Abstract OT1-18-01: A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study
Authors: Hara Fumikata , Ono Makiko , Kitano Shigehisa , Saji Shigehira , Shimomura Akihiko , Yamanaka Takashi , Kadoya Takayuki , Ito Mitsuya , Bando Hiroko , Yasojima Hiroyuki , Sasaki Keita , Kataoka Tomoko , Shien Tadahiko , Yonemori Kan , Iwata Hiroji 
Published: March 2022

Abstract
Background: Hormone receptor (HR)-positive HER2-negative breast cancers have a lower tumor mutation burden than other types of cancer and triple-negative breast cancer, resulting in relatively low immunogenicity. It is also known that estrogen suppressively regulates immunity through regulatory T cells in the tumor microenvironment. Therefore, the development of immunotherapy in HR-positive and HER2-negative breast cancer is a challenging issues. Anti-VEGF therapy has been shown to improve antigen presentation, local migration of cytotoxic T lymphocytes, and suppressive tumor microenvironment in preclinical and clinical studies of various cancers. Anti-VEGF therapy can be hypothesized to modulate immunotherapy. Methods: JCOG1919E (AMBITION) is a randomized, multicenter, open-label, phase III trial to evaluate efficacy and safety of bevacizumab and paclitaxel in combination with atezolizumab (BEV+PTX+ATZ) comparing to bevacizumab and paclitaxel (BEV+PTX) in patients with HR-positive HER2 negative locally advanced or metastatic breast cancer. The key eligibility criteria are as follows: 1) ECOG PS 0-2, 2) ER and/or PgR positive and HER2-negative breast cancer, 3) endocrine resistance or life-threatening disease, 4) measurable disease, 5) centrally confirmed programmed death-ligand 1 (PD-L1) status on tumor-infiltrating immune cells, 6) no prior chemotherapy for locally advanced or metastatic breast cancer, 7) adequate organ function. Patients will be randomized (staratified by recurrence/de novo, liver metastasis, or PD-L1 status) in a 1:1 ratio, to BEV+PTX arm or BEV+PTX+ATZ arm. Patients in arm A receive PTX (90 mg/m2/day, days 1, 8 and 15, iv) and BEV (10 mg/kg/day, days 1 and 15, iv) on a 28-day cycle. Patients in arm B receive PTX and BEV plus ATZ (840 mg/body/day, days 1 and 15, iv). Treatment in both arms is continued until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS) assessed by investigators. The secondary endpoints include overall survival, PFS assessed by blinded independent central review, response rate, adverse events, PFS (PD-L1 positive), and OS (PD-L1 positive). We assumed a median PFS of 16 months in BEV+PTX+ATZ arm and 11 months in BEV+PTX arm. The planned sample size was calculated as a total of 280 patients (140 patients per arm) with a one-sided alpha of 2.5%, power of 80%, an accrual period of 2.5 years, and a follow-up period of 2 years. Translational research also will be conducted accompanying with this trial. Patient accrual was started in January 29, 2021 and 37 patients were enrolled by June 18, 2021. Safety of patients in this study is being monitored by IDMC. For further information on this trial, visit ClinicalTrials.gov (NCT04732598).
Citation Format: Fumikata Hara, Makiko Ono, Shigehisa Kitano, Shigehira Saji, Akihiko Shimomura, Takashi Yamanaka, Takayuki Kadoya, Mitsuya Ito, Hiroko Bando, Hiroyuki Yasojima, Keita Sasaki, Tomoko Kataoka, Tadahiko Shien, Kan Yonemori, Hiroji Iwata. A randomized controlled phase III study of bevacizumab and paclitaxel in combination with atezolizumab as a treatment for patients with locally advanced or metastatic hormone receptor-positive HER2 negative breast cancer: JCOG1919E/AMBITION study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-18-01.