Vascular endothelial growth factor A (VEGF-A) amplification and long-term response to ramucirumab (ram) in metastatic gastric cancer (mGC): The VERA study.

person Alessandra Raimondi Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy info_outline Alessandra Raimondi, Patrizia Gasparini, Sara Lonardi, Salvatore Corallo, Lorenzo Fornaro, Maria Maddalena Laterza, Mariantonietta Di Salvatore, Elisa Giommoni, Claudio Lotesoriere, Sabina Murgioni, Serena Saggio, Antonia Martinetti, Monica Niger, Maria Antista, Serenella Pupa, Filippo G. De Braud, Maria Di Bartolomeo, Gabriella Sozzi, Federica Morano, Filippo Pietrantonio

Authors person Alessandra Raimondi Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy info_outline Alessandra Raimondi, Patrizia Gasparini, Sara Lonardi, Salvatore Corallo, Lorenzo Fornaro, Maria Maddalena Laterza, Mariantonietta Di Salvatore, Elisa Giommoni, Claudio Lotesoriere, Sabina Murgioni, Serena Saggio, Antonia Martinetti, Monica Niger, Maria Antista, Serenella Pupa, Filippo G. De Braud, Maria Di Bartolomeo, Gabriella Sozzi, Federica Morano, Filippo Pietrantonio Organizations Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Unit of Tumor Genomics, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Department of Clinical and Experimental Oncology, Medical Oncology 1 Unit, Istituto Oncologico Veneto IOV-IRCCS, Padua, Italy, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy, Second University of Naples, Naples, Italy, Medical Oncology Unit, Catholic University of the Sacred Heart, Rome, Italy, Azienda Ospedaliero Universitaria Careggi, Firenze, Italy, Medical Oncology Unit, IRCCS “Saverio De Bellis”, Castellana Grotte, Italy, Medical Oncology Unit 1, Clinical and Experimental Oncology Department, Veneto Institute of Oncology IOV – IRCCS, Padua, Italy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy, Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, Fondazione IRCCS-Istituto Nazionale dei Tumori, Milan, Italy, Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy Abstract Disclosures Research Funding Other Background: The anti-VEGFR-2 monoclonal antibody ram, alone or with paclitaxel, is a cornerstone of second-line treatment of mGC. Even if about half patients do not benefit from ram, no predictive biomarkers have been identified so far. In TCGA, VEGF-A amplification was found in 7% of cases, almost exclusively in chromosomal instability subtype. We hypothesize that VEGF-A amplification in tumor cells could lead to autocrine/paracrine stimulation of tumor growth beside angiogenesis, potentially identifying a patients’ subgroup with exceptional responses to ram. Methods: VERA was a multicentric, prospective study based on a translational hypothesis. mGC patients were included according to the following criteria: 1) complete (CR) or partial response (PR) to single-agent ram; 2) >6 months PFS to single-agent ram; 3) >10 months PFS to paclitaxel+ram. According to a Fleming single-stage design, hypothesizing a prevalence of VEGF-A amplification of 1% and 15% among all-comers and exceptional responders, 20 exceptional responders were required to reject the null hypothesis of low prevalence of VEGF-A amplification, with alpha- and beta- errors of 0.05 and 0.10, respectively. VEGF-A amplification (defined as >10% tumor cells with ≥10 VEGF-A copies, variably sized signal clusters or a ratio of VEGF-A gene to centromere of ≥2) was centrally assessed through fluorescent in situ hybridization on pre-treatment FFPE tumor tissue. Results: At 7 Italian Centers, we included 20 patients satisfying the 1st (n=1), 2nd (n=2), or 3rd (n=17) criterion. Clinical-pathological features were: M/F, 11/9; median age 63 years; gastric/GEJ, 17/3; intestinal/diffuse, 14/6, HER2+/HER2-, 4/16. Median PFS and overall survival to ram-based treatment were 15.6 and 25.7 months, with best response: CR/PR/SD, 0/10/10. VERA met its primary endpoint, revealing 3/20 (15%) tumors with VEGF-A amplification (1 case presenting big clusters, 1 small clusters and 1 with >10% tumor cells with ≥10 VEGF-A copies). Conclusions: Validation analyses of first- and second-line randomized trials could confirm VEGF-A amplification as a biomarker of long-term response to ram-based treatment in mGC patients, advancing treatment personalization.