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R. Morita



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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: 2
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      P2.03-036 - Comparing the Efficacy/Toxicity of Osimertinib and First Line EGFR-TKI by Individual Patient Analysis (ID 9380)

      09:30 - 09:30  |  Author(s): R. Morita

      • Abstract

      Background:
      Osimertinib is a third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), which showed its efficacy for T790M resistant mutation in patients with advanced and recurrent non small cell lung cancer (NSCLC). The efficacy and toxicity of osimertinib comparing to previous EGFR-TKIs are not fully elucidated. Since every patient receiving osimertinib has received previous EGFR-TKI therapy, we compared the efficacy and toxicity of those agents in the same patients.

      Method:
      We retrospectively reviewed medical records of patients with T790M mutation positive advanced and recurrent NSCLC, who had disease progression after previous EGFR-TKI, the standard first line therapy, and started osimertinib between April 2016 and March 2017 at National Caner Center Hospital. Progression free survival (PFS) of osimertinib, and 1st line EGFR-TKI PFS of the same patients were calculated by Kaplan-Meier method. Objective response rate (ORR) was assessed according to RECIST version 1,1. Adverse events (AEs) were also reviewed to evaluate the difference of safety profiles between osimertinib and previous EGFR-TKIs.

      Result:
      A total of 46 patients with T790M positive NSCLC received osimertinib after the failure of first line EGFR-TKI treatment. At May 2017, the median follow-up time since the start of osimertinib was 7.8months. The median age was 65 (range 36-82), the median number of treatment received before osimertinib was 3 (range 1-9), and the median wash out time of 1st line EGFR-TKI till the start of osimertinib was 14.0 months. The median PFS of osimertinib is not reached. The median PFS of first line EGFR-TKI was 15.2 months. ORR of osimertinib and first line EGFR-TKI was 56.0% and 65.2%, respectively. The most frequent AEs of any grade of osimertinib were rash, dry skin, paronychia, and diarrhea (39.4%, 35.8%, 32.1%, and 30.2%, respectively). Rash, paronychia, and diarrhea over grade 2 was 6.5%, 6.5%, and 0% with osimertinib, compared to 0%, 12.5%, and 4.1% with gefitinib, and 41.7%, 8.3%, and 0% with erlotinib. The incidence of pneumonitis with osimertinib treatment was 10.9% (5 cases) in any grade, and 6.5% (3 cases) in grade 3 to 4, though 2 of them (1 case in grade 1 and 1 in grade 3) had received nivolumab as the prior chemotherapy. Except for pneumonitis, there was no AE leading to permanent discontinuation related to osimertinib.

      Conclusion:
      Osimertinib showed the efficacy and feasibility even in practical use. Adverse effect of osimertinib was generally better tolerated than previous EGFR-TKIs, except for pneumonitis.

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      P2.03-048 - Mixed Response of Non-Small Cell Lung Cancer Harboring the EGFR T790M Mutation to Osimertinib (ID 9807)

      09:30 - 09:30  |  Author(s): R. Morita

      • Abstract

      Background:
      Although patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), most progress after approximately 1 year. At the time of progression, the EGFR T790M mutation is detected in more than half of these tumors. NSCLC harboring the T790M mutation shows a high response rate to osimertinib. However, the heterogeneous nature of NSCLC may limit the efficacy of osimertinib to those lesions with the T790M mutation, and a subset of patients may show a mixed response (MR), whereby some lesions shrink while others progress at the first evaluation. Previous study showed that about 20% of NSCLC patients exhibit MR to systemic therapies including EGFR-TKI. However, little is known about characteristics of MR to osimertinib.

      Method:
      To determine the frequency of a MR, we retrospectively reviewed patients treated with osimertinib for NSCLC harboring the EGFR T790M mutation at the National Cancer Center Hospital.

      Result:
      Between April and December 2016, 45 patients (median age 65 [36‒82] years, 19 [42%] males) who had NSCLC with the T790M mutation received osimertinib. The median numbers of previous chemotherapies and EGFR-TKI therapies received by the patients were 1 and 2, respectively. All measurable tumor lesions showed a response to therapy in 35 (77%) patients and progression in three (7%) patients. A MR was seen in seven (16%) patients. Of these seven patients, the re-biopsy specimens in which T790M was detected were derived from the primary lesion in six and a metastatic lymph node in one patient. Two types of MRs were seen among these seven patients: (1) the tumor including the re-biopsy site responded, while the other lesions progressed (five patients), and (2) the tumor including the re-biopsy site progressed (two patients). The most frequent progressive sites were liver and lung metastasis (four patients, respectively). Three patients continued to receive osimertinib after the MR, one of whom underwent drug-eluting bead transarterial chemoembolization (DEB-TACE) for progressive liver metastasis and achieved disease control on osimertinib for an additional 4 months after the MR.

      Conclusion:
      A MR to osimertinib was seen in 16% of patients with NSCLC harboring the EGFR T790M mutation. This suggests that resistance mechanism of 1st line EGFR-TKI may differ by the site in same patient. Since benefit of osimertinib is mainly seen in T790M mutation, addition of local therapy may be beneficial for patients who develop a MR to osimertinib.

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    P3.02 - Biology/Pathology (ID 620)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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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  |  Author(s): R. Morita

      • 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.