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P3.02b-099 Pharmacokinetics of Osimertinib (AZD9291) in Chinese Patients with Advanced NSCLC: A Phase I Study
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Background: T790M mutation is a major mechanism for clinical failure in non-small cell lung cancer (NSCLC) patients with EGFR-TKI therapy. Acknowledgement of its frequency/abundance and its correlation with clinical characteristics will be of significant importance for the management of those patients in clinical practice and future trial design. Due to the difficulty of rebiopsy, plasma ctDNA is an ideal biopsy for detection of T790M mutation. Methods: 314 patients with advanced or recurrent NSCLC who had progressed during EGFR-TKIs treatment were enrolled prospectively. T790M mutation was determined in plasma samples by ARMS and ddPCR assay. Disease failure site was defined into three types of chest limited (CP), brain limited (BP) and extensive progression (EP). The T790M mutation status was analyzed for their correlations with failure site and clinical characteristics. Results: T790M mutations were detected in 30.9% and 46.8% of the patients by ARMS and ddPCR. The concordance rate was 78.3% between two methods. Compared to patients with CP and BP, EP patients showed significant higher rate for T790M+ determined by both ARMS and ddPCR (73.8% and 54.7%, p<0.001). In T790M positive population, the median T790M abundance was 1.2% (range, 0.04%-70.3%), and the median abundance of CP, BP, and EP was 0.66%, 1.52%, and 2.61%, respectively (p＝0.062). When adjusting for TKI response, worse PFS was found correlated with the plasma T790M mutation by ddPCR. Conclusion: Plasma T790M status correlates the extensive progression in NSCLC patients with EGFR-TKI therapy, which may provide the important ancillary information for treatment decision-making. Keywords: ctDNA, ddPCR, TKI resistance, T790M
P3.02b-099 Pharmacokinetics of Osimertinib (AZD9291) in Chinese Patients with Advanced NSCLC: A Phase I Study Topic: EGFR RES Junning Cao,1 Jianhua Chang,1 Clara Zhang,2 Shiang Jiin Leaw,3 Jia Wang,3 Mireille Cantarini,4 Li Zhang5 1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai/China, 2 China Development Unit, Gmd, Zhangjiang Hi-Tech Park, Shanghai/China, 3Gmd, China Development Unit, Shanghai/China, 4Astrazeneca, Macclesfield/United
Journal of Thoracic Oncology
Vol. 12 No. 1S
Kingdom, 5Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou/China Background: Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), selective for EGFR-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA18 study (NCT02529995) assessed osimertinib pharmacokinetics (PK) in Chinese patients with advanced non-small cell lung cancer (aNSCLC) who progressed following prior EGFR-TKI therapy. Methods: Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), selective for EGFR-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA18 study (NCT02529995) assessed osimertinib pharmacokinetics (PK) in Chinese patients with advanced non-small cell lung cancer (aNSCLC) who progressed following prior EGFR-TKI therapy. Results: 31 patients were treated (Cohort 1, n¼15; Cohort 2, n¼16): median age, 57.0 years; female, 58%; never smokers, 74%. 26 harbored tumors with the EGFR T790M mutation (local test). The PK analysis set included 25 patients: 6 were excluded due to prior treatment with an osimertinib-like substance or a T790M-directed EGFR-TKI. Osimertinib exposure increased approximately dose-proportionally after single and multiple dosing, similar to previous global studies. 29 (94%) patients experienced at least one adverse event (AE), 3 patients experienced an AE of Grade 3; no patients discontinued treatment due to AEs. The most common AEs were: diarrhea (32%), white blood cell decreased (23%), neutrophil count decreased (19%), dry mouth and erythema (19%). ORR (all partial responses) in T790M mutation-positive subgroup was 36% for Cohort 1 (4/11; 95% CI 11, 69) and 67% for Cohort 2 (10/15; 95% CI 38, 88).
January 2017
Conclusion: Osimertinib PK in the AURA18 Chinese patient population is consistent with the global population and supports 80 mg once-daily dosing. Clinical benefit and a tolerable safety profile were demonstrated. Keywords: pharmacokinetics, osimertinib, EGFR-TKI, T790M
P3.02b-100 Comparison of Three T790M Testing Methods for the Detection of Non-Small Cell Lung Cancer after Tyrosine Kinase Inhibitor Failure Topic: EGFR RES Lucheng Zhu,1 Shirong Zhang,2 Bing Xia,3 Xueqin Chen,4 Limin Wang,5 Hong Jiang,6 Xufeng Chen,7 Shenglin Ma4 1Department of Radiation Oncology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 2Center for Translational Medicine, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 3 Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou/China, 4Department of Oncology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 5Department of Respiratory, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 6Department of Thoracic Surgery, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 7University of California at Los Angeles, California/CA/United States of America Background: The third generation of TKI showed promising activities in patients with acquired T790M mutation. However, many patients in this setting are unable to undergo rebiopsy due to limited tissue availability and procedural feasibility. Mutation detection in plasma has shown promises to conquer the clinical challenging of re-biopsy, with advantage of non-invasiveness and accessibility. Here, we chose and evaluated the performance of three methods, amplification refractory mutation system (ARMS), modified amplification refractory mutation system (SuperARMS), and droplet digital PCR (ddPCR), to assess
Abstracts
S1253
their concordance and feasibility for the detection of mutations in plasma samples. Methods: This study was performed between March 2015 and March 2016. Patients were considered eligible and were enrolled in this study if they met the following criteria: 1) histologically confirmed stage IIIB/IV NSCLC; 2) clinically resistant to first-generation EGFR-TKIs according to Jackman’s criteria. Blood samples were collected within 14 days after TKI resistance. Each sample was simultaneously detected by three methods. Results: In total, 169 patients were enrolled. 54.4% were female and 72.2% were diagnosed as stage IV; 97.6% were adenocarcinoma. The rates of patients in response to EGFR-TKI treatment were 35.5% for stable disease, 52.1% for partial response and 12.4% for complete response, respectively. T790M mutations were detected in 54 of 169 (32.0%) samples by ARMS, 33 of which simultaneously carried exon19 deletions and 21 of which carried L858R. For SuperARMS assay, 59 (34.9%) samples were detected T790M mutation and 110 (65.1%) were not detected. ddPCR results showed that 61 (36.1%) samples were with detectable T790M mutation and 108 (63.9%) samples were detected with wildtype T790M. T790M abundance ranged from 0.04% to 38.2%. The median T790M abundance was 0.15% for total samples and 2.98% for T790M mutation samples. The overall concordance was 81.1% (137/169) among ARMS, SuperARMS, and ddPCR. The crude and adjust agreement between ARMS and SuperARMS was 87.6% and 86.1%, 88.8% and 87.7% between ARMS and ddPCR, 85.8% and 84.5% between SuperARMS and ddPCR, respectively. We also found that detection of T790M with ddPCR showed a sensitivity of 94.6% (95%CI: 90%-97.5%) and a specificity of 59.9% (95% CI: 51.2%-67.9%) when took ARMS as reference. Conclusion: Liquid biopsy showed promises with advantage of non-invasiveness and accessibility. T790M detection based on plasma circulation tumor DNA showed high concordance. Compared with nondigital platforms, ddPCR showed higher sensitivity and provided both frequency and abundance information, which might be important for treatment decisionmaking. Keywords: amplification refractory mutation system, T790M, TKI resistance, droplet digital PCR
Background: T790M mutation is a major mechanism for clinical failure in non-small cell lung cancer (NSCLC) patients with EGFR-TKI therapy. Acknowledgement of its frequency/abundance and its correlation with clinical characteristics will be of significant importance for the management of those patients in clinical practice and future trial design. Due to the difficulty of rebiopsy, plasma ctDNA is an ideal biopsy for detection of T790M mutation. Methods: 314 patients with advanced or recurrent NSCLC who had progressed during EGFR-TKIs treatment were enrolled prospectively. T790M mutation was determined in plasma samples by ARMS and ddPCR assay. Disease failure site was defined into three types of chest limited (CP), brain limited (BP) and extensive progression (EP). The T790M mutation status was analyzed for their correlations with failure site and clinical characteristics. Results: T790M mutations were detected in 30.9% and 46.8% of the patients by ARMS and ddPCR. The concordance rate was 78.3% between two methods. Compared to patients with CP and BP, EP patients showed significant higher rate for T790M+ determined by both ARMS and ddPCR (73.8% and 54.7%, p<0.001). In T790M positive population, the median T790M abundance was 1.2% (range, 0.04%-70.3%), and the median abundance of CP, BP, and EP was 0.66%, 1.52%, and 2.61%, respectively (p＝0.062). When adjusting for TKI response, worse PFS was found correlated with the plasma T790M mutation by ddPCR. Conclusion: Plasma T790M status correlates the extensive progression in NSCLC patients with EGFR-TKI therapy, which may provide the important ancillary information for treatment decision-making. Keywords: ctDNA, ddPCR, TKI resistance, T790M
P3.02b-099 Pharmacokinetics of Osimertinib (AZD9291) in Chinese Patients with Advanced NSCLC: A Phase I Study Topic: EGFR RES Junning Cao,1 Jianhua Chang,1 Clara Zhang,2 Shiang Jiin Leaw,3 Jia Wang,3 Mireille Cantarini,4 Li Zhang5 1Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai/China, 2 China Development Unit, Gmd, Zhangjiang Hi-Tech Park, Shanghai/China, 3Gmd, China Development Unit, Shanghai/China, 4Astrazeneca, Macclesfield/United
Journal of Thoracic Oncology
Vol. 12 No. 1S
Kingdom, 5Medical Oncology, Sun Yat-Sen University Cancer Center, Guangzhou/China Background: Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), selective for EGFR-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA18 study (NCT02529995) assessed osimertinib pharmacokinetics (PK) in Chinese patients with advanced non-small cell lung cancer (aNSCLC) who progressed following prior EGFR-TKI therapy. Methods: Osimertinib is a potent, irreversible epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), selective for EGFR-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA18 study (NCT02529995) assessed osimertinib pharmacokinetics (PK) in Chinese patients with advanced non-small cell lung cancer (aNSCLC) who progressed following prior EGFR-TKI therapy. Results: 31 patients were treated (Cohort 1, n¼15; Cohort 2, n¼16): median age, 57.0 years; female, 58%; never smokers, 74%. 26 harbored tumors with the EGFR T790M mutation (local test). The PK analysis set included 25 patients: 6 were excluded due to prior treatment with an osimertinib-like substance or a T790M-directed EGFR-TKI. Osimertinib exposure increased approximately dose-proportionally after single and multiple dosing, similar to previous global studies. 29 (94%) patients experienced at least one adverse event (AE), 3 patients experienced an AE of Grade 3; no patients discontinued treatment due to AEs. The most common AEs were: diarrhea (32%), white blood cell decreased (23%), neutrophil count decreased (19%), dry mouth and erythema (19%). ORR (all partial responses) in T790M mutation-positive subgroup was 36% for Cohort 1 (4/11; 95% CI 11, 69) and 67% for Cohort 2 (10/15; 95% CI 38, 88).
January 2017
Conclusion: Osimertinib PK in the AURA18 Chinese patient population is consistent with the global population and supports 80 mg once-daily dosing. Clinical benefit and a tolerable safety profile were demonstrated. Keywords: pharmacokinetics, osimertinib, EGFR-TKI, T790M
P3.02b-100 Comparison of Three T790M Testing Methods for the Detection of Non-Small Cell Lung Cancer after Tyrosine Kinase Inhibitor Failure Topic: EGFR RES Lucheng Zhu,1 Shirong Zhang,2 Bing Xia,3 Xueqin Chen,4 Limin Wang,5 Hong Jiang,6 Xufeng Chen,7 Shenglin Ma4 1Department of Radiation Oncology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 2Center for Translational Medicine, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 3 Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou/China, 4Department of Oncology, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 5Department of Respiratory, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 6Department of Thoracic Surgery, Hangzhou First People’s Hospital, Nanjing Medical University, Hangzhou/China, 7University of California at Los Angeles, California/CA/United States of America Background: The third generation of TKI showed promising activities in patients with acquired T790M mutation. However, many patients in this setting are unable to undergo rebiopsy due to limited tissue availability and procedural feasibility. Mutation detection in plasma has shown promises to conquer the clinical challenging of re-biopsy, with advantage of non-invasiveness and accessibility. Here, we chose and evaluated the performance of three methods, amplification refractory mutation system (ARMS), modified amplification refractory mutation system (SuperARMS), and droplet digital PCR (ddPCR), to assess
Abstracts
S1253
their concordance and feasibility for the detection of mutations in plasma samples. Methods: This study was performed between March 2015 and March 2016. Patients were considered eligible and were enrolled in this study if they met the following criteria: 1) histologically confirmed stage IIIB/IV NSCLC; 2) clinically resistant to first-generation EGFR-TKIs according to Jackman’s criteria. Blood samples were collected within 14 days after TKI resistance. Each sample was simultaneously detected by three methods. Results: In total, 169 patients were enrolled. 54.4% were female and 72.2% were diagnosed as stage IV; 97.6% were adenocarcinoma. The rates of patients in response to EGFR-TKI treatment were 35.5% for stable disease, 52.1% for partial response and 12.4% for complete response, respectively. T790M mutations were detected in 54 of 169 (32.0%) samples by ARMS, 33 of which simultaneously carried exon19 deletions and 21 of which carried L858R. For SuperARMS assay, 59 (34.9%) samples were detected T790M mutation and 110 (65.1%) were not detected. ddPCR results showed that 61 (36.1%) samples were with detectable T790M mutation and 108 (63.9%) samples were detected with wildtype T790M. T790M abundance ranged from 0.04% to 38.2%. The median T790M abundance was 0.15% for total samples and 2.98% for T790M mutation samples. The overall concordance was 81.1% (137/169) among ARMS, SuperARMS, and ddPCR. The crude and adjust agreement between ARMS and SuperARMS was 87.6% and 86.1%, 88.8% and 87.7% between ARMS and ddPCR, 85.8% and 84.5% between SuperARMS and ddPCR, respectively. We also found that detection of T790M with ddPCR showed a sensitivity of 94.6% (95%CI: 90%-97.5%) and a specificity of 59.9% (95% CI: 51.2%-67.9%) when took ARMS as reference. Conclusion: Liquid biopsy showed promises with advantage of non-invasiveness and accessibility. T790M detection based on plasma circulation tumor DNA showed high concordance. Compared with nondigital platforms, ddPCR showed higher sensitivity and provided both frequency and abundance information, which might be important for treatment decisionmaking. Keywords: amplification refractory mutation system, T790M, TKI resistance, droplet digital PCR