- Email: [email protected]
P2.03-014 A Phase I Study of Afatinib for Patients Aged 75 or Older with Advanced NSCLC Harboring EGFR Mutations
S2132 negative. When plasma specimens by cobas method were tested after insurance approval, plasma T790M was positive, and osimertinib could be finally administered. Although it was effective for axillary lymph node metastases, it had no effect on liver metastases. Conclusion: The sensitivity of the test method and the tumor heterogeneity between individuals may influence the detection of T790M mutation. In order to reliably administer osimertinib to patients with indication, it is desirable to establish an appropriate time and site for re-biopsy, and establish examination methods. Keywords: T790M mutation, re-biopsy, liquid biopsy
P2.03-012 Characterization of the Efficacies of Osimertinib and Nazartinib against Cells Expressing Epidermal Growth Factor Receptor Mutations K. Masuzawa,1 H. Yasuda,2 J. Hamamoto,2 I. Kawada,2 K. Naoki,2 K. Soejima,2 T. Betsuyaku2 1Department of Medicine, Keio University, Shinjukuku/JP, 2Pulmonary Medicine, Keio University School of Medicine, Tokyo/JP Background: A significant subgroup of non-small cell lung cancers harbors epidermal growth factor receptor (EGFR) mutations. Thirdgeneration EGFR tyrosine kinase inhibitors (EGFR-TKIs) were developed to overcome EGFR T790M-mediated resistance to firstand second-generation EGFR-TKIs. Third-generation EGFR-TKIs, such as osimertinib and nazartinib, are effective for patients with EGFR T790M mutation. However, there are no direct comparison data to guide the selection of a third-generation EGFR-TKI for patients with different EGFR mutations. We previously established an in vitro model to estimate the therapeutic windows of EGFRTKIs by comparing their relative efficacies against cells expressing mutant or wild type EGFRs. The present study used this approach to characterize the efficacies of third-generation EGFR-TKIs and compare them with those of other EGFR-TKIs such as erlotinib and afatinib. Method: We evaluated the drug sensitivity and EGFR downstream signals of human lung cancer cell lines (PC9, H3255, H1975, PC9ER, BID007) and Ba/F3 cells harboring clinically relevant EGFR mutants for first (erlotinib), second (afatinib) and third (osimertinib and nazartinib) generation EGFR-TKIs with MTS assay and western blotting. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. Result: Among various mutation types, sensitivities to EGFR-TKI were different. For classic EGFR mutations, exon 19 deletion and L858R, with or without T790M osimertinib showed lower IC50 values and wider therapeutic windows than nazartinib. Afatinib, osimertinib and nazartinib inhibited the phosphorylation of EGFR, AKT, and ERK for human cell lines and Ba/F3 cells harboring these EGFR mutations. For uncommon EGFR mutations, G719S or L861Q, afatinib showed lowest IC50 values. For G719S+T790M or L861Q+T790M, the IC50 values of osimertinib and nazartinib were around 100 nM, 10 to 100 fold higher than those of classic+T790M mutations. On the other hand, osimertinib and nazartinib showed similar efficacies in cells expressing EGFR exon 20 insertions. For C797S mutations, no EGFR-TKIs demonstrated efficacy. Conclusion: The present study provides fundamental osimertinib and nazartinib sensitivity/resistance data in cells expressing a range of EGFR mutations, including uncommon EGFR mutations. The findings highlight the diverse mutation selective sensitivity pattern of EGFR-TKIs. These data may help to inform the selection of EGFR-TKIs for nonsmall cell lung cancer patients harboring EGFR mutations. Keywords: EGFR tyrosine kinase inhibitors, EGFR uncommon mutations, lung cancer
Journal of Thoracic Oncology
Vol. 12 No. 11S2
P2.03-013 Uncommon Mutation Types of EGFR and Response to EGFR Tyrosine Kinase Inhibitors in Chinese Non-Small Cell Lung Cancer Patients K. Chen,1 X. Yu,1 H. Wang,1 Z. Huang,2 Y. Xu,2 L. Gong,2 Y. Fan2 Zhejiang Cancer Hospital, Hangzhou/CN, 2Chemotherapy, Zhejiang Cancer Hospital, Hangzhou/CN
1
Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined. Method: Seven hundred and fifty-five nonsmall cell lung cancer (NSCLC) patients with EGFR mutation analyzes for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis. Result: Rare sensitive mutations (G719X, L861Q, S768I), primary resistant mutation (Ex20 ins), and complex mutations (G719X + L861Q, G719X+S768I, 19 del+T790M, 19 del+L858R, L858R+S768I, and L858R+T790M) of EGFR were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) patients, respectively. TKI treatment in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Importantly, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins (8.6 versus 4.1 versus 3.1 months; p¼0.041). Furthermore, complex EGFR mutations were independent predictors of increased overall survival in NSCLC patients (Hazard Ratios¼0.31; 95% confidence intervals: 0.11-0.90; p¼0.031). Among them, patients harboring Del-19 compound L858R mutations showed a tendency to have higher response rate and improved median PFS than those regarding patients with other complex mutations patterns (66.7% verse14.3%, p¼0.021; 10.1 verse 8.6 months, p¼0.232). Conclusion: Personalized treatment should be evolving in different types of uncommon EGFR mutations. And complex mutations of EGFR may benefit more from EGFR-TKIs than other uncommon mutations in Chinese NSCLC patients. Keywords: Epidermal growth factor receptor, uncommon mutation, Tyrosine kinase inhibitors
P2.03-014 A Phase I Study of Afatinib for Patients Aged 75 or Older with Advanced NSCLC Harboring EGFR Mutations K. Baba,1 Y. Hasegawa,1 H. Tanaka,2 K. Taima,2 Y. Tanaka,2 M. Itoga,2 Y. Ishioka,2 T. Morimoto,3 H. Nakagawa,3 S. Takanashi,4 S. Tasaka2 1Aomori Prefectural Central Hospital, Aomori/JP, 2 Department of Respiratory Medicine, Hirosaki University, Hirosaki/JP, 3 Hirosaki National Hospital, Hirosaki/JP, 4Health Administration Center, Hirosaki University, Hirosaki/JP Background: The efficacy and safety of afatinib therapy among elderly (aged 75 or older) populations diagnosed with EGFR-mutated nonsmall cell lung cancer (NSCLC) has not been evaluated yet. This phase I trial was conducted to determine the maximum tolerated dose (MTD), recommended phase II dose of afatinib in elderly patients with advanced NSCLC harboring EGFR mutations. Method: The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or
November 2017 older advanced NSCLC harboring EGFR mutations were enrolled. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ function. The doses of afatinib, which was given once daily, were planned as follows: level 1, 20 mg/body; level 2, 30 mg/body; level 3, 40 mg/body. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic or grade 3 non-hematologic toxicity. DLT was evaluated during day1-28. Result: From February 2015 to October 2016, 15 patients were enrolled from 3 participating institutions. Patient characteristics were: male/female 3/12; median age 79 (range 7587); Performance status 0/1 2/13. Six patients have been treated at level 1, 3 and three patients have been treated at level 2, respectively. At level 1, 1 of 6 patients showed DLTs. The patient grade 3 rush, grade 3 anorexia, and grade 3 infection was observed. At level 2, none of 3 patients experienced a DLT. At level 3, 2 to 6 patients were observed DLTs. One patient developed grade 3 diarrhea, another patient developed grade 3 diarrhea and grade 3 anorexia. Most frequent adverse events (AEs, any grade) were diarrhea, paronychia, rush, and nausea. Most patients at level 3 required dose reduction in three months. No treatment-related deaths were observed at either level. An objective response was 73.3%. Conclusion: We considered level 3 was the MTD and recommended phase II dose level was 3. Clinical Trial Information: UMIN000016441. Keywords: lung cancer, afatinib, elderly
P2.03-015 Efficacy of EGFR-TKIs for EGFR Mutant NSCLC Patients with Central Nervous System Metastases: A Retrospective Analysis K. Koyama,1 Y. Saida,2 T. Abe,3 M. Satokata,2 Y. Mishina,2 K. Sato,4 S. Shoji,2 T. Tanaka,5 K. Nozaki,1 K. Ichikawa,2 T. Miyabayashi,6 T. Ota,5 F. Fujimori,7 R. Ito,8 R. Kondo,2 T. Hiura,7 M. Okajima,9 S. Miura,1 S. Watanabe,2 N. Matsumoto,10 H. Tanaka,11 T. Kikuchi2 1 Niigata Cancer Center Hospital, Niigata/JP, 2Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata/JP, 3Shinrakuen Hospital, Niigata/ JP, 4Nagaoka Red Cross Hospital, Nagaoka/JP, 5Niigata Prefectural Central Hospital, Joetsu/JP, 6Niigata City General Hospital, Niigata/JP, 7 Shibata Hospital, Shibata/JP, 8Nagaoka Chuo General Hospital, Nagaoka/JP, 9Saiseikai Niigata Daini Hospital, Niigata/JP, 10NishiNiigata Chuo National Hospital, Niigata/JP, 11Internal Medicine, Niigata Cancer Center Hospital, Niigata/JP Background: Central nervous system (CNS) is a common site of metastases of non-small cell lung cancer (NSCLC). The prognosis for patients with brain metastases and/or leptomeningeal metastases is extremely poor. NSCLC harboring epidermal growth factor receptor (EGFR) mutation generally shows good response to tyrosine kinase inhibitors (TKI). However, the efficacy of EGFR-TKI in patients with CNS metastases is unclear. And the data on the occurrence of leptomeningeal metastases in the patients with brain metastases after use or EGFR-TKI remain limited. Method: We retrospectively evaluated clinical outcome and background of EGFR mutant NSCLC patients with CNS metastases who received EGFR-TKI for the first line drug therapy between January 2008 and December 2014 in the facilities belong to Niigata lung cancer treatment group. Result: A total of 104 eligible patients were enrolled. The response rate was 62%. The median time to treatment failure was 7.8 months. The median survival time (MST) was 24.0 months. The response rate of CNS was 37%. The median CNS-progression free survival (PFS) was 13.2 months. There was no statistical significant difference in TTF, overall survival (OS) and CNS-PFS between patients with exon 19 deletion
Abstracts
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and those with exon 21 L858R point mutation (mTTF 8.3 vs. 7.8 months, MST 26.1 vs. 24.9 months, mCNS-PFS 14.4 vs. 12.4 months) or between patients treated by Gefitinib and those treated by Erlotinib (mTTF 8.4 vs. 6.3 months, MST 26.0 vs. 20.2 months, mCNS-PFS 13.8 vs. 13.2months). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months) and tended to prolong CNS-PFS (15.6 vs. 11.1 months), but was not significantly associated with OS (MST 26.1 vs. 24.0 months). There was no significant difference in treatment outcome between patients who received stereotactic irradiation and those who received whole brain irradiation as brain radiotherapy prior to EGFR-TKI. Leptomeningeal metastases (LM) were primarily found in 8 of 104 patients (8%), and those occurred subsequently during the clinical course in 19 patients (18%). Median time to occurrence of LM in the patients who had LM subsequently was 14.5 months. There was no significant difference in OS between patients who had LM subsequently and those without LM during the course (MST 28.1 vs. 24.9 months). MST from diagnosis of subsequent LM was 3.7 months. Conclusion: EGFR-TKI showed favorable effect for EGFR mutant NSCLC patients with CNS metastases. A longer TTF and CNS-PFS were observed with prior brain radiotherapy. Prognosis after occurrence of LM was poor. Keywords: brain metastases, EGFR TKI, Leptomeningeal metastases
P2.03-016 Clinical Utility of Liquid Biopsy for Detecting EGFR T790M Mutation Is Very Limited T. Sakamoto, K. Yamane, N. Tanaka, M. Yanai, H. Izumi, K. Yamaguchi, K. Takeda, H. Makino, T. Igishi, A. Yamasaki, E. Simizu Tottori University Hospital, Yonago/JP Background: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor targeting EGFR T790M acquired resistance mutation, has demonstrated strong clinical activity. Therefore, we have to do a second biopsy to detect T790M when the tumor has progressed. On the other hand, liquid based assays are expected as minimally invasive methods for detecting resistance mutations. Recently, liquid-biopsy for detecting EGFR T790M mutation has been approved by the Japanese ministry of health, labor and welfare. The aim of this study is to assess the clinical utility of liquid biopsy for detecting EGFR T790M mutation. Method: Seventeen consecutive patients who underwent cobas® EGFR Mutation Test ver.2 for liquid biopsy from January to April 2017 were enrolled. Patient information and examination results were collected from electronic medical records and analyzed retrospectively. Concordance between liquid biopsy and tissue or cytological specimen was assessed in patients who underwent re-biopsy at the same time as liquid biopsy. Result: Median age: 70 (51-82); Women: 10 (58.8%); Never smoker: 12 (70.6%); Adenocarcinoma: 17 (100%); Stage IV: 16 (94.1%); Primary EGFR mutation: exon19 deletion ¼ 11 (64.7%), exon21 L858R ¼ 5 (29.4%), exon18+20 mutations ¼ 1 (5.9%). Two patients (11.8%) were positive for T790M mutation in plasma. Tissue biopsy or cytology was done in 8 cases at the same time as liquid biopsy. Only one patient of four patients who were positive for T790M in tissue or pleural effusion was positive for T790M in plasma (sensitivity: 25%). One patient of two patients who were positive for T790M in plasma was negative for T790M in spinal fluid. Conclusion: There is no doubt that liquid biopsy is a minimally invasive and very convenient method. However, at least currently, liquid biopsy cannot replace tissue biopsy in clinical setting because of its sensitivity. In order to deliver the appropriate medication to the patient, it is necessary to selectively use well the tissue biopsy and liquid biopsy. Keywords: liquid biopsy, T790M, rebiopsy
P2.03-012 Characterization of the Efficacies of Osimertinib and Nazartinib against Cells Expressing Epidermal Growth Factor Receptor Mutations K. Masuzawa,1 H. Yasuda,2 J. Hamamoto,2 I. Kawada,2 K. Naoki,2 K. Soejima,2 T. Betsuyaku2 1Department of Medicine, Keio University, Shinjukuku/JP, 2Pulmonary Medicine, Keio University School of Medicine, Tokyo/JP Background: A significant subgroup of non-small cell lung cancers harbors epidermal growth factor receptor (EGFR) mutations. Thirdgeneration EGFR tyrosine kinase inhibitors (EGFR-TKIs) were developed to overcome EGFR T790M-mediated resistance to firstand second-generation EGFR-TKIs. Third-generation EGFR-TKIs, such as osimertinib and nazartinib, are effective for patients with EGFR T790M mutation. However, there are no direct comparison data to guide the selection of a third-generation EGFR-TKI for patients with different EGFR mutations. We previously established an in vitro model to estimate the therapeutic windows of EGFRTKIs by comparing their relative efficacies against cells expressing mutant or wild type EGFRs. The present study used this approach to characterize the efficacies of third-generation EGFR-TKIs and compare them with those of other EGFR-TKIs such as erlotinib and afatinib. Method: We evaluated the drug sensitivity and EGFR downstream signals of human lung cancer cell lines (PC9, H3255, H1975, PC9ER, BID007) and Ba/F3 cells harboring clinically relevant EGFR mutants for first (erlotinib), second (afatinib) and third (osimertinib and nazartinib) generation EGFR-TKIs with MTS assay and western blotting. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. Result: Among various mutation types, sensitivities to EGFR-TKI were different. For classic EGFR mutations, exon 19 deletion and L858R, with or without T790M osimertinib showed lower IC50 values and wider therapeutic windows than nazartinib. Afatinib, osimertinib and nazartinib inhibited the phosphorylation of EGFR, AKT, and ERK for human cell lines and Ba/F3 cells harboring these EGFR mutations. For uncommon EGFR mutations, G719S or L861Q, afatinib showed lowest IC50 values. For G719S+T790M or L861Q+T790M, the IC50 values of osimertinib and nazartinib were around 100 nM, 10 to 100 fold higher than those of classic+T790M mutations. On the other hand, osimertinib and nazartinib showed similar efficacies in cells expressing EGFR exon 20 insertions. For C797S mutations, no EGFR-TKIs demonstrated efficacy. Conclusion: The present study provides fundamental osimertinib and nazartinib sensitivity/resistance data in cells expressing a range of EGFR mutations, including uncommon EGFR mutations. The findings highlight the diverse mutation selective sensitivity pattern of EGFR-TKIs. These data may help to inform the selection of EGFR-TKIs for nonsmall cell lung cancer patients harboring EGFR mutations. Keywords: EGFR tyrosine kinase inhibitors, EGFR uncommon mutations, lung cancer
Journal of Thoracic Oncology
Vol. 12 No. 11S2
P2.03-013 Uncommon Mutation Types of EGFR and Response to EGFR Tyrosine Kinase Inhibitors in Chinese Non-Small Cell Lung Cancer Patients K. Chen,1 X. Yu,1 H. Wang,1 Z. Huang,2 Y. Xu,2 L. Gong,2 Y. Fan2 Zhejiang Cancer Hospital, Hangzhou/CN, 2Chemotherapy, Zhejiang Cancer Hospital, Hangzhou/CN
1
Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the standard therapy for advanced lung adenocarcinomas with common EGFR mutations. However, the efficacy of EGFR-TKIs in patients with these uncommon EGFR mutations (other than exon 19 deletions or exon 21 L858R mutation) remains undetermined. Method: Seven hundred and fifty-five nonsmall cell lung cancer (NSCLC) patients with EGFR mutation analyzes for TKI therapy were identified between October 2010 and December 2015 in East of China. And 66 patients bearing uncommon EGFR mutations were included to collect data from TKI response and prognosis. Result: Rare sensitive mutations (G719X, L861Q, S768I), primary resistant mutation (Ex20 ins), and complex mutations (G719X + L861Q, G719X+S768I, 19 del+T790M, 19 del+L858R, L858R+S768I, and L858R+T790M) of EGFR were identified in 37 (56.1%), 9 (13.6%), and 20 (33.3%) patients, respectively. TKI treatment in patients harboring uncommon EGFR mutations exhibited a tumor response rate of 28.8% and a median progression-free survival (PFS) of 4.8 months. Importantly, patients with complex EGFR mutations had significantly longer PFS when compared with the remaining sensitizing rare mutations or Ex20 ins (8.6 versus 4.1 versus 3.1 months; p¼0.041). Furthermore, complex EGFR mutations were independent predictors of increased overall survival in NSCLC patients (Hazard Ratios¼0.31; 95% confidence intervals: 0.11-0.90; p¼0.031). Among them, patients harboring Del-19 compound L858R mutations showed a tendency to have higher response rate and improved median PFS than those regarding patients with other complex mutations patterns (66.7% verse14.3%, p¼0.021; 10.1 verse 8.6 months, p¼0.232). Conclusion: Personalized treatment should be evolving in different types of uncommon EGFR mutations. And complex mutations of EGFR may benefit more from EGFR-TKIs than other uncommon mutations in Chinese NSCLC patients. Keywords: Epidermal growth factor receptor, uncommon mutation, Tyrosine kinase inhibitors
P2.03-014 A Phase I Study of Afatinib for Patients Aged 75 or Older with Advanced NSCLC Harboring EGFR Mutations K. Baba,1 Y. Hasegawa,1 H. Tanaka,2 K. Taima,2 Y. Tanaka,2 M. Itoga,2 Y. Ishioka,2 T. Morimoto,3 H. Nakagawa,3 S. Takanashi,4 S. Tasaka2 1Aomori Prefectural Central Hospital, Aomori/JP, 2 Department of Respiratory Medicine, Hirosaki University, Hirosaki/JP, 3 Hirosaki National Hospital, Hirosaki/JP, 4Health Administration Center, Hirosaki University, Hirosaki/JP Background: The efficacy and safety of afatinib therapy among elderly (aged 75 or older) populations diagnosed with EGFR-mutated nonsmall cell lung cancer (NSCLC) has not been evaluated yet. This phase I trial was conducted to determine the maximum tolerated dose (MTD), recommended phase II dose of afatinib in elderly patients with advanced NSCLC harboring EGFR mutations. Method: The study used a standard 3 + 3 dose escalation design. Patients aged 75 years or
November 2017 older advanced NSCLC harboring EGFR mutations were enrolled. Patients were required to have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 and adequate organ function. The doses of afatinib, which was given once daily, were planned as follows: level 1, 20 mg/body; level 2, 30 mg/body; level 3, 40 mg/body. Dose-limiting toxicity (DLT) was defined as grade 4 hematologic or grade 3 non-hematologic toxicity. DLT was evaluated during day1-28. Result: From February 2015 to October 2016, 15 patients were enrolled from 3 participating institutions. Patient characteristics were: male/female 3/12; median age 79 (range 7587); Performance status 0/1 2/13. Six patients have been treated at level 1, 3 and three patients have been treated at level 2, respectively. At level 1, 1 of 6 patients showed DLTs. The patient grade 3 rush, grade 3 anorexia, and grade 3 infection was observed. At level 2, none of 3 patients experienced a DLT. At level 3, 2 to 6 patients were observed DLTs. One patient developed grade 3 diarrhea, another patient developed grade 3 diarrhea and grade 3 anorexia. Most frequent adverse events (AEs, any grade) were diarrhea, paronychia, rush, and nausea. Most patients at level 3 required dose reduction in three months. No treatment-related deaths were observed at either level. An objective response was 73.3%. Conclusion: We considered level 3 was the MTD and recommended phase II dose level was 3. Clinical Trial Information: UMIN000016441. Keywords: lung cancer, afatinib, elderly
P2.03-015 Efficacy of EGFR-TKIs for EGFR Mutant NSCLC Patients with Central Nervous System Metastases: A Retrospective Analysis K. Koyama,1 Y. Saida,2 T. Abe,3 M. Satokata,2 Y. Mishina,2 K. Sato,4 S. Shoji,2 T. Tanaka,5 K. Nozaki,1 K. Ichikawa,2 T. Miyabayashi,6 T. Ota,5 F. Fujimori,7 R. Ito,8 R. Kondo,2 T. Hiura,7 M. Okajima,9 S. Miura,1 S. Watanabe,2 N. Matsumoto,10 H. Tanaka,11 T. Kikuchi2 1 Niigata Cancer Center Hospital, Niigata/JP, 2Department of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata/JP, 3Shinrakuen Hospital, Niigata/ JP, 4Nagaoka Red Cross Hospital, Nagaoka/JP, 5Niigata Prefectural Central Hospital, Joetsu/JP, 6Niigata City General Hospital, Niigata/JP, 7 Shibata Hospital, Shibata/JP, 8Nagaoka Chuo General Hospital, Nagaoka/JP, 9Saiseikai Niigata Daini Hospital, Niigata/JP, 10NishiNiigata Chuo National Hospital, Niigata/JP, 11Internal Medicine, Niigata Cancer Center Hospital, Niigata/JP Background: Central nervous system (CNS) is a common site of metastases of non-small cell lung cancer (NSCLC). The prognosis for patients with brain metastases and/or leptomeningeal metastases is extremely poor. NSCLC harboring epidermal growth factor receptor (EGFR) mutation generally shows good response to tyrosine kinase inhibitors (TKI). However, the efficacy of EGFR-TKI in patients with CNS metastases is unclear. And the data on the occurrence of leptomeningeal metastases in the patients with brain metastases after use or EGFR-TKI remain limited. Method: We retrospectively evaluated clinical outcome and background of EGFR mutant NSCLC patients with CNS metastases who received EGFR-TKI for the first line drug therapy between January 2008 and December 2014 in the facilities belong to Niigata lung cancer treatment group. Result: A total of 104 eligible patients were enrolled. The response rate was 62%. The median time to treatment failure was 7.8 months. The median survival time (MST) was 24.0 months. The response rate of CNS was 37%. The median CNS-progression free survival (PFS) was 13.2 months. There was no statistical significant difference in TTF, overall survival (OS) and CNS-PFS between patients with exon 19 deletion
Abstracts
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and those with exon 21 L858R point mutation (mTTF 8.3 vs. 7.8 months, MST 26.1 vs. 24.9 months, mCNS-PFS 14.4 vs. 12.4 months) or between patients treated by Gefitinib and those treated by Erlotinib (mTTF 8.4 vs. 6.3 months, MST 26.0 vs. 20.2 months, mCNS-PFS 13.8 vs. 13.2months). Brain radiotherapy prior to EGFR-TKI prolonged TTF (11.2 vs. 6.8 months) and tended to prolong CNS-PFS (15.6 vs. 11.1 months), but was not significantly associated with OS (MST 26.1 vs. 24.0 months). There was no significant difference in treatment outcome between patients who received stereotactic irradiation and those who received whole brain irradiation as brain radiotherapy prior to EGFR-TKI. Leptomeningeal metastases (LM) were primarily found in 8 of 104 patients (8%), and those occurred subsequently during the clinical course in 19 patients (18%). Median time to occurrence of LM in the patients who had LM subsequently was 14.5 months. There was no significant difference in OS between patients who had LM subsequently and those without LM during the course (MST 28.1 vs. 24.9 months). MST from diagnosis of subsequent LM was 3.7 months. Conclusion: EGFR-TKI showed favorable effect for EGFR mutant NSCLC patients with CNS metastases. A longer TTF and CNS-PFS were observed with prior brain radiotherapy. Prognosis after occurrence of LM was poor. Keywords: brain metastases, EGFR TKI, Leptomeningeal metastases
P2.03-016 Clinical Utility of Liquid Biopsy for Detecting EGFR T790M Mutation Is Very Limited T. Sakamoto, K. Yamane, N. Tanaka, M. Yanai, H. Izumi, K. Yamaguchi, K. Takeda, H. Makino, T. Igishi, A. Yamasaki, E. Simizu Tottori University Hospital, Yonago/JP Background: Osimertinib, a third-generation EGFR tyrosine kinase inhibitor targeting EGFR T790M acquired resistance mutation, has demonstrated strong clinical activity. Therefore, we have to do a second biopsy to detect T790M when the tumor has progressed. On the other hand, liquid based assays are expected as minimally invasive methods for detecting resistance mutations. Recently, liquid-biopsy for detecting EGFR T790M mutation has been approved by the Japanese ministry of health, labor and welfare. The aim of this study is to assess the clinical utility of liquid biopsy for detecting EGFR T790M mutation. Method: Seventeen consecutive patients who underwent cobas® EGFR Mutation Test ver.2 for liquid biopsy from January to April 2017 were enrolled. Patient information and examination results were collected from electronic medical records and analyzed retrospectively. Concordance between liquid biopsy and tissue or cytological specimen was assessed in patients who underwent re-biopsy at the same time as liquid biopsy. Result: Median age: 70 (51-82); Women: 10 (58.8%); Never smoker: 12 (70.6%); Adenocarcinoma: 17 (100%); Stage IV: 16 (94.1%); Primary EGFR mutation: exon19 deletion ¼ 11 (64.7%), exon21 L858R ¼ 5 (29.4%), exon18+20 mutations ¼ 1 (5.9%). Two patients (11.8%) were positive for T790M mutation in plasma. Tissue biopsy or cytology was done in 8 cases at the same time as liquid biopsy. Only one patient of four patients who were positive for T790M in tissue or pleural effusion was positive for T790M in plasma (sensitivity: 25%). One patient of two patients who were positive for T790M in plasma was negative for T790M in spinal fluid. Conclusion: There is no doubt that liquid biopsy is a minimally invasive and very convenient method. However, at least currently, liquid biopsy cannot replace tissue biopsy in clinical setting because of its sensitivity. In order to deliver the appropriate medication to the patient, it is necessary to selectively use well the tissue biopsy and liquid biopsy. Keywords: liquid biopsy, T790M, rebiopsy