrence and metastasis. Understanding how NSCLC cells sensitize to radiation is therefore important for developing new treatments and prognostics. It has been shown that mTORC1 can regulate tumor cell radiosensitivity, although the mechanisms that underlie this phenomenon are unclear. It have found that mTORC1 also regulates EMT, important to metastasis and recurrence. We therefore hypothesized that mTORC1 might affect NSCLC cell radiosensitivity by suppressing EMT.
a9ded1e5ce5d75814730bb4caaf49419 Method
We analyzed the expression of mTOR protein in NSCLC tissues from patients, in addition to adjacent and normal tissue.These data showed that mTOR protein was elevated in NSCLC tissue. We then evaluated the effect of the mTORC1 inhibitor RAD001 (everolimus) on in vitro radiosensitivity, protein levels, and dose-survival curves using NCI-H460 and NCI-H661 NSCLC cell lines. RAD001 inhibited the mTORC1 pathway in both lines and enhanced the radiosensitivity of NCI-H661 cells with wildtype PIK3CA and KRASgenes. However, there was no evidence of a similar effect in NCI-H460 cells with mutant PIK3CA and KRAS genes. We also analyzed the expression of various EMT-associated proteins after irradiation in RAD001-treated and control cells. This showed that mTORC1 inhibition led to changes in the expression of several EMT-associated proteins in NCI-H661 cells after irradiation. Finally, we used publicly available expression data to confirm that mTOR and EMT-associated genes were affected by irradiation at the transcript level in NSCLC cells.
4c3880bb027f159e801041b1021e88e8 Result
In conclusion, our study has revealed that the mTORC1 signaling pathway is involved in regulating the radiosensitivity of some non-small cell lung cancer (NSCLC) cells. Our data showed that there was increased expression of mTOR in primary tumors and matched adjacent tissues in patients with NSCLC. We also confirmed that the mTORC1 inhibitor RAD001 had a cytostatic effect on NCI-H661 and NCI-H460 NSCLC cells lines. However, mTORC1 inhibition only increased radiosensitivity and affected mTOR signaling downstream targets in NCI-H661 cells with wildtype PIK3CA and KRAS genes. RAD001 had only a marginal effect on NCI-H460 cells with mutant PIK3CA and KRASgenes. Finally, the effect of radiation on EMT-associated markers was also assessed, revealing that mTORC1 inhibition couldalleviate irradiation-specific EMT changesin NCI-H661 cells.
8eea62084ca7e541d918e823422bd82e Conclusion
these data suggest that mTORC1 inhibition in NSCLC may enhance radiosensitivity by affecting the expression of EMT-associated proteins.This suggests targeting mTORC1 may provide a potential new strategy for the treatment of NSCLC with wildtype PIK3CA and KRAS genes.
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