Amendment to address accrual barriers for NRG-BR004 is activated

October 12 2021

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

The NRG-BR004 study opened to enrollment in March 2019. The trial is designed to compare the addition of the immunotherapy drug, atezolizumab (Tecentriq®), or placebo to the standard treatment regimen for people with HER2-positive metastatic breast cancer (MBC) to determine if atezolizumab will improve patient outcomes. Treatment includes patient/physician choice of paclitaxel or docetaxel administered with trastuzumab and pertuzumab plus atezolizumab or placebo.

According to Charles E. Geyer, Jr., MD, NRG Oncology NRG-BR004 Principal Investigator, and Deputy Director at Houston Methodist Cancer Center: “The CLEOPATRA study demonstrated the addition of pertuzumab to what was then a standard combination regimen of trastuzumab and docetaxel chemotherapy for patients with newly diagnosed metastatic HER2+ breast cancer, improved median survival to almost 5 years with 40% of patients alive 7 years after beginning the therapy. Trastuzumab and pertuzumab were both designed to engage the immune system, and the results of CLEOPATRA were very consistent with an improved, but incomplete immune effect in this setting. The NRG-BR004 trial will determine if atezolizumab can further improve this partial immune effect.”

Because enrollment of patients remained below projections one year after activation, an investigator survey was initiated to identify barriers to accrual and trial participation. The results were in line with information received from investigators during the activation of the trial and through the first year of accrual. Three major barriers were identified in the original version of the trial. First, because mandated central testing can require up to 7 days to confirm HER2 positive status and determine PD-L1 status before randomization could occur and drug shipment following randomization can require up to 7 days, patients entering NRG-BR004 could not begin therapy for 2-3 weeks when the blinded investigational therapy arrived. For patients presenting with an extensive burden of disease precluded participation since they often had an urgent need to begin standard therapy. Second, the weekly paclitaxel regimen was problematic for cancer centers serving large rural populations since weekly trips for therapy can be challenging. The challenges of mandatory weekly therapy were also magnified by the COVID-19 pandemic, and investigators indicated the option of every-3-week docetaxel would be helpful in addressing this barrier. Finally, the exclusion of biosimilar trastuzumab was increasingly problematic as use of biosimilar trastuzumab products was becoming more widespread.

To address these barriers, Amendment 3 now stipulates that patients who meet eligibility criteria for BR004 should receive the loading doses of trastuzumab and pertuzumab along with the first cycle of chemotherapy while waiting for the central testing results required for randomization. Following final confirmation of eligibility patients are randomized in time for shipment for the assigned investigational therapy (atezolizumab or placebo) to be shipped in time for the study medication to be initiated concurrently with the first maintenance dose of trastuzumab and pertuzumab 3 weeks later. This ensures patients begin standard therapy promptly and, also, allows for an initial assessment of toxicity related to the standard therapy before beginning the investigational therapy. The amendment also allows for use of docetaxel and provides dose modification guidelines patients receiving docetaxel in addition to the original guidelines for paclitaxel. To address the biosimilar exclusion trastuzumab is being provided as long as patients remain on study medication and patients who received a loading dose with a trastuzumab biosimilar for Cycle 1 will no longer be excluded from participation in the trial. Finally, eligibility and ineligibility criteria were loosened to allow for more participation by patients with brain metastases.

NRG Oncology activated NRG-BR004 Amendments 3 and 4 on July 30, 2021. Amendment 4 was drafted to address a CTEP Request for Rapid Amendment for atezolizumab. More information about the NRG-BR004 study may be found on

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