BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT) (NCT04296942), a non-randomized phase 1 study. The primary outcome is Overall Response (Partial Response + Complete Response) for Participants With Human Epidermal Growth Factor Receptor 2 (HER2) + Breast Cancer (BC).

2. Clinical Question

3. Trial Design

NCT04296942, titled BrEAsT, was a phase 1b trial sponsored by the National Cancer Institute. Its stated purpose was to investigate combinations of immunotherapy and other study drugs in metastatic breast cancer. The registry lists a non-randomized allocation, no masking, and a sequential model. The brief description says participants would be assigned to 1 of 3 groups, with treatment determined by group. The registry reports enrollment of 1 and a terminated status.

The arms were organized around disease subtype and treatment combination. Arm 1 was for triple-negative breast cancer and included M7824, also called bintrafusp alfa, plus BN-Brachyury. Arms 2 and 3 were for HER2-positive breast cancer and included M7824, BN-Brachyury, and ado-trastuzumab emtansine; Arm 3 also included entinostat. The study description identifies M7824 as a bifunctional molecule involving PD-L1 and a TGF-beta-sequestering agent, and BN-Brachyury as a vaccine for the tumor-associated antigen brachyury.

The brief description says treatment was delivered in cycles, with each cycle lasting 3 weeks and clinic visits planned before each new cycle. Screening and follow-up procedures described included clinical assessments, blood testing, and tumor imaging. These are descriptions of the intended study procedures; the registry record does not establish which procedures were completed for the enrolled participant.

The record lists a start date of 2021-05-04 and a primary completion date of 2021-10-22. The reason for termination, the detailed accrual history, and whether the planned sequential treatment stages were completed are not reported in the registry record. Because allocation was not randomized and there was no masking, the design does not support a controlled causal comparison across the arms.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: This outcome measure pertains to Arm 1 TNBC participants only.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Population: No participants were enrolled in group 2 and 3 due to study closure by the sponsor.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response (Partial Response + Complete Response) for Participants With Human Epidermal Growth Factor Receptor 2 (HER2) + Breast Cancer (BC), measured over From start of treatment until disease progression/recurrence, approximately 5 months and 17 days..

The primary outcome was overall response in participants with HER2-positive breast cancer. It was defined as the best response recorded from the start of treatment until disease progression or recurrence, combining complete responses and partial responses. Assessment was based on RECIST version 1.1. A complete response meant disappearance of all target lesions. A partial response required at least a 30% decrease in the sum of target-lesion diameters relative to baseline. Progression was defined in the registry description as at least a 20% increase in that sum, with appearance of new lesions also described as progression.

In general, response categories provide a way to summarize tumor changes using prespecified measurement rules rather than relying on an unstructured impression. A best-response endpoint captures whether a participant reached a response category at any point during the stated assessment period; it does not by itself describe how long that response lasted. The registry's timeframe was from treatment start until progression or recurrence, approximately 5 months and 17 days.

The primary outcome was specific to Arms 2 and 3, but the registry states that no participants with HER2-positive breast cancer were accrued and that the outcome was not assessed. Consequently, the record contains no observed primary response result to interpret. The outcome definition is available, but an estimate of response in the intended cohort is not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical interpretation is constrained by the design and by the lack of an assessed primary outcome. The registry identifies a non-randomized, unmasked, sequential phase 1b study, with enrollment of 1 and 0 analyses reported. The primary endpoint was defined, but no participants in its intended HER2-positive population were accrued. Statistical methods can clarify what kinds of conclusions would ordinarily follow from different designs and estimates, but they cannot create an efficacy estimate where none was observed.

What does a confidence interval communicate?

In general, a confidence interval expresses the uncertainty around an estimated quantity under a statistical model and its assumptions. A narrow interval indicates greater precision under those assumptions, while a wide interval indicates less precision. A confidence interval does not establish that a result is clinically important, and it does not correct for bias in how participants were selected or compared. The registry record does not report a confidence interval for the primary outcome because that outcome was not assessed.

Why does the non-randomized design matter?

In general, random allocation helps make treatment groups comparable with respect to both measured and unmeasured characteristics, on average. Without randomization, differences between groups may reflect who entered each group as well as treatment. This study's sequential, non-randomized allocation therefore does not provide a like-for-like controlled comparison. The registry explicitly notes that the arms are not a like-for-like control comparison. Even if outcomes had been available in more than one arm, direct differences between arms would need careful interpretation and could not automatically be attributed to the treatment combinations.

No masking was listed. In general, knowing which treatment is being given can influence outcome assessment or reporting, particularly where outcomes involve judgment. RECIST criteria provide structured rules for classifying tumor response, but the registry record does not report details of independent review, assessor masking, or adjudication. Those details are not reported in the registry record.

What can the response definition establish?

The registry defines overall response as the best complete or partial response recorded over the stated assessment period, assessed using RECIST version 1.1. The response rules use changes in the sum of target-lesion diameters and the appearance of new lesions. In general, a categorical response endpoint condenses measurements into clinically interpretable categories, but it does not describe all dimensions of disease course. It does not, by itself, quantify duration of response or time until progression. The registry lists progression-free survival as a secondary outcome, but no analysis is reported for it.

The primary outcome was limited to Arms 2 and 3, and no HER2-positive participants were accrued. Thus, there are no response observations for the population the primary endpoint was intended to describe. A confidence interval, hypothesis test, or effect estimate for that outcome cannot be inferred from the endpoint definition or the arm descriptions.

How should the planning illustrations be read?

The planning assumptions describe illustrations based on a stated fraction of an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For time-to-event outcomes, the stated planning quantity is a total number of events; for other outcomes, it is participants per arm. In general, such calculations show how sample-size requirements depend on assumptions about the effect and design. They are not observed results, evidence of achieved power, or a justification for the study's actual enrollment.

The record does not report a sample-size justification or an observed primary response effect in the HER2-positive cohort. Accordingly, numerical planning illustrations should not be treated as an empirical estimate of treatment effect or as evidence that the trial could detect a particular effect. The underlying effect assumptions and the trial's own design rationale are not reported in the registry record.

What does over-dispersion mean in general?

For outcomes analyzed as counts or rates, over-dispersion means that observed variability is greater than a statistical model expects. If it is ignored, uncertainty estimates may be too small and tests may be too optimistic. This is a general statistical issue, not a reported feature of this trial: the registry lists 0 analyses and does not identify a fitted count model or an over-dispersion assessment.

More broadly, interpretation depends on the analysis population, outcome definitions, follow-up, and handling of incomplete observations. The registry record does not report a statistical analysis plan, interim analyses, missing-data procedures, or the analysis populations used for outcomes. These omissions prevent assessment of how the planned endpoints would have been analyzed if accrual had allowed them to be evaluated.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures, including the primary overall-response outcome for the HER2-positive cohort and secondary outcomes involving progression-free survival and stromal tumor-infiltrating lymphocytes. It reports 0 analyses. The record does not describe a multiplicity strategy, such as whether testing across outcomes or treatment arms was planned to be adjusted or treated as exploratory. That information is not reported in the registry record.

In general, evaluating multiple outcomes or multiple comparisons increases the chance of finding an apparently notable result by chance if each is tested separately. A prespecified testing hierarchy or other multiplicity approach can clarify which results are confirmatory and how uncertainty should be interpreted. No such plan is reported, and the lack of analyses means there are no posted hypothesis-test results to assess for multiplicity.

The registry also does not report how missing outcome data would have been handled, what constituted an evaluable participant, or which analysis populations were planned. It does not report interim analyses or a statistical analysis plan. These details matter because exclusions, incomplete follow-up, and the choice of analysis population can affect estimates and their interpretation.

The primary endpoint was not assessed because no participants with HER2-positive breast cancer were accrued before the study closed to accrual. This is distinct from missing response measurements among enrolled HER2-positive participants: the registry says that there were no such participants. The reason the study terminated and whether other outcomes were collected or analyzed are not reported in the registry record.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety entries are small descriptive counts, not estimates of event rates in a broad population. In Arm 1, the registry lists 1 participant at risk for serious adverse events and 0 affected. For other adverse events, it lists 1 participant at risk and 1 affected. It also lists 1 death in that arm. Arms 2 and 3 each have 0 participants at risk and 0 events listed in these fields. No serious adverse-event terms are listed.

The registry does not report the cause of death, its timing, or whether it was considered related to treatment. It also does not clarify the relationship between the death entry and the other adverse-event entry. Those details are not reported in the registry record. The record lists 1 participant enrolled overall, but the safety entries alone do not establish the clinical circumstances of that participant's outcome.

In general, the number at risk is essential context for safety counts: a count without its denominator can be misleading. With only 1 participant at risk in Arm 1 and none in the other arms, these entries cannot characterize comparative safety or the frequency of adverse events in a larger population. They should be read as the posted experience, not as a stable estimate of risk.

12. What the Result Does, and Does Not, Mean

The registry record documents a planned study of sequential treatment combinations in advanced breast cancer, with a primary response question for the HER2-positive cohort. It also documents that the trial was terminated, that enrollment was 1, and that no HER2-positive participants were accrued. As a result, the primary outcome was not assessed. The record therefore provides no observed primary response result for the intended HER2-positive population.

This does not establish that the combinations did or did not produce tumor responses. It means the registry record contains no assessment of that endpoint in the target cohort. A treatment effect, response rate, or comparative benefit cannot be inferred from a study objective, an endpoint definition, or planning assumptions alone. The listed secondary outcomes likewise have no analyses reported in the registry.

The safety entries describe the limited experience recorded in Arm 1: 0 serious adverse events among 1 participant at risk, 1 participant with other adverse events among 1 at risk, and 1 death. They do not identify the cause or attribution of the death, and they cannot support a broad safety estimate. The other arms have no participants at risk recorded, so their zero entries do not indicate absence of events among treated participants.

In general, a trial's design determines which comparisons can be interpreted, while the amount and completeness of outcome data determine how precisely those comparisons can be estimated. Here, non-randomized allocation limits between-arm comparison, and the absence of HER2-positive accrual prevents evaluation of the primary response question. No conclusion about efficacy or comparative safety should be drawn from these registry entries.

13. Why This Trial Matters Statistically

This trial illustrates a basic distinction in clinical research: a carefully defined endpoint is not the same as an observed endpoint result. The registry gives a detailed definition of overall response, including RECIST-based criteria, but the intended HER2-positive cohort did not accrue. Without observations in that cohort, there is no response estimate to interpret, regardless of how clearly the outcome was defined.

It also illustrates why enrollment and analysis populations need to be considered alongside study objectives. The registry reports enrollment of 1 and 0 analyses. The primary outcome applied to Arms 2 and 3, while the safety entries show participants at risk only in Arm 1. Reading the intended design without the accrual information could create the mistaken impression that the primary endpoint had been measured in its target population.

The non-randomized sequential design is also important statistically. Treatment groups assembled without random allocation are not automatically comparable, and these arms were intended for different breast cancer subtypes and treatment combinations. They cannot be treated as randomized alternatives or as a controlled comparison. This remains true even when treatment regimens are described in detail.

Finally, the record separates descriptive safety reporting from comparative inference. A count of events in a very small exposure group can document what was recorded, but it cannot establish a reliable frequency or treatment-related risk. These features make the record useful for understanding the study's design and the limits of its evidence, while leaving the primary efficacy question unanswered.

14. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation is that the primary outcome was not assessed. The registry states that the HER2-positive cohort did not accrue participants before the study closed to accrual. Consequently, the record offers no primary response data for the cohort the endpoint was designed to address.

Enrollment was 1, and the study was non-randomized, unmasked, and sequential. The registry cautions that the arms are not a like-for-like control comparison. The safety entries include participants at risk only in Arm 1, so they do not permit a comparison of adverse events across the planned combinations. The record does not report why the study was terminated or whether the planned sequential stages were completed.

The registry reports 0 analyses. A statistical analysis plan, sample-size justification, interim analyses, missing-data procedures, and analysis populations are not reported in the registry record. The record also does not report the cause or treatment attribution of the listed death, or the relationship between that entry and other adverse events. These gaps restrict interpretation of both study conduct and safety.

Although the registry describes secondary outcomes, it does not provide their analysis results. The existence of an outcome definition does not show that the outcome was measured or analyzed. Overall, the available record supports description of the intended design and the limited posted safety counts, but not an efficacy estimate or a comparative assessment of treatment effects.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: BN-Brachyury, Entinostat, Adotrastuzumab Emtansine and M7824 in Advanced Stage Breast Cancer (BrEAsT) — NCT04296942.
• Registry record last updated 2022-01-11; status last verified 2021-12.
• Results first posted 2022-01-11.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT04296942, BrEAsT, was a National Cancer Institute-sponsored phase 1b study of sequential combinations involving M7824 and BN-Brachyury, with ado-trastuzumab emtansine and entinostat included in specified HER2-positive arms. The registry describes non-randomized allocation, no masking, enrollment of 1, and terminated status. The recorded start date was 2021-05-04, and the primary completion date was 2021-10-22.

The primary outcome was overall response in the HER2-positive breast cancer cohort, assessed using RECIST version 1.1. The registry states that this outcome was not assessed because no participants with HER2-positive breast cancer were accrued. It reports 0 analyses. Safety entries list 1 participant at risk in Arm 1, with 0 serious adverse events, 1 participant with other adverse events, and 1 death; the other arms have no participants at risk recorded. The cause and attribution of the death are not reported in the registry record.