A Study of Bevacizumab in Combination With First- or Second-Line Therapy in Subjects With Treated Brain Metastases Due to Non-Squamous NSCLC (PASSPORT): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Bevacizumab in Combination With First- or Second-Line Therapy in Subjects With Treated Brain Metastases Due to Non-Squamous NSCLC (PASSPORT) (NCT00312728), a na phase 2 study. The primary outcome is Percentage of Participants With Symptomatic National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0 (NCI CTCAE) Grade ≥2 Central Nervous System (CNS) Hemorrhage.

2. Clinical Question

3. Trial Design

PASSPORT is registered as a Phase II, open-label, multicenter, single-group trial of bevacizumab combined with first- or second-line therapy. The registry reports enrollment of 115 participants and a completed study status. Because there was no randomized allocation and no concurrent control arm, results from the study cannot directly estimate a treatment contrast against an alternative regimen or usual care.

The study population was described as people with metastatic non-squamous NSCLC and previously treated CNS metastases. The primary endpoint applied to a safety-evaluable population consisting of patients who received at least one dose of bevacizumab. The registry record does not report the number in that population for the primary endpoint, nor does it describe additional analysis-population rules.

The primary outcome was a safety measure: the percentage of participants with symptomatic CNS hemorrhage graded 2 or higher. Its assessment period began with the first bevacizumab administration and extended until 60 days after treatment discontinuation; the timeframe is reported as up to 2 years. The endpoint description defines symptoms as clinical symptoms judged by the investigator to be directly referable to the hemorrhage. A 90% confidence interval is named as the dispersion measure.

First-line and second-line therapy appear in the trial description as treatment settings, not as randomized comparison arms. The registry record does not report how treatment setting was assigned, whether the settings were analyzed separately for the primary endpoint, or whether there were protocol-defined subgroup comparisons. Detailed treatment schedules and the specific chemotherapy agents used are also 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.

Before assignment: This was an open-label, multicenter, single-arm, Phase II trial of bevacizumab combined with first- or second-line therapy in subjects with metastatic non-squamous non-small cell lung cancer (NSCLC) with previously treated CNS metastases.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The safety-evaluable population consisted of all patients who received at least one dose of bevacizumab.

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 Percentage of Participants With Symptomatic National Cancer Institute's Common Terminology Criteria for Adverse Events v3.0 (NCI CTCAE) Grade ≥2 Central Nervous System (CNS) Hemorrhage, measured over From the first administration of bevacizumab until 60 days after discontinuation of bevacizumab treatment was reported (up to 2 years).

The primary endpoint measures the percentage of participants who experienced symptomatic CNS hemorrhage graded 2 or higher under NCI CTCAE v3.0. The description requires clinical symptoms that the investigator determined were directly referable to a hemorrhage of the specified grade. The grade definitions distinguish asymptomatic radiographic findings from events requiring medical intervention and from more severe outcomes involving procedures, life-threatening consequences, or death.

This kind of endpoint is used to describe a safety outcome during exposure to a treatment and a defined follow-up period. Reporting a percentage communicates how common the recorded event was in the safety-evaluable population, while a confidence interval conveys uncertainty around that estimate. The registry names a 90% confidence interval as the dispersion measure, but the result itself is not reported in the registry record. Consequently, the event percentage and its precision cannot be assessed from the registry entry.

The endpoint is not a measure of tumor response, survival, or comparative treatment benefit. Nor does the endpoint description alone establish that every hemorrhage was caused by bevacizumab: it specifies the timing, grading threshold, symptoms, and investigator attribution used to identify qualifying events. The record does not report further adjudication procedures or the observed count of qualifying hemorrhages.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint describe?

A percentage endpoint expresses the share of an analysis population that experienced a defined event during the stated assessment period. Its interpretation depends on a clear event definition, a relevant denominator, and consistent follow-up. In PASSPORT, the qualifying event was symptomatic CNS hemorrhage graded 2 or higher, and the primary endpoint population was defined by receipt of at least one dose of bevacizumab. The registry record does not report the observed event percentage or the primary endpoint denominator, so the percentage cannot be reconstructed or checked from the entry.

What does the confidence interval add?

In general, a confidence interval describes the uncertainty associated with an estimated quantity under a statistical procedure. A narrower interval indicates greater precision than a wider interval, while the interval’s location indicates the range of values compatible with the data and method. The registry identifies a 90% confidence interval for the primary endpoint, but does not report its limits. Without the event estimate and interval, readers cannot judge the magnitude or precision of the primary safety result. A confidence interval is not a guarantee that the true value lies within a particular interval, nor does it resolve limitations in design or measurement.

Why does the single-group design matter?

General statistical interpretation of a single-group study differs from interpretation of a randomized comparison. A single-group event percentage can describe what happened among observed participants, but there is no concurrent randomized group to represent what would have happened under an alternative treatment. Differences in disease characteristics, prior care, follow-up, and event ascertainment may affect comparisons with results from other studies. Cross-study contrasts are not substitutes for a randomized treatment contrast because populations and methods may differ.

Here, allocation is listed as not applicable and the model as single-group. First-line and second-line settings are part of the treatment context; the registry does not characterize them as randomized arms. Thus, a result for the cohort would be descriptive of that cohort, rather than an estimate of a causal difference between treatment strategies.

How should event counts and denominators be read?

For an event proportion, the denominator should correspond to the population at risk for that particular outcome, and the event definition should match the endpoint being interpreted. Different outcomes can use different analysis populations or observation rules. The record defines the primary safety-evaluable population as patients who received at least one dose, whereas the adverse-event summary lists 106 participants at risk. It does not state the primary endpoint denominator. The enrollment count should not be substituted for an outcome-specific denominator without a record explaining that choice.

In general, participants can experience more than one adverse event, and a person may contribute to more than one event-term category. Event-term percentages therefore should not be added to infer a total or treated as mutually exclusive. The registry’s serious-event terms are separate descriptive entries; the listed percentages do not identify the primary CNS hemorrhage result.

What can be said about the analysis plan?

The registry record names the primary endpoint, its dispersion measure, and its timeframe. It does not report the statistical test or estimation procedure, the confidence-interval method, covariate adjustment, subgroup methods, interim analyses, or a statistical analysis plan. Those details should not be inferred from a general convention or from the fact that a 90% confidence interval was specified.

The registry’s sample-size assumptions describe a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Such planning calculations are not observed power and do not show what the study was designed to detect unless the relevant inputs and intended design are documented. The registry entry does not report a primary endpoint estimate or the corresponding planning outputs, and the single-group study design does not match the stated equal-allocation two-arm illustration. The sample-size assumptions therefore do not establish the trial’s own design rationale or provide evidence about the observed endpoint.

In general, planning estimates depend on assumptions about the effect size, variability, event frequency, allocation, and analysis method. If those assumptions differ from the eventual study conditions, the resulting planning calculation may not represent the precision achieved. No sample-size justification or power analysis for the trial itself is reported in the registry record.

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("Bevacizumab")
n      <- c(106)
events <- c(0)
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  Bevacizumab  106  0  0.0  0.0  3.4  0.0  3.5  0.0  3.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety endpoint and secondary outcome topics that include overall survival in first-line and combined first- and second-line settings, survival of one year or more, and selected adverse events. Considering several outcomes can increase the chance that at least one result appears notable by chance when many statistical tests are performed. In general, multiplicity procedures can control that risk or clarify that analyses are exploratory. The registry record does not report a multiplicity adjustment or an approach to interpreting multiple outcomes.

The registry record contains no analysis entries. It does not report statistical tests, outcome estimates, confidence intervals for the secondary outcomes, or whether any outcome analyses were planned as confirmatory or exploratory. Interim analyses and stopping rules are also not reported in the registry record. Their absence from the entry should not be taken as evidence that such procedures were or were not used outside the information registered.

Missing-data procedures are not reported in the registry record. It does not explain how incomplete follow-up, withdrawal, or missing outcome assessments were handled, or whether the observation window differed among participants. For an event percentage, incomplete observation can affect both event ascertainment and the appropriate denominator; the registry’s endpoint definition alone does not show how those issues were addressed.

The primary safety-evaluable population is defined as all patients who received at least one dose of bevacizumab. The number analyzed for the primary endpoint is not reported. The adverse-event summary separately records 106 at risk, while enrollment was 115. The registry does not explain the relationship between these figures or specify whether all registered outcomes used the same analysis population. These omissions limit assessment of completeness, denominator choice, and the potential impact of missing information.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pulmonary embolism (5.7%), convulsion (3.8%), pulmonary hemorrhage (2.8%), pneumonia (2.8%), urinary tract infection (1.9%).

The adverse-event summary reports 45 participants affected by serious adverse events among 106 at risk, and 7 affected in the other adverse-event category among 106 at risk. These are reported counts, not percentages calculated from those counts. No total should be inferred by combining the categories: their overlap and category definitions are not detailed in the registry entry. Deaths are not reported in the registry record.

The serious-event terms listed include pulmonary embolism at 5.7%, convulsion at 3.8%, pulmonary hemorrhage at 2.8%, pneumonia at 2.8%, urinary tract infection at 1.9%, and gastrointestinal hemorrhage at 1.9%. These term-specific percentages should be read as descriptive safety information. They are not the primary endpoint result, which concerns symptomatic CNS hemorrhage graded 2 or higher, and they do not indicate whether an event was caused by study treatment.

In general, adverse-event summaries depend on event definitions, observation time, and the population considered at risk. A participant may experience more than one event or appear under more than one term. The registry record does not report further detail about event duration, severity distributions beyond the listed serious terms, or attribution. The listed percentages alone do not permit a controlled comparison or establish relative risk.

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

The registry record establishes that PASSPORT was a completed, open-label, multicenter, single-group Phase II study of bevacizumab combined with first- or second-line therapy in participants with metastatic non-squamous NSCLC and previously treated CNS metastases. It defines a primary safety question about symptomatic CNS hemorrhage graded 2 or higher and identifies the period over which that outcome was to be assessed. Those design and definition details help describe what the trial set out to evaluate.

However, the primary endpoint’s observed percentage, event count, and 90% confidence interval are not reported in the registry record. The entry therefore does not establish the frequency or precision of the primary outcome. The serious-adverse-event summary provides descriptive counts and term-specific percentages, but those figures address different safety summaries and cannot fill the gap in the primary endpoint result.

Because there was no concurrent control group, the study design cannot isolate a treatment effect by comparing outcomes under randomized alternatives. A cohort event rate, if reported, would describe observations under the studied treatment context rather than demonstrate what would have occurred without that treatment. The record also does not provide the analysis details needed to assess adjustments, missing data, or other statistical choices.

These limits do not make the registered questions meaningless. Clear endpoint definitions, stated follow-up, and safety summaries are useful for understanding what was monitored and how the registry characterizes the study. But the available entry is insufficient to quantify the primary safety outcome or make a comparative efficacy claim. Overall survival is among the registered outcome topics, yet its numerical results are not reported in the registry record. Conclusions should remain within the information the record documents.

14. Why This Trial Matters Statistically

This trial is statistically notable because its main question is framed as a safety proportion in a defined population and observation window, while the design has no concurrent control group. That combination makes the endpoint definition, denominator, and follow-up central to interpretation. Readers need the event estimate and its confidence interval to assess both the observed frequency and the precision of the result; neither is reported in the registry record for the primary endpoint.

The study also illustrates the distinction between a treatment setting and a treatment comparison. First-line and second-line therapy are named in the regimen description, but the registered design is single-group. Those labels do not create randomized arms or support a direct estimate of differences between treatment settings. Similarly, the presence of overall survival outcomes in the registry does not establish that the study supplies a comparative survival analysis.

The record offers some adverse-event counts and term-specific percentages, but these are descriptive and do not answer the primary CNS hemorrhage question. They also require attention to the at-risk population and event categories. Enrollment and the adverse-event denominator are reported separately, while the primary safety-evaluable population size is not. This is a practical reminder that every outcome needs its own clearly reported analysis population.

Finally, the entry names a confidence-interval level and includes planning assumptions, but does not report an analysis plan or primary endpoint result. Statistical labels alone are not evidence of precision or of a treatment effect. The distinction between registered methods, observed data, and missing results is essential when reading a clinical-trial record.

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 most direct limitation of the registry information is that the primary endpoint result is absent. Although the endpoint definition, timeframe, safety-evaluable population definition, and 90% confidence interval are specified, no event count, percentage, or interval limits are reported. The registry therefore cannot support a quantitative interpretation of the primary CNS hemorrhage outcome.

The single-group design is an additional limitation for comparative inference. There is no concurrent control group, and the first- and second-line treatment settings are not described as randomized arms. Observed outcomes cannot establish how outcomes would differ under another regimen. The open-label design is stated, but the registry record does not explain event-adjudication procedures or whether outcome assessment was blinded.

Population and analysis details are incomplete. Enrollment is 115, while the adverse-event summary gives 106 at risk; the primary endpoint denominator is not reported, and the registry does not explain the relationship among these figures. The entry defines the safety-evaluable population by receipt of at least one dose but does not give its size for the primary analysis. Eligibility details beyond the broad disease description, treatment schedules, and specific chemotherapy agents are also not reported in the registry record.

Statistical details that would inform assessment of the results are not reported in the registry record, including the estimation method, handling of missing data, multiplicity procedures, and subgroup or interim-analysis methods. The registry contains no analysis entries. The listed serious adverse events are descriptive, and deaths are not reported in the registry record. These limitations restrict assessment of endpoint precision, completeness of follow-up, and comparative interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Bevacizumab in Combination With First- or Second-Line Therapy in Subjects With Treated Brain Metastases Due to Non-Squamous NSCLC (PASSPORT) — NCT00312728.
• Registry record last updated 2023-01-06; status last verified 2022-12.
• Results first posted 2011-06-22.
• 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

PASSPORT is a completed, open-label, multicenter, single-group Phase II trial of bevacizumab combined with first- or second-line therapy for metastatic non-squamous NSCLC with previously treated CNS metastases. Enrollment was 115.

The primary endpoint was the percentage of participants with symptomatic CNS hemorrhage graded 2 or higher, assessed from the first bevacizumab administration until 60 days after treatment discontinuation, up to 2 years. The registry specifies a 90% confidence interval but does not report the endpoint estimate or interval.

The adverse-event summary reports 45 participants with serious adverse events and 7 with other adverse events, each among 106 at risk. The registry record does not provide analysis entries, missing-data methods, or a concurrent control comparison.