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Jhanelle Elaine Gray
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MA 12 - Circumventing EGFR Resistance (ID 665)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Wan Ling Tan, Nobuyuki Yamamoto
- Coordinates: 10/17/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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MA 12.05 - Genomic Profiling of EGFR T790M Mutated Non-Small Cell Lung Cancer to Evaluate the Mechanisms of Resistance to Osimertinib (ID 9555)
11:30 - 11:35 | Author(s): Jhanelle Elaine Gray
- Abstract
- Presentation
Background:
The T790M mutation in the epidermal growth factor receptor (EGFR) gene altering the kinase domain is the most common mechanism of resistance to first or second-generation EGFR tyrosine kinase inhibitors (TKIs). Osimertinib is currently approved for treatment of metastatic EGFR T790M mutation positive non-small cell lung cancer (NSCLC). However, resistance to osimertinib is an emerging issue. Evaluation of the genomic profiles of patients with EGFR T790M mutated NSCLC treated with osimertinib is necessary to gain an understanding of the potential resistance mechanisms.
Method:
Between January 2014 and June 2017, we retrospectively reviewed DNA profiling data from blood and/or tissue (FoundationONE/ACT, Guardant 360, TruSight panel and/or Pyrosequencing) from patients with advanced NSCLC to identify those with an EGFR T790M mutation. For patients harboring the EGFR T790M mutation, electronic health records were reviewed to identify the clinical variables , outcomes and genotyping at the time of progression on osimertinib. Survival analysis was done using the Kaplan-Meier method (SPSS version 23).
Result:
We identified a total of 433 NSCLC patients who underwent genotypic profiling; EGFR T790M mutation was present in 29 (6.7%) patients. All patients received EGFR-TKIs prior to testing. Patient demographics included: Caucasian (76%), female (76%), adenocarcinoma (100%), never-smokers (52%) with a median age of 65 years and 3 median prior lines of treatment. At the time of identification of the T790M mutations, 27 (93%) patients retained their EGFR exon 19 deletion or exon 21 mutations and 24 (82%) patients received osimertinib. The median overall survival was 4.9 ± 3 months in patients not on osimertinib, and was not reachable in patients on osimertinib in the current follow up period. 7 of the 24 patients had repeat genotyping at the time of progression on osimertinib which revealed presence of acquired secondary mutations including EGFR C797S (43%, N=3), EGFR C797G (14%, N=1), amplifications in EGFR (43%, N=3), ERBB2 (HER2, 28%, N=2) and cell cycle genes (CD-K4, CCND1, CCND2, 28%, N=2), MAPK/ERK pathway alteration (KRAS amplification and Q61R mutation, 28%, N=2), PI3K/AKT/mTOR pathway alteration (ATK3 and PIK3C2B amplification, 14%, N=1) and RET fusion (NCOA4-RET, 14%, N=1).
Conclusion:
There is limited data regarding the mechanisms of resistance to osimertinib. In addition to the acquired mutations in C797S, our study identified several potential pathways for developing resistance to osimertinib including emergence of acquired amplification in EGFR and ERBB2, as well as MAP Kinase and PI3K/AKT pathway aberrations. Updated data will be presented at the meeting.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.02 - Osimertinib vs SoC EGFR-TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC (FLAURA): Plasma ctDNA Analysis (ID 8978)
15:55 - 16:05 | Presenting Author(s): Jhanelle Elaine Gray
- Abstract
- Presentation
Background:
FLAURA (NCT02296125) is a Phase III, double-blind, randomized study assessing efficacy and safety of osimertinib vs standard of care (SoC) EGFR-TKI as first-line treatment for patients with EGFRm advanced NSCLC. Concordance between tissue and plasma testing for EGFRm (Ex19del/L858R), and progression-free survival (PFS) by baseline plasma EGFRm status were evaluated.
Method:
Eligible patients: ≥18 years (Japan ≥20 years); Ex19del/L858R mutation-positive lung adenocarcinoma; no prior systemic anti-cancer/EGFR-TKI therapy for advanced NSCLC. Randomization: 1:1 to osimertinib 80 mg once daily (qd) orally (po) or SoC (gefitinib 250 mg or erlotinib 150 mg, qd po). At baseline, patients provided tumor tissue samples for central analysis of EGFRm status (cobas EGFR Mutation Test) and blood samples for retrospective analysis of EGFRm status by plasma ctDNA (cobas EGFR Mutation Test v2). PFS by baseline plasma EGFRm status was assessed. Comparison of EGFRm status between baseline tumor tissue and evaluable ctDNA samples was an exploratory endpoint.
Result:
Globally, 556 patients were randomized: osimertinib, n=279; SoC, n=277. Good concordance was observed between central laboratory tissue and plasma testing for EGFRm in the screened population (see table). In plasma EGFRm-positive patients (n=359), osimertinib (n=183) reduced the risk of progression or death by 56% vs SoC (n=176), hazard ratio (HR) 0.44 (95% CI 0.34, 0.57). This was consistent with the overall PFS result observed with osimertinib vs SoC in the full analysis set (FAS; tumor tissue EGFRm-positive by local/central testing), HR 0.46 (95% CI 0.37, 0.57); p<0.0001 and in plasma EGFRm-negative patients (n=124: osimertinib, n=60; SoC, n=64), HR 0.48 (95% CI 0.28, 0.80).Figure 1
Conclusion:
In the subgroup of plasma EGFRm-positive patients, clinical benefit of osimertinib was superior to SoC, consistent with the overall FLAURA FAS. These results, and good concordance between tissue and plasma testing for EGFRm, support the utility of plasma EGFRm testing for selecting patients eligible for first-line osimertinib treatment.
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