Abstract OT2-16-05: Safety Analyses of 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 (MBC)
Bibliographic record
Abstract
Abstract Background: The CLEOPATRA trial established trastuzumab, pertuzumab and a taxane (THP) as a standard of care for first line metastatic, HER2-positve breast cancer with median progression-free survival (PFS) of 18.7 months and median 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 progression-free survival (PFS), relative to THP/placebo in patients with newly documented HER2-positive measurable metastatic breast cancer. Methods: BR004 was designed to detect an improvement in the primary endpoint of PFS in patients with measurable disease from 16.5 to 22.5 months with addition of atezolizumab (HR 0.733). A sample size of 600 would provide 80% power with a type I error rate of 0.05 to detect such an improvement when 326 PFS events had been reported. Monthly accrual was projected at 30 patients per month with completion of accrual in 24 months. In addition to routine monitoring of safety data by the IDMC every 6 months, a formal analysis of the toxicity data was to be performed 16 weeks after the 100th patient had been randomized with review by the IDMC. Results: First patient was randomized on May 1, 2019, and after 37 months 190 patients had been randomized. Several amendments were not successful in addressing the low accrual rate. The IDMC began regular monitoring of safety and accrual data in July 2020 and reviewed the formal safety analysis in February 2022. As of the February 2022 IDMC meeting, four Grade 5 adverse events (AEs) had been reported (2 occurring in 2020 and 2 in 2021), one of which occurred in a patient with evolving liver failure due to rapid disease progression at the start of therapy. The recommendation was to continue without modification, but notice was given the Grade 5 AEs had occurred on the same treatment arm without unblinding. When additional Grade 5 AEs occurred on 3/4/2022 and 4/27/2022 both on the same study arm with none reported on the other arm, accrual was held until the IDMC could review updated safety data, narratives of the Grade 5 AEs and the overall context of the trial. There was no evidence of clinically important imbalances between Grade 3 and Grade 4 AEs between the arms., Based on an uncertain but material safety signal, the ongoing accrual challenges, and determination that the clinical question being addressed was no longer sufficiently compelling, the IDMC recommended that the trial should be permanently closed to further enrollment. Summary safety data from 187 treated patients are provided in the Table. A decision was made to discontinue atezolizumab/placebo in patients receiving the investigational component of the trial therapy and unblind investigators and patients. The study will continue to collect information on PFS events, deaths and late immune AEs through April of 2024 when PFS and OS will be analyzed. Conclusions: The imbalance in Grade 5 AEs which occurred on BR004 coupled with continued poor accrual and the changing landscape in HER2+ MBC resulted in early closure of enrollment and unblinding of patients. Follow-up continues to assess PFS, OS and monitor for delayed immune AEs. Support: U10CA180868, -189867, -180822; U24CA196067; and Genentech. Citation Format: Charles E. Geyer, Jr, Gong Tang, Priya Rastogi, Vicente Valero, Stephen K. Chia, Erin F. Cobain, Elias Obeid, David B. Page, Andrew S. Poklepovic, William J. Irvin, Jr., Adam M. Brufsky, Irene L. Wapnir, Jennifer M. Suga, Eleftherios (Terry) Mamounas, Norman Wolmark. Safety Analyses of 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 (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-05.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.003 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.003 | 0.000 |
| Bibliometrics | 0.002 | 0.004 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".