Celine Pallaud1, Martin Reck2, Erzsebet Juhasz3, Barna Szima4, Chung-Jen Yu5, Olga Burdaeva6, Sergey Orlov7, Magalie Hilton1, Venice Archer8, Tony Mok9. 1. F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070 Basel, Switzerland. 2. Department of Thoracic Oncology, LungClinic Grosshansdorf, Member of the German Center for Lung Research (DZL), Wöhrendamm 80, 22927 Grosshansdorf, Germany. 3. Országos Korányi TBC és Pulmonológiai Intézet, Pihenő str 1, 1121 Budapest, Hungary. 4. Markusovszky Teaching Hospital, Markusovszky u. 5, 9700 Szombathely, Hungary. 5. National Taiwan University Hospital, No. 1, Changde St., Zhongzheng Dist., Taipei City 10048, Taiwan. 6. Arkhangelsk Clinical Oncology Dispensary, Obvodny kanal Avenue 145, building 1, Arkhangelsk, Arkhangelsk region, 163045 Russia. 7. St Petersburg State Medical University, St Petersburg, Russia. 8. Roche Products Ltd, Shire Park, 1 Falcon Way, Welwyn Garden City, Hertfordshire AL7 1TW, UK. 9. Department of Clinical Oncology, State Key Laboratory of South China, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong. Electronic address: tony@clo.cuhk.edu.hk.
Abstract
OBJECTIVES: ABIGAIL, a phase II, randomized, open-label, multicenter study evaluated the correlation between biomarkers and best overall response (BOR) to bevacizumab with chemotherapy in patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Exploratory analyses of vascular endothelial growth factor (VEGF) clinical genotyping data are presented. MATERIALS AND METHODS: A total of 303 patients with NSCLC were randomized to receive bevacizumab 7.5mg/kg or 15mg/kg until progression or unacceptable toxicity (plus six cycles of chemotherapy). Patients provided blood samples for biomarker analysis. Exploratory analyses were conducted to assess whether genetic variants in VEGF-A or VEGFR-1/-2 act as efficacy or safety biomarkers. Single nucleotide polymorphisms (SNPs) were determined using individual genotyping assays. DNA analysis for 12 SNPs across three genes is reported: VEGF-A (five SNPs), VEGFR-1 (three SNPs), and VEGFR-2 (four SNPs). RESULTS VEGF-A: c.+405/c.-634 (CG), VEGF-A: c.-460 >C; c-1498 >C (CT), and VEGF-A: c.-2578 C>A were associated with >50% higher odds of responding to treatment. VEGFR-1: rs9554316 (GT) was associated with >30% higher risk of progression and >40% higher risk of death. VEGF-A: c.+936 C>T was associated with higher incidence of hypertension. CONCLUSIONS: Four genetic variants of VEGF-A and VEGFR-1 were associated with bevacizumab treatment outcome. Three variants in VEGF-A were associated with increased BOR, one variant in VEGFR-1 was associated with worse progression-free survival/overall survival. These associations were not statistically significant after correction for multiple testing. No genetic variant was associated with significantly higher risk of hypertension. Replication in additional studies may provide insight into the use of these variants to predict response to bevacizumab.
RCT Entities:
OBJECTIVES: ABIGAIL, a phase II, randomized, open-label, multicenter study evaluated the correlation between biomarkers and best overall response (BOR) to bevacizumab with chemotherapy in patients with advanced or recurrent non-small-cell lung cancer (NSCLC). Exploratory analyses of vascular endothelial growth factor (VEGF) clinical genotyping data are presented. MATERIALS AND METHODS: A total of 303 patients with NSCLC were randomized to receive bevacizumab 7.5mg/kg or 15mg/kg until progression or unacceptable toxicity (plus six cycles of chemotherapy). Patients provided blood samples for biomarker analysis. Exploratory analyses were conducted to assess whether genetic variants in VEGF-A or VEGFR-1/-2 act as efficacy or safety biomarkers. Single nucleotide polymorphisms (SNPs) were determined using individual genotyping assays. DNA analysis for 12 SNPs across three genes is reported: VEGF-A (five SNPs), VEGFR-1 (three SNPs), and VEGFR-2 (four SNPs). RESULTS VEGF-A: c.+405/c.-634 (CG), VEGF-A: c.-460 >C; c-1498 >C (CT), and VEGF-A: c.-2578 C>A were associated with >50% higher odds of responding to treatment. VEGFR-1: rs9554316 (GT) was associated with >30% higher risk of progression and >40% higher risk of death. VEGF-A: c.+936 C>T was associated with higher incidence of hypertension. CONCLUSIONS: Four genetic variants of VEGF-A and VEGFR-1 were associated with bevacizumab treatment outcome. Three variants in VEGF-A were associated with increased BOR, one variant in VEGFR-1 was associated with worse progression-free survival/overall survival. These associations were not statistically significant after correction for multiple testing. No genetic variant was associated with significantly higher risk of hypertension. Replication in additional studies may provide insight into the use of these variants to predict response to bevacizumab.
Authors: John M Mariadason; Niall C Tebbutt; Fiona Chionh; Val Gebski; Sheren J Al-Obaidi; Jennifer K Mooi; Maressa A Bruhn; Chee K Lee; Anderly C Chüeh; David S Williams; Andrew J Weickhardt; Kate Wilson; Andrew M Scott; John Simes; Jennifer E Hardingham; Timothy J Price Journal: Sci Rep Date: 2022-01-24 Impact factor: 4.379
Authors: Adriana Albini; Francesco Bertolini; Barbara Bassani; Antonino Bruno; Cristina Gallo; Stefano Giuseppe Caraffi; Sally Maramotti; Douglas M Noonan Journal: Ecancermedicalscience Date: 2015-11-24