- Email: [email protected]
Norwood Operation with Anterior Translocation of Pulmonary Artery
abstracts MO2 18 5
Real-World Effectiveness and Safety of Nivolumab in Special Subgroups of NSCLC pts: A Multicenter-Retrospective Study
Satoru Kitazono1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Haruhiro Saito2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 2Nivolumab Japan Real World Study Group, 3BristolMyers Squibb K.K, 4ONO Pharmaceutical Co., Ltd
MO2 18 6
Real-World Effectiveness and Safety of Nivolumab in NSCLC pts in Japan: A Multicenter-Retrospective Observational Study
Haruhiro Saito1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Makoto Nishio2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Kanagawa Cancer Center, 2Nivolumab Japan Real World Study Group, 3Bristol-Myers Squibb K.K, 4Ono Pharmaceutical Co., Ltd Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large cohorts of patients from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report a retrospective data analysis accessing effectiveness and safety of nivolumab in 901 Japanese NSCLC pts from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Among 901 pts, median age of the pts treated with nivolumab was 67 ys old and proportion of 75 ys or over was 19.8%. Pts with ECOG PS 0 or 1 account for 75.8%, and pts with SQ and adeno histology were 24.5% and 67.7%, respectively. Pts with EGFR mutation account for 12.9%. Median numbers of nivolumab dose was five and nivolumab was most frequently used at 2nd line (46.8%) and followed by at 3rd line (26.5%). Rate of 1 yr overall survival (OS) was 54.3% and, median PFS was 2.1 months and overall ORR was 20.6%. There was no significant difference in effectiveness among histology. Although there was no difference in effectiveness of nivolumab by age, ECOG PS status significantly influence effectiveness of nivolumab. Analysis is ongoing to access various factors that may be associated with the effectiveness of nivolumab. Overall irAE incidence for all grade and grade 3-4 will be reported as well as categorized irAE. Further analysis is planned for safety management of irAEs and prognosis. Conclusion: The effectiveness and safety of nivolumab observed in real-world data from NSCLC patients in Japan was comparable to results observed in clinical trials. ECOG PS status was identified as a factor influencing effectiveness of nivolumab.
MO3 1 1
JAK2 (V617F) positively regulates PD-L1 mRNA expression via STAT3/5 activation in MNP (PV and ET) patients
Sameer Ahmad Guru1, Mamta P Alpana1, Rashid Mir1,2, Imtiyaz A Najar1, Mariyam Zuberi1, Naresh Gupta1, Pramod Lali1, Alpana Saxena1 1 Department of Biochemistry, Maulana Azad Medical College, India, 2University of Tabouk Background:Escalated PD-L1 expression is reported in many cancer types initiating an immune escape mechanism. This led to the development of checkpoint inhibitors against PD-1/PD-L1. However, the mechanisms underlying escalated production of PD-L1 in many cancers is not clear yet.
vi110 | Oral Session : Mini-Oral Abstracts Session
Methods:In this study, we studied PD-L1 mRNA expression levels in concert to JAK2 (V617F) mutation in a group of 72 MPN patients (38 PV and 33 of ET). Clinical and demographical characters were noted carefully. Results:Confirmed MPN patients were screened for JAK2 (V617F) mutation by tetraprimer ARMS-PCR. We next quantified JAK2 (V617F) with ASO-PCR. The patients were also screened for BCR/ABL1 fusion gene transcripts to clarify Ph negative MPN status. The mRNA expression levels of PD-L1, STAT3/5 in all MPN patients were evaluated and it was identified that PD-L1, STAT3 but not STAT5 mRNA levels were significantly high in JAK2 (V617F) patients compared to JAK2 (WT) ones. It was also identified that PD-L1, STAT3/5 mRNA expression was upregulated in MPN patients with more JAK2 (V617F) percentage/allele burden than those MPN patients with less JAK2 (V617F) percentage/allele burden. Finally, we evaluated correlation of JAK2 (V617F) percentage with PD-L1, STAT3/5 mRNA expression levels and discovered that PD-L1 and STAT3 are in strong and direct correlation with JAK2 (V617F) burden while STAT5 was found to be moderately correlated. In addition, we identified strong coexpression of PD-L1 and STAT3 and as expected STAT5 moderately coexisted with PD-L1. Conclusion: In summary,this study shows that increased PD-L1 expression accompanies JAK2 (V617F) mutation. The increased expression of PD-L1 may be caused by excessive activation of STAT3/5 which are regulators of PD-L1. The study finds that PD-L1 expression is mainly mediated by JAK2 (V617F) via STAT3 and thatSTAT5 only plays a minor role.The study supports the concept of using PD-L1/STAT3/5 axes as targets for developing checkpoint inhibitors.
MO3 1 2
Escalated activation ofSTAT3 due to JAK2 V617F activatingmutation causesdownregulation ofPTEN via miRNA 21overexpression
Mamta P Sumi1, Sameer A Guru1, Rashid Mir2, Imtiyaz Najar1, Mariyam Zuberi1, Naresh K Gupta1, Pramod Lali1, Alpana Saxena1 1 Maulana Azad Medical College, India, 2University of Tabouk Background: Mutations in Janus kinase 2 (JAK2) genes are the genetic characteristic of BCR-ABL1-negative myeloproliferative neoplasms (MPN). JAK2 V617F mutation is frequently found in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). We aimed to determine the effect of JAK2 V617F on expression of phosphatase and tensin homolog (PTEN) and its regulator miR-21. Materials and Methods: Seventy two (72) (MPN) patients were screened for JAK2 V617F burden using ASO-PCR. Out of 72 MPN patients, 58 were JAK2 V617F positive and 14 were JAK2 V617F negative. BCR/ABL1 fusion gene transcript screening by multiplex PCR was done to rule out Philadelphia positive MPN. We performed SYBR green based qRT-PCR assay to characterize relative STAT3, PTEN mRNA expression and miR21 expression in 72 MPN patients. Results: The mRNA expression levels of STAT3 and PTEN and mi-21 expression in all MPN patients were evaluated and compared withJAK2 (V617F) and JAK2 (WT) MPN patients. We identified that STAT3 mRNA expression was significantly upregulated in patients with JAK2 (V617F) genotype (mean fold6SD¼2.14 61.2) compared to patients with JAK2 (WT) genotype (mean fold6SD¼1.2360.95). Further, we observed a significantly increased miR 21 expression (mean fold6SD¼2.1860.44) in JAK2 (V617F) patients in comparison to JAK2 (WT) patients (mean fold6SD¼1.7060.49) (p ¼ 0.0003). In addition, we observed that PTEN expression was substantially and significantly downregulated in JAK2 (V617F) patients (mean fold6SD¼ 1.73 6 0.36) compared JAK2 (WT) patients (mean fold6SD¼2.55 6 0.25) (p < 0.0001). Conclusion: In summary, STAT3 activation caused by JAK (V617F) mutation in MPN patients causes overexpression of miR-21 which leads to downregulation of tumour supressor PTEN MPN patients. Thus, our suggests that JAK2 activated STAT3/ miRNA-21 may play a valuable prognostic biomarker for MPN.
MO3 1 4
Vascular Endothelial Growth Factor Receptor Polymorphisms and im Treatment Response in Chronic Myeloid Leukemia Patients
Siti Mariam Ismail1, Ahmad Aizat Abdul Aziz1, Mohd Zaki Husin1, Mohamed Qais Abu Baker1, Mohd Ismail Ibrahim4, Rosline Hasaan2, Sarina Sulong1, Azlan Husin3, Ravindran Ankathil1 1 Human Genome Centre, Universiti Sains Malaysia, Malaysia, 2Department of Haematology, PPSP, Universiti Sains Malaysia, 3Department of Internal Medicine, PPSP,Universiti Sains Malaysia, 4Department of Community Medicine, PPSP,Universiti Sains Malaysia Background: Imatinib mesylate (IM) is the gold standard drug for chronic myeloid leukemia (CML) treatment. However, intrinsic and acquired resistance against IM has become a problem in CML treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a pivotal role in leukemia associated angiogenesis. Its expression is a good predictor of poor survival in CML. Genetic polymorphisms in VEGFR2 result in varied VEGFR2 expression and may lead to inter individual variation in disease progression and outcome to IM therapy. Aim of this study was to investigate the frequencies of VEGFR2 polymorphisms rs1531289 and
Volume 30 | Supplement 6 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.085/5582989 by guest on 24 October 2019
Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large-scale cohorts of patients with special backgrounds from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report retrospective analysis of all 901 pts data and focus on effectiveness and safety in special subgroups of the Japanese NSCLC patients, from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Patients with EGFR mutations showed significantly shorter PFS as compared to EGFR wild-type patients. Among other special groups, 316 pts with high blood pressure, in which 272 pts was on antihypertensive, showed superior ORR as compared to 585 pts with normal pressure at baseline. Safety analysis showed higher pulmonary toxicity in patients with pulmonary infection at baseline and higher hepatotoxicity in a group of pts infected with hepatitis virus. In this presentation, further analysis on the other subgroups will be presented.
Annals of Oncology
Real-World Effectiveness and Safety of Nivolumab in Special Subgroups of NSCLC pts: A Multicenter-Retrospective Study
Satoru Kitazono1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Haruhiro Saito2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Department of Thoracic Medical Oncology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 2Nivolumab Japan Real World Study Group, 3BristolMyers Squibb K.K, 4ONO Pharmaceutical Co., Ltd
MO2 18 6
Real-World Effectiveness and Safety of Nivolumab in NSCLC pts in Japan: A Multicenter-Retrospective Observational Study
Haruhiro Saito1,2, Ryo Morita2, Kyoichi Okishio2, Junichi Shimizu2, Hiroshi Sakai2, Young Hak Kim2, Osamu Hataji2, Makiko Yomota2, Makoto Nishio2, Keisuke Aoe2, Osamu Kanai2, Toru Kumagai2, Kayoko Kibata2, Hiroaki Tsukamoto2, Satoshi Oizumi2, Keisuke Tomii2, Hiroshi Tanaka2, Keiko Mizuno2, Hirotoshi Hoshiyama3, Kenya Ochi4, Yuichiro Ohe2 1 Kanagawa Cancer Center, 2Nivolumab Japan Real World Study Group, 3Bristol-Myers Squibb K.K, 4Ono Pharmaceutical Co., Ltd Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large cohorts of patients from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report a retrospective data analysis accessing effectiveness and safety of nivolumab in 901 Japanese NSCLC pts from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Among 901 pts, median age of the pts treated with nivolumab was 67 ys old and proportion of 75 ys or over was 19.8%. Pts with ECOG PS 0 or 1 account for 75.8%, and pts with SQ and adeno histology were 24.5% and 67.7%, respectively. Pts with EGFR mutation account for 12.9%. Median numbers of nivolumab dose was five and nivolumab was most frequently used at 2nd line (46.8%) and followed by at 3rd line (26.5%). Rate of 1 yr overall survival (OS) was 54.3% and, median PFS was 2.1 months and overall ORR was 20.6%. There was no significant difference in effectiveness among histology. Although there was no difference in effectiveness of nivolumab by age, ECOG PS status significantly influence effectiveness of nivolumab. Analysis is ongoing to access various factors that may be associated with the effectiveness of nivolumab. Overall irAE incidence for all grade and grade 3-4 will be reported as well as categorized irAE. Further analysis is planned for safety management of irAEs and prognosis. Conclusion: The effectiveness and safety of nivolumab observed in real-world data from NSCLC patients in Japan was comparable to results observed in clinical trials. ECOG PS status was identified as a factor influencing effectiveness of nivolumab.
MO3 1 1
JAK2 (V617F) positively regulates PD-L1 mRNA expression via STAT3/5 activation in MNP (PV and ET) patients
Sameer Ahmad Guru1, Mamta P Alpana1, Rashid Mir1,2, Imtiyaz A Najar1, Mariyam Zuberi1, Naresh Gupta1, Pramod Lali1, Alpana Saxena1 1 Department of Biochemistry, Maulana Azad Medical College, India, 2University of Tabouk Background:Escalated PD-L1 expression is reported in many cancer types initiating an immune escape mechanism. This led to the development of checkpoint inhibitors against PD-1/PD-L1. However, the mechanisms underlying escalated production of PD-L1 in many cancers is not clear yet.
vi110 | Oral Session : Mini-Oral Abstracts Session
Methods:In this study, we studied PD-L1 mRNA expression levels in concert to JAK2 (V617F) mutation in a group of 72 MPN patients (38 PV and 33 of ET). Clinical and demographical characters were noted carefully. Results:Confirmed MPN patients were screened for JAK2 (V617F) mutation by tetraprimer ARMS-PCR. We next quantified JAK2 (V617F) with ASO-PCR. The patients were also screened for BCR/ABL1 fusion gene transcripts to clarify Ph negative MPN status. The mRNA expression levels of PD-L1, STAT3/5 in all MPN patients were evaluated and it was identified that PD-L1, STAT3 but not STAT5 mRNA levels were significantly high in JAK2 (V617F) patients compared to JAK2 (WT) ones. It was also identified that PD-L1, STAT3/5 mRNA expression was upregulated in MPN patients with more JAK2 (V617F) percentage/allele burden than those MPN patients with less JAK2 (V617F) percentage/allele burden. Finally, we evaluated correlation of JAK2 (V617F) percentage with PD-L1, STAT3/5 mRNA expression levels and discovered that PD-L1 and STAT3 are in strong and direct correlation with JAK2 (V617F) burden while STAT5 was found to be moderately correlated. In addition, we identified strong coexpression of PD-L1 and STAT3 and as expected STAT5 moderately coexisted with PD-L1. Conclusion: In summary,this study shows that increased PD-L1 expression accompanies JAK2 (V617F) mutation. The increased expression of PD-L1 may be caused by excessive activation of STAT3/5 which are regulators of PD-L1. The study finds that PD-L1 expression is mainly mediated by JAK2 (V617F) via STAT3 and thatSTAT5 only plays a minor role.The study supports the concept of using PD-L1/STAT3/5 axes as targets for developing checkpoint inhibitors.
MO3 1 2
Escalated activation ofSTAT3 due to JAK2 V617F activatingmutation causesdownregulation ofPTEN via miRNA 21overexpression
Mamta P Sumi1, Sameer A Guru1, Rashid Mir2, Imtiyaz Najar1, Mariyam Zuberi1, Naresh K Gupta1, Pramod Lali1, Alpana Saxena1 1 Maulana Azad Medical College, India, 2University of Tabouk Background: Mutations in Janus kinase 2 (JAK2) genes are the genetic characteristic of BCR-ABL1-negative myeloproliferative neoplasms (MPN). JAK2 V617F mutation is frequently found in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). We aimed to determine the effect of JAK2 V617F on expression of phosphatase and tensin homolog (PTEN) and its regulator miR-21. Materials and Methods: Seventy two (72) (MPN) patients were screened for JAK2 V617F burden using ASO-PCR. Out of 72 MPN patients, 58 were JAK2 V617F positive and 14 were JAK2 V617F negative. BCR/ABL1 fusion gene transcript screening by multiplex PCR was done to rule out Philadelphia positive MPN. We performed SYBR green based qRT-PCR assay to characterize relative STAT3, PTEN mRNA expression and miR21 expression in 72 MPN patients. Results: The mRNA expression levels of STAT3 and PTEN and mi-21 expression in all MPN patients were evaluated and compared withJAK2 (V617F) and JAK2 (WT) MPN patients. We identified that STAT3 mRNA expression was significantly upregulated in patients with JAK2 (V617F) genotype (mean fold6SD¼2.14 61.2) compared to patients with JAK2 (WT) genotype (mean fold6SD¼1.2360.95). Further, we observed a significantly increased miR 21 expression (mean fold6SD¼2.1860.44) in JAK2 (V617F) patients in comparison to JAK2 (WT) patients (mean fold6SD¼1.7060.49) (p ¼ 0.0003). In addition, we observed that PTEN expression was substantially and significantly downregulated in JAK2 (V617F) patients (mean fold6SD¼ 1.73 6 0.36) compared JAK2 (WT) patients (mean fold6SD¼2.55 6 0.25) (p < 0.0001). Conclusion: In summary, STAT3 activation caused by JAK (V617F) mutation in MPN patients causes overexpression of miR-21 which leads to downregulation of tumour supressor PTEN MPN patients. Thus, our suggests that JAK2 activated STAT3/ miRNA-21 may play a valuable prognostic biomarker for MPN.
MO3 1 4
Vascular Endothelial Growth Factor Receptor Polymorphisms and im Treatment Response in Chronic Myeloid Leukemia Patients
Siti Mariam Ismail1, Ahmad Aizat Abdul Aziz1, Mohd Zaki Husin1, Mohamed Qais Abu Baker1, Mohd Ismail Ibrahim4, Rosline Hasaan2, Sarina Sulong1, Azlan Husin3, Ravindran Ankathil1 1 Human Genome Centre, Universiti Sains Malaysia, Malaysia, 2Department of Haematology, PPSP, Universiti Sains Malaysia, 3Department of Internal Medicine, PPSP,Universiti Sains Malaysia, 4Department of Community Medicine, PPSP,Universiti Sains Malaysia Background: Imatinib mesylate (IM) is the gold standard drug for chronic myeloid leukemia (CML) treatment. However, intrinsic and acquired resistance against IM has become a problem in CML treatment. Vascular endothelial growth factor receptor 2 (VEGFR2) plays a pivotal role in leukemia associated angiogenesis. Its expression is a good predictor of poor survival in CML. Genetic polymorphisms in VEGFR2 result in varied VEGFR2 expression and may lead to inter individual variation in disease progression and outcome to IM therapy. Aim of this study was to investigate the frequencies of VEGFR2 polymorphisms rs1531289 and
Volume 30 | Supplement 6 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.085/5582989 by guest on 24 October 2019
Background: In December 2015, nivolumab was approved as treatment for previously treated NSCLC irrespective of PD-L1 expression or histology in Japan. There are few reports that include real-world data on large-scale cohorts of patients with special backgrounds from Japan. Method: Data from patients who initiated nivolumab treatment from April 1, 2016 to December 31, 2016 were collected at 23 regional medical institutions across Japan. Here we report retrospective analysis of all 901 pts data and focus on effectiveness and safety in special subgroups of the Japanese NSCLC patients, from a multicenter, observational study; CA209-9CR (NCT03273790). Result: Patients with EGFR mutations showed significantly shorter PFS as compared to EGFR wild-type patients. Among other special groups, 316 pts with high blood pressure, in which 272 pts was on antihypertensive, showed superior ORR as compared to 585 pts with normal pressure at baseline. Safety analysis showed higher pulmonary toxicity in patients with pulmonary infection at baseline and higher hepatotoxicity in a group of pts infected with hepatitis virus. In this presentation, further analysis on the other subgroups will be presented.
Annals of Oncology