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P3.02b-118 Potential Mechanism Revealed by Targeted Sequencing from Lung Adenocarcinoma Patients with Primary Resistance to EGFR-TKIs
January 2017
Results: At the data cut-off (Aug 1, 2016), 33 patients were enrolled at five capmatinib BID/EGF816 QD mg dose levels (200/50 [n¼4]; 200/100 [n¼5]; 400/75 [n¼3]; 400/100 [n¼16]; 400/150 mg [n¼5]); 18/33 (55%) patients discontinued treatment, mainly (13 [39%] patients) due to disease progression. Doselimiting toxicities (DLTs) occurred in 4 patients: in 1 patient at the 200/50 dose level (increased alanine aminotransferase), 1 patient at the 400/100 dose level (anaphylactic reaction), and 2 patients at the 400/150 dose level (pyrexia, maculopapular rash, and allergic dermatitis). The most frequent (30%) any-grade adverse events (AEs), regardless of causality, were nausea (55%), peripheral edema (45%), increased amylase (42%), increased blood creatinine (36%), decreased appetite and diarrhea (both 30%). The most frequent (>10%) Grade 3 AEs were maculopapular rash (18% [mainly in the 400/150 cohort]) and increased amylase (12%). Capmatinib and EGF816 exposure increased with dose; preliminary data indicate a w35% increase in EGF816 exposure (AUC) at steady state when co-administered with the capmatinib RP2D, compared with single-agent exposure. The investigator-assessed overall response rate was 42% (2/33 complete responses; 12/33 partial responses) across all dose levels and 50% (8/16 patients) at the 400/100 dose level, regardless of molecular status of resistance. Conclusion: The RP2D of the combination was declared as capmatinib 400 mg BID + EGF816 100 mg QD. Preliminary antitumor activity was observed across dose levels, independent of T790M status. Keywords: Capmatinib (INC280), EGF816, NSCLC, EGFR-TKI resistance
P3.02b-118 Potential Mechanism Revealed by Targeted Sequencing from Lung Adenocarcinoma Patients with Primary Resistance to EGFR-TKIs Topic: EGFR RES Jia Zhong,1 Yanyan Zhang,2 Zhijie Wang,1 Hua Bai,3 Jie Wang3 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital & Institute, Beijing/China, 2 Novogene Bioinformatics Institute, Beijing/China, 3 Department of Internal Medicine, Cancer Hospital Chinese Academy of Medical Sciences, Beijing/China
Abstracts
S1265
Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) has greatly improved the prognosis of lung adenocarcinoma. However, there are still approximately 20% lung adenocarcinoma patients with EGFR sensitive mutations that were primary resistance to EGFR-TKIs treatment The underlying mechanism is unknown. Methods: This study explored the mechanisms of primary resistance by analyzing 11 paired patients with corresponding primary resistance (PFS<3months or without objective response) and sensitivity (PFS>12months) to EGFR-TKIs by next-generation sequencing (NGS). NGS targeted sequencing was performed on the Illumina X platform for 483 cancer-related genes. EGFR mutation was detected by ARMS initially. Results: Potential primary resistance mechanism was revealed by high frequency mutations unique in EGFRTKIs resistance group. Among the 11 patients, 54.55% (6/11) carried known resistance mechanism, (2 patients carried MET amplification; 2 patients carried T790M mutation; 1 patient carried Her2 amplification; 1 patient carried PTEN loss). And 45.45% (5/11) carried novel mutations that may lead to drug resistance (2 patients carried TGFBR1 mutation; 1 patient carried TMPRSS2 fusion gene; 1 patient both have BIM deletion polymorphism and EGFR uncommon mutation). By analyzing somatic single-nucleotide mutation patterns, we found the frequency of C:G/T:A transitions in primary resistance group was significantly higher than that in sensitive group (0.54 vs 0.39, P¼0.012). Conclusion: The mechanism of EGFR-TKIs primary resistance is sporadic. TGFBR1 mutation, TMPRSS2 fusion gene and EGFR multiple mutations might be associated with EGFR-TKIs primary resistance. Cytosine spontaneous deamination (C:G/T:A) was positively associated with EGFR-TKIs primary resistance. Keywords: lung adenocarcinoma, EGFR-TKIs, NGS
P3.02b-119 YH25448, a Highly Selective 3rd Generation EGFR TKI, Exhibits Superior Survival over Osimertinib in Animal Model with Brain Metastases from NSCLC Topic: EGFR RES Min Hee Hong,1 In Yong Lee,2 Jong Sung Koh,2 Jaekyoo Lee,2 Byung-Chul Suh,2 Ho-Juhn Song,2 Paresh Salgaonkar,2 Jaesang Lee,2 Young-Sung Lee,3 Se-Woong Oh,3 Jong Kyun Kim,3 Su Youn Nam,3
Results: At the data cut-off (Aug 1, 2016), 33 patients were enrolled at five capmatinib BID/EGF816 QD mg dose levels (200/50 [n¼4]; 200/100 [n¼5]; 400/75 [n¼3]; 400/100 [n¼16]; 400/150 mg [n¼5]); 18/33 (55%) patients discontinued treatment, mainly (13 [39%] patients) due to disease progression. Doselimiting toxicities (DLTs) occurred in 4 patients: in 1 patient at the 200/50 dose level (increased alanine aminotransferase), 1 patient at the 400/100 dose level (anaphylactic reaction), and 2 patients at the 400/150 dose level (pyrexia, maculopapular rash, and allergic dermatitis). The most frequent (30%) any-grade adverse events (AEs), regardless of causality, were nausea (55%), peripheral edema (45%), increased amylase (42%), increased blood creatinine (36%), decreased appetite and diarrhea (both 30%). The most frequent (>10%) Grade 3 AEs were maculopapular rash (18% [mainly in the 400/150 cohort]) and increased amylase (12%). Capmatinib and EGF816 exposure increased with dose; preliminary data indicate a w35% increase in EGF816 exposure (AUC) at steady state when co-administered with the capmatinib RP2D, compared with single-agent exposure. The investigator-assessed overall response rate was 42% (2/33 complete responses; 12/33 partial responses) across all dose levels and 50% (8/16 patients) at the 400/100 dose level, regardless of molecular status of resistance. Conclusion: The RP2D of the combination was declared as capmatinib 400 mg BID + EGF816 100 mg QD. Preliminary antitumor activity was observed across dose levels, independent of T790M status. Keywords: Capmatinib (INC280), EGF816, NSCLC, EGFR-TKI resistance
P3.02b-118 Potential Mechanism Revealed by Targeted Sequencing from Lung Adenocarcinoma Patients with Primary Resistance to EGFR-TKIs Topic: EGFR RES Jia Zhong,1 Yanyan Zhang,2 Zhijie Wang,1 Hua Bai,3 Jie Wang3 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Medical Oncology-I, Peking University Cancer Hospital & Institute, Beijing/China, 2 Novogene Bioinformatics Institute, Beijing/China, 3 Department of Internal Medicine, Cancer Hospital Chinese Academy of Medical Sciences, Beijing/China
Abstracts
S1265
Background: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKIs) has greatly improved the prognosis of lung adenocarcinoma. However, there are still approximately 20% lung adenocarcinoma patients with EGFR sensitive mutations that were primary resistance to EGFR-TKIs treatment The underlying mechanism is unknown. Methods: This study explored the mechanisms of primary resistance by analyzing 11 paired patients with corresponding primary resistance (PFS<3months or without objective response) and sensitivity (PFS>12months) to EGFR-TKIs by next-generation sequencing (NGS). NGS targeted sequencing was performed on the Illumina X platform for 483 cancer-related genes. EGFR mutation was detected by ARMS initially. Results: Potential primary resistance mechanism was revealed by high frequency mutations unique in EGFRTKIs resistance group. Among the 11 patients, 54.55% (6/11) carried known resistance mechanism, (2 patients carried MET amplification; 2 patients carried T790M mutation; 1 patient carried Her2 amplification; 1 patient carried PTEN loss). And 45.45% (5/11) carried novel mutations that may lead to drug resistance (2 patients carried TGFBR1 mutation; 1 patient carried TMPRSS2 fusion gene; 1 patient both have BIM deletion polymorphism and EGFR uncommon mutation). By analyzing somatic single-nucleotide mutation patterns, we found the frequency of C:G/T:A transitions in primary resistance group was significantly higher than that in sensitive group (0.54 vs 0.39, P¼0.012). Conclusion: The mechanism of EGFR-TKIs primary resistance is sporadic. TGFBR1 mutation, TMPRSS2 fusion gene and EGFR multiple mutations might be associated with EGFR-TKIs primary resistance. Cytosine spontaneous deamination (C:G/T:A) was positively associated with EGFR-TKIs primary resistance. Keywords: lung adenocarcinoma, EGFR-TKIs, NGS
P3.02b-119 YH25448, a Highly Selective 3rd Generation EGFR TKI, Exhibits Superior Survival over Osimertinib in Animal Model with Brain Metastases from NSCLC Topic: EGFR RES Min Hee Hong,1 In Yong Lee,2 Jong Sung Koh,2 Jaekyoo Lee,2 Byung-Chul Suh,2 Ho-Juhn Song,2 Paresh Salgaonkar,2 Jaesang Lee,2 Young-Sung Lee,3 Se-Woong Oh,3 Jong Kyun Kim,3 Su Youn Nam,3