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N. Kobayashi
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-009 - Potential Predictive Markers with Plasma for Re-Challenge with EGFR-TKIs (ID 735)
09:30 - 09:30 | Author(s): N. Kobayashi
- Abstract
Background:
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have produced dramatic anti-cancer effects in non-small cell lung cancer patients carrying EGFR activating mutations. However, patients eventually acquire resistance resulting from various mechanisms such as secondary EGFR mutation, T790M, MET amplification, and hepatocyte growth factor (HGF) overexpression. Recently, the second generation EGFR-TKI, afatinib which was expected for anti-cancer efficacy in T790M positive lung cancer patients has been developed. However, it has not evidenced acceptable anti-cancer efficacy in lung cancer patients who acquired resistance to first generation EGFR-TKI because of difficulty to identify mechanisms of acquired resistance by re-biopsy. The purpose of this study is to investigate whether T790M and HGF in plasma are useful as predictive markers for determination efficacious treatment including re-challenge of the first generation of EGFR-TKI and treatment with the second generation, afatinib after acquired resistance.
Methods:
We analyzed retrospectively 16 re-challenges with first generation EGFR-TKI, and 6 treatments with afatinib after acquired resistance with first generation EGFR-TKI undertaken by investigating T790M and HGF in plasma coupled with clinical characteristics. EGFR mutations in plasma DNA were detected using the wild inhibiting PCR and quenched probe (WIP-QP) system for exon 19 deletions, and T790M and L858R were detected using the mutation-biased PCR and quenched probe (MBP-QP) system. HGF level in plasma was measured by enzyme-linked immunosorbent assay; ratio of HGF level before re-challenge or afatinib to that prior to the previous EGFR-TKI treatment was calculated.
Results:
Two re-challenges demonstrated partial response (PR), six remained as stable disease (SD), and eight had progressive disease (PD). Four of five patients with a history of T790M positivity had PD. Seven of eight patients who showed greater than 1.5-fold elevation of HGF before re-challenge with EGFR-TKI suffered PD. Elevation of HGF ratio to above 1.5 was significantly associated with poor response to EGFR-TKI re-challenge (p = 0.005). Having no history of T790M and an HGF ratio less than 1.5 was significantly associated with a good response to EGFR-TKI re-challenge (p<0.001). Afatinib demonstrated one PR and four SD, and one had PD. T790M was detected in four of six patients before afatinib treatment. Three of four patients with a history of T790M positivity had PR or SD. Elevation of HGF ratio to above 1.5 was not detected in six patients who treated with afatinib.
Conclusion:
Combination of T790M detection and HGF quantification using plasma is a potentially useful assay system for predicting the effect of EGFR-TKI re-challenge with not only first generations but also afatinib. Eventually, we strive to develop more effective treatment strategies for NSCLC patients with EGFR activating mutations depending on the status of T790M and HGF level in plasma, for example the second or the third generation EGFR-TKI for detection of T790M, MET inhibitor for elevation of HGF level, and EGFR-TKI re-challenge without detection of T790M and elevation of HGF level.
