Abstract RF3-04: NRG-BR004: A Randomized, Double-blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab with Atezolizumab or Placebo in First-line HER2-positive Metastatic Breast Cancer

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Abstract Background: The CLEOPATRA trial established trastuzumab, pertuzumab, and docetaxel (THP) as a standard of care for first-line metastatic, HER2-positive breast cancer with median progression-free survival (PFS) of 18.7 months and median overall survival (OS) of 57 months. NRG-BR004 was a phase III, placebo-controlled trial designed to determine whether the addition of the PD-L1 inhibitor atezolizumab to THP would improve PFS, relative to THP/placebo in patients with newly documented HER2-positive measurable metastatic breast cancer. Methods: In this double-blinded phase III trial, patients with newly documented HER2-positive measurable metastatic breast cancer were randomly assigned (in a 1:1 ratio) to receive atezolizumab (1200 mg IV) or placebo on days 1 and 22 every six weeks until progression or for two years, combined with 1) a taxane regimen selected by investigator (weekly paclitaxel 80 mg/m2 IV on days 1, 8, 15, 22, 29, and 36, or docetaxel 75 mg/m2 IV on days 1 and 22 every six weeks) administered until progression or toxicity required discontinuation and 2) trastuzumab with pertuzumab on days 1 and 22 every six weeks until progression or toxicity required discontinuation. The primary endpoint, PFS, was assessed by investigators using RECIST 1.1 criteria. Results: One hundred ninety out of the planned 600 patients were randomized over 37 months from May 1, 2019, to May 20, 2022. An imbalance in Grade 5 AEs coupled with continued poor accrual and the changing landscape in HER2+ metastatic breast cancer resulted in the permanent closure to further enrollment in May of 2022. A decision was made to discontinue atezolizumab/placebo in patients receiving the investigational component of the trial therapy and to unblind investigators and patients. Treatment with the standard components of therapy continued at investigator discretion. The study continued to collect information on PFS events, deaths, and late immune adverse events through April of 2024. The primary analyses were performed in September 2024. Median follow-up for PFS was 31.1 months and 35.6 months for OS. Characteristics for the randomly assigned patient population included median age of 52 years, 66% had estrogen-receptor positive disease, 79% had visceral metastases, 4% had brain metastases, 82% had presented with de novo metastatic disease, and only 14% were PD-L1 positive. Characteristics were balanced between the two arms. The mean and median number of cycles of trastuzumab, pertuzumab, and taxanes were similar in the atezolizumab and placebo arms. Total grade 2, 3, and 4 adverse events were similar across both arms. Grade 5 events totaled 6 in the atezolizumab arm and 0 in the placebo arm at the time of closure of the study and discontinuation of atezolizumab/placebo. Two-year PFS was 54.0% and 45.6% in the atezolizumab-THP arm and placebo-THP arm (hazard ratio 0.73 [0.49, 1.09]), respectively. Three-year OS was 86.4% and 81.7% in the atezolizumab-THP arm and placebo-THP arm (hazard ratio 0.8 [0.39, 1.63]), respectively. Stratified log-rank test was used to compare the distribution of PFS and OS between the two treatment arms with estrogen receptor status and prior neoadjuvant or adjuvant trastuzumab as the stratification factors. Conclusions: Accrual to BR004 was closed to further enrollment in May 2022 and atezolizumab/placebo was discontinued due to poor accrual and the imbalance in Grade 5 events between the two arms, 6 deaths in the atezolizumab-THP arm versus 0 in the placebo-THP arm. The results suggest checkpoint inhibitors may have activity in metastatic HER2+ breast cancer, but further studies would be necessary to establish efficacy and improve safety. NCT #: NCT03199885 Support: U10 CA180868, U10 CA180822, UG1 CA189867, U24 CA196067, Genentech/Roche Citation Format: Vicente Valero, Gong Tang, Charles E. Geyer, Jr, Priya Rastogi, Shannon L. Puhalla, Jiahe Li, Stephen K.L. Chia, Erin F. Cobain, Elias Obeid, David B. Page, Andrew S. Poklepovic, William J. Irvin, Jr, Adam M. Brufsky, Irene L. Wapnir, J. Marie Suga, Eleftherios P. Mamounas, Norman Wolmark. NRG-BR004: A Randomized, Double-blind, Phase III Trial of Taxane/Trastuzumab/Pertuzumab with Atezolizumab or Placebo in First-line HER2-positive Metastatic Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr RF3-04.

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