Brigatinib Before Brain Irradiation Trial (B3i Trial): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Brigatinib Before Brain Irradiation Trial (B3i Trial) (NCT04634110), a na phase 2 study. The primary outcome is Number of Participants Who Meet Disease Control Rate (DCR) Criteria of Brain Metastases at 3 Months.

2. Clinical Question

The clinical question was whether disease control could be documented after brigatinib alone in this selected population before brain irradiation. The trial name refers to the strategy of brigatinib before brain irradiation, and a secondary outcome was time until administration of whole-brain radiotherapy. However, the registry record does not provide the outcome results needed to describe how often disease control occurred or when subsequent radiotherapy was administered.

The question is limited to the participants enrolled in this single-group phase II study. It is not a randomized test of brigatinib against brain irradiation, another drug, or a control group. The record also does not report enough information to determine how many people completed the MRI assessment or which analysis population was used.

3. Trial Design

The B3i Trial was registered as a phase II, single-group study of brigatinib alone for brain metastases from ALK-positive non-small cell lung cancer. The sponsor was the University of Colorado, Denver. The registry lists allocation as NA and masking as none. Enrollment was 1. The study status is terminated; the registry record does not state why it was terminated.

The brief summary describes eligibility for people who had not previously received an ALK-targeted tyrosine kinase inhibitor or who had previously received crizotinib. The arm description says the study included people with no neurologic symptoms or only mild neurologic symptoms, characterized as an RTOG acute neurologic morbidity score of 0-2. The registry information does not provide the full eligibility criteria, so other selection requirements are not reported in the registry record.

The primary outcome was the number of participants meeting disease control criteria for brain metastases at the 13-week MRI, with an assessment window of ±7 days. Secondary outcomes included time until progression in four parts, overall survival under a strategy of brigatinib alone, brain-metastases-specific mortality, objective response rates, and time until whole-brain radiotherapy. The record lists 12 outcome measures, but it does not report an analysis for them in the information.

The registry lists a start date of 2020-11-17 and a primary completion date of 2022-04-14. It does not report a randomized control group, a masking procedure, or a statistical analysis count. The protocol’s sample-size justification, planned statistical analysis, interim analyses, and detailed follow-up procedures are not reported in the registry record.

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

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.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Who Meet Disease Control Rate (DCR) Criteria of Brain Metastases at 3 Months, measured over 13-week MRI ±7 days.

The primary endpoint counts participants whose brain metastases met disease control criteria at the scheduled 13-week MRI, allowing an assessment window of ±7 days. The record defines disease control as complete response, partial response, or stable disease according to RANO-BM criteria. These categories distinguish tumors that have disappeared, decreased, or remained stable under the stated response framework.

A count is a direct description of how many participants met the criterion. It is not, by itself, a comparison with another treatment, and it does not show how frequently an outcome would occur in a broader population. The registry describes the endpoint as a participant count rather than a percentage or a time-to-event measure. The observed count and the number assessed at the MRI are not reported in the registry record.

General: A defined imaging time point helps make response assessments comparable by specifying when the outcome is to be evaluated. A disease-control endpoint can include stable disease as well as tumor shrinkage; it therefore answers a broader question than whether tumors responded by shrinking. The interpretation depends on the response criteria, timing, and availability of an evaluable assessment. The record names the criteria and assessment window, but does not report the assessment procedures, missing-scan handling, or endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count tell the reader?

The primary outcome is specified as the number of participants meeting the disease control criteria. A count states how many people had the defined outcome; it is not automatically a rate, a risk difference, or a treatment effect. To interpret a count as a frequency, readers also need to know how many participants were assessed and how missing assessments were handled. Those details, along with the observed endpoint count, are not reported in the registry record.

General: Counts are often useful for describing a small study because they make the observed number of outcomes explicit. But a count alone does not show how representative that observation might be beyond the enrolled participants. A percentage would require a denominator, while a comparative effect would require a meaningful comparison. Neither can be reconstructed from the endpoint description alone.

What does disease control mean?

The registry defines disease control as complete response, partial response, or stable disease under RANO-BM criteria. The definition groups several possible response states together. A result for this combined endpoint would indicate whether participants met at least one of those categories at the specified MRI assessment; it would not tell readers the separate counts for complete response, partial response, and stable disease unless those component results were also reported.

The assessment was scheduled for a 13-week MRI with a window of ±7 days. General: A prespecified time point helps clarify when a response is evaluated, while an allowable window can accommodate some scheduling variation. The record does not describe how MRI images were reviewed, whether assessments were independently reviewed, or how a scan outside the assessment window would be treated.

What can a single-group design establish?

The registry lists a single-group model, allocation as NA, and masking as none. There is no separate comparator group in the record. General: A single-group study can describe outcomes observed among people who received a study intervention, but it does not provide a concurrent control for separating treatment effects from other influences. Changes over time, participant selection, and other aspects of care can affect observed outcomes. This does not invalidate a descriptive result, but it limits the kind of causal comparison the design can support.

The study’s secondary outcome titles include progression, survival, mortality, objective response, and time until whole-brain radiotherapy. These are different outcome types. General: A count at a set assessment and a time-to-event outcome answer different questions. Time-to-event methods account for the time until an event and can also account for participants whose event has not been observed by the end of follow-up. The registry record does not report the methods used for these outcomes or any resulting estimates.

How should uncertainty be understood?

General: A confidence interval describes a range of values compatible with the observed data under a specified statistical method. It helps communicate estimation uncertainty, rather than simply labeling a result as statistically significant or not. No confidence interval or other uncertainty estimate for the primary endpoint is reported in the registry record. With enrollment listed as 1, any estimate based on the enrolled group would also have to be interpreted in light of the limited available information, but the record does not establish the endpoint denominator or result.

The registry record does not report a p-value for the primary outcome. General: A p-value, when used, addresses how compatible data are with a specified statistical model and null hypothesis. It is not a measure of the size or clinical importance of an effect. The absence of a reported p-value means there is no such statistic to interpret for this endpoint; it does not indicate a positive or negative finding.

What do planning illustrations mean?

Planning illustrations are not observed outcomes and are not a reconstruction of the trial’s protocol. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect expressed as a stated fraction of the observed effect. For time-to-event calculations, the illustration is expressed as a total number of events; other calculations are expressed as participants per arm.

Those assumptions describe hypothetical planning exercises, not the design of this single-group study. The registry record does not report a sample-size justification for the trial. Any participants-per-arm figures in a planning illustration should be read as hypothetical requirements under its assumptions, never as the number enrolled, the number analyzed, or observed power. The number of participants enrolled in the study is reported as 1, and the primary outcome result is not reported.

General: Over-dispersion matters when observed variation exceeds what a statistical model assumes. If it is ignored, standard errors and uncertainty estimates can be misleading. The registry record does not report a dispersion estimate or an analysis model for the primary endpoint, so there is no basis to describe over-dispersion as an issue that was assessed in this trial.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Patients With ALK+ NSCLC and Brain Metastases")
n      <- c(1)
events <- c(1)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Patients With ALK+ NSCLC and Brain Metastases  1  1  100.0  2.5  100.0  20.7  100.0  15.8  98.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 12 outcome measures, including the primary disease-control endpoint and secondary outcomes covering progression, survival, mortality, objective response, and time until whole-brain radiotherapy. Having multiple outcomes can raise multiplicity questions because testing many hypotheses may increase the chance of at least one apparently notable finding. General: Statistical plans sometimes address this by prioritizing outcomes or adjusting inference across tests. The registry record does not report a multiplicity strategy, a hierarchy of secondary outcomes, or the results of any such adjustment.

The record lists zero analyses. This means the information recorded does not include analysis entries; it does not establish that no analyses were conducted outside the registry. The planned statistical analysis, interim analyses, and any stopping rules are not reported in the registry record. The reason the study was terminated is also not reported.

Missing-data handling is not reported in the registry record. In particular, the record does not state how participants without an evaluable 13-week MRI would be handled, whether missing scans would be treated as non-response, or how incomplete follow-up would be addressed for time-to-event outcomes. The primary endpoint population and analysis population are not reported either. Enrollment of 1 should not be treated as proof that 1 participant contributed an outcome assessment.

General: Missing outcome data can affect interpretation when the probability of having an assessment is related to participants’ health or response. Different assumptions about unobserved outcomes can lead to different conclusions. Without a stated analysis population and missing-data approach, the available registry information does not support judging the direction or size of any such effect.

12. 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 registry’s adverse-event group lists 1 participant at risk for serious adverse events and 0 affected by serious adverse events. It lists 1 participant at risk for other adverse events and 1 affected by other adverse events. Deaths are listed as 0. No top serious adverse-event terms are listed. The record does not name the other adverse event or provide further detail about its nature, timing, severity, or relationship to brigatinib.

These figures describe the entries in the registry record; they do not establish whether every relevant event was collected or reported. The number at risk is small, and the registry does not report additional safety-analysis details. General: An event count is a descriptive observation, not proof that an intervention caused an event. Likewise, zero recorded serious events in a small group does not establish that serious events cannot occur.

The safety entries should be read separately from the missing efficacy result. They do not tell readers whether disease control occurred, and they do not explain why the trial was terminated. The record does not report a comparative safety analysis because there was no separate comparator group.

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

The record establishes that the B3i Trial was registered as a phase II, single-group study of brigatinib alone for ALK-positive non-small cell lung cancer with brain metastases. Its primary question concerned the number of participants meeting RANO-BM disease control criteria at the 13-week MRI, with a window of ±7 days. The registry lists enrollment of 1 and a terminated status. It does not report the primary outcome result.

These registry entries do not establish how many participants had complete response, partial response, stable disease, or progression. They do not establish whether an MRI assessment was completed, or whether the participant received the intervention. The reason for termination and the analysis population are not reported in the registry record. The secondary outcome titles describe intended areas of evaluation, but their results are not reported.

The single-group design also matters to interpretation. Even if an outcome count were available, it would describe observations in the study group and would not constitute a randomized comparison with another treatment or a control group. Without a reported outcome and appropriate uncertainty information, the registry record cannot support an estimate of the frequency of disease control or a comparative effect.

General: A statistical result is most informative when the outcome definition, denominator, analysis population, uncertainty, and design are considered together. A planned endpoint is not itself evidence of an observed outcome. Similarly, a planning calculation is not evidence that a study achieved a particular level of power or that an effect was observed. Any sample-size illustration associated with the record is a hypothetical calculation based on its stated assumptions, not observed power and not the trial’s reported sample-size rationale.

The appropriate reading is therefore limited but clear: the registry describes the study question and design, and records very small enrollment, but does not provide the primary result needed to answer the question. The absence of a posted result should not be interpreted as evidence either for or against brigatinib’s effect.

14. Why This Trial Matters Statistically

This trial is statistically notable because its registry record pairs a clinically specific question with very limited reported outcome information. The study was intended to examine disease control in brain metastases using a defined response framework and a scheduled MRI assessment. The primary endpoint is therefore identifiable, but its observed result is not reported in the registry record.

The single-group design makes the distinction between description and comparison especially important. A single-group study can document what was observed among its participants, but it does not create a randomized control contrast. The registry lists no comparator, and enrollment is reported as 1. Those features limit the amount and type of inference that can be drawn from the record, quite apart from the missing endpoint result.

The study also illustrates why outcome definitions and reporting completeness matter. Disease control combines complete response, partial response, and stable disease. For readers to interpret a result, the count must be accompanied by information about who was assessed and how incomplete assessments were treated. The registry record provides the definition and timing, but does not report those analysis details or the result.

General: Statistical interpretation is not only a matter of calculating a test statistic. Study design, denominator, missingness, precision, and the way outcomes are grouped all shape what a result can mean. A carefully defined endpoint cannot compensate for the absence of an observed estimate, and a planning illustration cannot substitute for trial results. The record’s limitations make transparent reporting particularly important for understanding what this study can contribute.

15. 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 principal limitation of interpretation is that the registry record does not report the primary disease-control count or the number assessed at the scheduled MRI. It also does not report confidence intervals, p-values, or other estimates of uncertainty. As a result, the main clinical question cannot be answered from the recorded outcome information.

Enrollment was 1, and the study had no comparator group. The registry does not state whether the enrolled participant completed treatment or follow-up, or whether that person contributed to an endpoint analysis. The reason for termination is not reported. These omissions prevent readers from distinguishing incomplete outcome reporting from an outcome assessment that was not performed.

The record does not report the full eligibility criteria, dose or schedule, detailed imaging procedures, analysis population, missing-data approach, or statistical analysis plan. It does not report whether response assessments were independently reviewed, or how progression and other secondary outcomes were operationalized beyond their listed titles. The reported secondary outcome names therefore do not provide enough detail to interpret their measurement or results.

Multiplicity procedures, interim analyses, and the sample-size justification are not reported in the registry record. Planning illustrations, where included, are hypothetical and use stated assumptions; they do not establish the trial’s planned sample size, actual statistical power, or observed treatment effect. The absence of a reported result should not be treated as a null finding.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Brigatinib Before Brain Irradiation Trial (B3i Trial) — NCT04634110.
• Registry record last updated 2022-10-24; status last verified 2022-09.
• Results first posted 2022-10-24.
• 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.

19. Record Summary

The B3i Trial, registered as NCT04634110, was a phase II single-group study of brigatinib alone for ALK-positive non-small cell lung cancer with brain metastases. The sponsor was the University of Colorado, Denver. The registry lists no masking, enrollment of 1, a start date of 2020-11-17, a primary completion date of 2022-04-14, and terminated status.

The primary outcome was the number of participants meeting brain-metastasis disease control criteria at a 13-week MRI ±7 days. Disease control was defined as complete response, partial response, or stable disease under RANO-BM criteria. The registry record does not report the primary result, the reason for termination, or the analysis population. It lists secondary outcomes related to progression, survival, mortality, objective response, and time until whole-brain radiotherapy, but their results are not reported in the registry record.