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Sho Watanabe
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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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P2.03-033 - Propensity Score-Adjusted Survival Analysis of Non-Small Cell Lung Cancer Patients with Acquired Resistance to EGFR-TKI (ID 9257)
09:30 - 09:30 | Presenting Author(s): Sho Watanabe
- Abstract
Background:
Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations are treated with EGFR-tyrosine kinase inhibitors (TKIs). However, most patients acquire resistance to EGFR-TKIs and receive subsequent treatments. To determine the optimal treatment for patients with TKI-resistance, we retrospectively examined the outcomes in advanced or recurrent NSCLC patients and analyzed the efficacy of the prevalent treatment options for those with TKI-resistance, using propensity score modeling.
Method:
EGFR-mutated NSCLC patients who acquired resistance to EGFR-TKIs during their first-line EGFR-TKI therapy were assigned to the TKI-resistant group based on the response of progressive disease (PD) according to the Response Evaluation Criteria in Solid Tumors. Patients with wild-type (WT) EGFR were assigned to the EGFR-WT group. By multivariate analysis of the two groups, a propensity score for chemotherapy use was calculated for each patient using logistic regression model. TKI treatment-free survival (TFS) was defined as "the overall survival (OS) - total progression-free survival (PFS) of every EGFR-TKI therapy".
Result:
A total of 415 patients with NSCLC were screened for EGFR mutations in the National Center for Global Health and Medicine, from April 2007 through March 2012. Of these, 158 (39%) patients harbored EGFR mutations, and 101 of these patients with activating EGFR mutations developed TKI-resistance. Seventy-five patients with EGFR-mutations who acquired TKI-resistance received a second-line chemotherapy or other EGFR-TKIs. Fifty-seven patients (75%) in the TKI-resistant group received ≥2 lines of EGFR-TKI treatments (beyond PD). Of the 252 EGFR-WT patients, 139 patients who received first-line chemotherapy or EGFR-TKIs formed the EGFR-WT group. OS was significantly longer in the TKI-resistant group compared to the EGFR-WT group (median, 43.8 vs 14.8 months, p<0.001). TFS did not significantly differ between the two groups (median, 16.6 vs 14.4 months, p=0.83). TKI-resistant patients receiving three or two lines of EGFR-TKIs had a better total PFS than those receiving a single line of EGFR-TKI (median, 28.2 vs 21.1 vs 9.0 month, p<0.001). In the propensity score-adjusted multivariate analysis, TFS was significantly associated with the post-operative recurrence (hazard ratio [HR] 0.40, p<0.000) and the use of chemotherapy (HR 0.32, p=0.005). Total PFS of EGFR-TKIs significantly correlated with the post-operative recurrence (HR 0.27, p=0.02) and sequential use of other EGFR-TKIs (HR 0.25, p=0.03).
Conclusion:
The use of chemotherapy prolonged the TFS in TKI-resistant NSCLC patients to the same extent as that seen in EGFR-WT patients. In TKI-resistant patients with EGFR mutations, sequential use of different EGFR-TKIs improved the total PFS of EGFR-TKIs.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-041 - EGFR Amplification Mediates Resistance to TAS121, A Third-Generation EGFR-TKI, in EGFR T790M-Positive Non-Small Cell Lung Cancer (ID 9168)
09:30 - 09:30 | Presenting Author(s): Sho Watanabe
- Abstract
Background:
Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown promising efficacy in EGFR T790M-mutation-positive non-small cell lung cancer (NSCLC). However, acquired resistance to third-generation EGFR-TKIs has been reported in EGFR T790M-positive NSCLC. The mechanism of resistance to these third-generation EGFR-TKIs has not been fully elucidated. We report a case of metastatic NSCLC harboring an EGFR T790M mutation in which EGFR amplification mediated acquired resistance to TAS121, a novel third-generation EGFR-TKI.
Method:
A 68-year-old woman with metastatic lung adenocarcinoma, harboring an EGFR L858R mutation, received gefitinib in September 2013. Although the patient achieved a partial response, the tumor progressed and she was treated with 4 cycles of chemotherapy using cisplatin and pemetrexed followed by pemetrexed maintenance therapy. In April 2015, computed tomography (CT) showed disease progression (PD) with liver metastases, and re-biopsy of hepatic lesions was performed. Tumor genotyping with the PNA LNA PCR-Clamp method revealed an original mutation of EGFR L858R in exon 21 and a secondary mutation of EGFR T790M in exon 20. Tumor progression was noted after completion of one cycle of docetaxel, and she was enrolled into a phase 1 trial of TAS121 in June 2015. Although she showed a partial response to TAS121, PD was confirmed on CT, which indicated progression of liver metastases. She discontinued TAS121 and received supportive care. She died in October 2015, and an autopsy was performed. To determine the mechanism of resistance to TAS121, we performed next-generation sequencing (NGS) (NCC OncoPanel, Agilent) with post-TAS121 samples obtained from progressing liver lesions during TAS121 treatment. We also conducted fluorescence in situ hybridization (FISH) analysis for EGFR in pre-TAS121 liver lesions, post-TAS121 liver lesions, and autopsy samples from the lung and liver. The study protocol was approved by the Ethical Review Committee of the National Cancer Center Hospital.
Result:
NGS with the post-TAS121 liver samples showed EGFR amplification in the tumor cells (log2 ratio 2.2). On FISH analysis, EGFR amplification was not detected in the pre-TAS121 liver lesions (the ratio of EGFR signals to CEP signals 1.7), but was detected in the post-TAS121 liver lesions (2.1) and those obtained at autopsy (3.0). EGFR amplification was not detected in the autopsy samples of the lung lesions (1.0), which remained stable during TAS121 treatment.
Conclusion:
Our case revealed that genomic instability of the EGFR domain contributed to the development of resistance to TAS121. Further molecular analysis is warranted to understand the role of EGFR amplification in acquired resistance to third-generation EGFR-TKIs.
