Abstract PS4-14: Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2-negative MBC in NEWBEAT trial (WJOG9917BTR)
Authors: Ozaki Yukinori , Kitano Shigehisa , Tsurutani Junji , Iwasa Tsutomu , Takahashi Masato , Mukohara Toru , Masuda Norikazu , Futamura Manabu , Minami Hironobu , Matsumoto Koji , Kawabata Hidetaka , Yamashita Makiko , Yoshimura Kenichi , Takano Toshimi 
Published: February 2021

Abstract
Background: Synergistic antitumor effect of combined anti-PD-1 antibody and anti-VEGF agent has been expected, based on previous preclinical data. We have conducted NEWBEAT trial to evaluate efficacy of triple combination regimen of nivolumab + paclitaxel + bevacizumab in patients (pts)with HR+ HER2- MBC or metastatic TNBC, and clinical results were presented in SABCS 2019. A biomarker study (WJOG9917BTR) was conducted to evaluate the VEGF and immune status of these patients. Methods: HER2-negative breast cancer patients in the NEWBEAT trial were enrolled. To explore the biomarkers for the triple combination treatment, immune status and its dynamics were evaluated with multicolor flowcytometry, multiplex ELISA in peripheral blood before and after treatment. Results: Among the 57 patients who were enrolled to the NEWBEAT trial, 50 patients were registered to the biomarker study. The expression of Ki67 and inducible T-cell co-stimulator (ICOS) on T cells increased after treatment, indicating induction of the T cell proliferation and activation. In responder (defined as patients with progression-free survival longer than 1 year, n = 30), the number of naïve CD4+ T cells at pretreatment were higher and effector memory CD4+ T cells were lower than non-responder. On the other hand, CD86+ myeloid DC at pretreatment were lower in non-responder pts. The median concentration of VEGF-A in serum before treatment was 116.065 pg/ml (range: 0-740.23) and decreased below 37 pg/ml at day 8 after treatment. Although serum VEGF-A level is inversely correlated with clinical outcome of pts with anti-PD-1 antibody in previous reports, in this trial VEGF-A high subgroup had better objective response than VEGF-A low subgroup, suggesting that blockade of VEGF by bevacizumab may overcome immunosuppression via VEGF signaling. Interestingly, in recurrent pts , the number of VEGFR-2+ CD4+ T cells / Monocyte were higher, and PD-L1+ CD4+ T cells / Monocyte / myeloid Dendritic Cell tended to be higher than in de novo stage IV pts. These results suggested that immune status of recurrent pts were more immunosuppressive than de novo stage IV pts, and that it might be more effective by the combination therapy to block the VEGF and PD-1 pathways. Moreover, the changes of immune status and dynamics on CD8+ T cells were not observed, suggesting that the therapeutic strategy of breast cancer might require the re-activation of CD8+ effector T cells through the stimulation of antigen-presenting cells followed by modification of CD4+ helper T cells.Conclusions: Our analysis showed the different immune status depending stage, subtype and response in advanced breast cancer pts. The dynamic decrease of serum VEGF-A concentration and high expression of VEGFR-1 or VEGFR-2 in the immune suppressive cells in advanced breast cancer pts suggested that combination treatment with bevacizumab might clinically overcome the immune suppression via inhibition of VEGF-A. (UMIN000029590)
Citation Format: Yukinori Ozaki, Shigehisa Kitano, Junji Tsurutani, Tsutomu Iwasa, Masato Takahashi, Toru Mukohara, Norikazu Masuda, Manabu Futamura, Hironobu Minami, Koji Matsumoto, Hidetaka Kawabata, Makiko Yamashita, Kenichi Yoshimura, Toshimi Takano. Immunological analysis of the combination therapy of nivolumab, paclitaxel and bevacizumab in patients with HER2-negative MBC in NEWBEAT trial (WJOG9917BTR) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS4-14.