Pembrolizumab and Combination Chemotherapy Before Surgery for the Treatment of Muscle-Invasive Bladder Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pembrolizumab and Combination Chemotherapy Before Surgery for the Treatment of Muscle-Invasive Bladder Cancer (NCT04383743), a na phase 2 study. The primary outcome is Pathologic Complete Response Rate.

2. Clinical Question

3. Trial Design

This was a phase 2 pilot trial sponsored by the University of Washington. The registry describes a single-group treatment model, with allocation listed as not applicable and no masking listed. Enrollment was 17, and the record lists the trial status as completed. The recorded start date was 2020-11-24 and the primary completion date was 2024-06-17.

Participants received pembrolizumab with aMVAC chemotherapy as neoadjuvant therapy, meaning the regimen was given before surgery. The treatment description schedules pembrolizumab by intravenous infusion on day 1 of weeks 0, 3, and 6. Methotrexate, vinblastine, doxorubicin, and cisplatin were scheduled on day 1 of weeks 0, 2, 4, and 6, in the absence of disease progression or unacceptable toxicity. Pegfilgrastim was given subcutaneously on day 1 or 2, as described in the record. Radical cystectomy was the surgical procedure associated with assessment of the primary endpoint.

The primary endpoint was assessed at cystectomy, described as approximately within 10 weeks of the last neoadjuvant infusion. Secondary outcomes included adverse-event frequencies, estimated 2-year event-free survival, and the number of participants able to undergo radical cystectomy within 10 weeks from completion of study therapy. The registry lists six outcome measures, but does not report a separate control arm or comparative treatment effect. The record does not report further detail about the pilot design rationale, enrollment target, or statistical analysis plan.

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:

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 Pathologic Complete Response Rate, measured over At time of radical cystectomy at approximately within 10 weeks of last neoadjuvant infusion.

The primary endpoint, pathologic complete response rate, measures the percentage of patients whose cystectomy specimen has no histologic evidence of tumor, with the response defined as ypT0N0. This is a pathology-based endpoint: it relies on examination of tissue removed at surgery rather than on symptoms or imaging alone. The planned assessment was at radical cystectomy, approximately within 10 weeks of the last neoadjuvant infusion.

In general, a pathologic response endpoint can describe what is found in the surgical specimen after treatment given before surgery. It is distinct from event-free survival, which concerns the occurrence of specified events over time, and from adverse-event outcomes, which characterize harms. Those outcomes address different questions and should not be treated as interchangeable measures of benefit or risk.

The registry record reports the endpoint definition but does not report how many participants met the ypT0N0 definition or the resulting response rate. It also does not report an interval estimate for the response rate. Consequently, the posted record does not establish the magnitude or precision of the primary endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes this as a single-group phase 2 pilot trial. The primary endpoint is binary at the participant level: a participant either meets the stated pathologic complete response definition, ypT0N0, or does not. The endpoint is expressed as a percentage of patients at cystectomy. The record does not report the observed count meeting this definition, the response percentage, or an interval estimate.

What does a confidence interval communicate?

As a general statistical concept, a confidence interval describes uncertainty around an estimate under a specified statistical method. For a response rate, it would help readers judge how compatible the observed data are with a range of underlying response rates. A narrow interval generally indicates greater precision than a wide interval. It does not remove limitations arising from a single-group design, selection of participants, or incomplete outcome reporting. No confidence interval for the primary endpoint is reported in the registry record.

What can a single-group design estimate?

In general, a single-group trial can describe outcomes observed among participants who receive the study regimen. Without a concurrent control group, it cannot isolate the treatment effect from other influences or estimate a randomized between-group contrast. Differences between this group and patients treated elsewhere could reflect differences in eligibility, disease mix, follow-up, or outcome assessment, not only treatment. The registry lists no random allocation and no like-for-like control comparison.

The primary endpoint is assessed at surgery, so interpretation also depends on the relationship between treatment completion and reaching cystectomy. The registry lists the ability to undergo radical cystectomy within 10 weeks from completion of study therapy as a secondary outcome, but does not report its result. The record does not specify how missing pathology assessments or participants who did not undergo surgery were handled in the primary analysis. That information is important because the group included in an endpoint analysis can affect the interpretation of a percentage.

How should the adverse-event counts be read?

The posted safety summary reports participants with events, rather than a rate per unit of follow-up time. It lists the treatment group as having 17 participants at risk, with 6 affected by serious adverse events and 17 affected by other adverse events. These categories should be read as the registry reports them; the record does not describe exposure-adjusted rates or provide event timing. A count of participants with an event is not necessarily the same as the total number of event episodes, because an individual may experience more than one event. The record does not give episode counts in the registry record described.

General statistical interpretation of event counts depends on the observation period, the event definitions, and completeness of follow-up. If participants are observed for different lengths of time, counts alone do not capture differences in exposure time. Methods that account for time at risk can be useful in suitable settings, but the registry record does not report such an analysis for these adverse events. The record also does not report whether every event was considered related to study therapy, beyond the outcome descriptions that specify events related to study therapy.

What do the listed statistical methods establish?

The record lists six outcome measures and zero analyses. It does not report inferential tests, adjusted estimates, confidence intervals, or a statistical analysis plan. It is therefore not possible to determine from the registry record how the sponsor planned to handle repeated outcome testing, missing data, or analysis populations. The definitions of outcomes do not by themselves reveal which statistical procedures were used or whether any result was adjusted for other variables.

General methods can help explain why these details matter. An analysis population specifies which enrolled participants contribute to an estimate; a missing-data approach states what happens when an outcome is unavailable. Multiplicity concerns arise when several outcomes or comparisons are tested, because repeated testing can affect the chance of a false-positive finding. These concepts do not imply that any particular procedure was used in this trial. The relevant plan and implementation are not reported in the registry record.

How should planning calculations be understood?

Any sample-size illustrations based on an observed effect are planning scenarios, not observed power and not evidence that an outcome occurred. The stated assumptions for such illustrations use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect defined as a stated fraction of the observed effect. The record describes time-to-event illustrations as using a total number of events and other illustrations as participants per arm. These assumptions are not a description of this trial's single-group design, and the registry does not report that the trial was randomized between two equal groups. The trial's own sample-size justification is not reported in the registry record.

In general, a planning calculation depends on its assumed effect size, variability or event rate, error rate, allocation, and analysis method. Changing assumptions can change the resulting planning requirement. Such calculations do not indicate the probability that this completed trial found a significant result, and they cannot substitute for the missing primary outcome estimate. No recalculated treatment effect or comparative estimate 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("Treatment (Pembrolizumab, aMVAC)")
n      <- c(17)
events <- c(9)
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  Treatment (Pembrolizumab, aMVAC)  17  9  52.9  27.8  77.0  31.0  73.8  30.8  74.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists six outcome measures, including the primary pathologic complete response endpoint, adverse-event outcomes, estimated 2-year event-free survival, and ability to undergo radical cystectomy within 10 weeks from completion of study therapy. It reports zero analyses. The statistical plan for prioritizing or testing these outcomes is not reported in the registry record.

As a general concept, multiplicity arises when researchers evaluate multiple outcomes or perform multiple statistical tests. Without a prespecified testing strategy, readers cannot tell whether results were intended to be confirmatory, exploratory, or adjusted to account for multiple testing. This is not a claim that a particular error occurred; the record does not describe the relevant testing procedure.

The registry record also does not report how missing outcome data were handled, which participants were included in each analysis population, or how participants without a cystectomy specimen were treated in the primary endpoint analysis. These details matter because a response percentage depends on both the numerator and the population used as its denominator. The primary response count and rate are not reported, and the record does not state whether any endpoint assessments were unavailable.

The distinction between enrollment and an endpoint-specific analysis population is important in general. Enrollment identifies those entering the trial; an analysis may include a subset depending on eligibility, treatment receipt, surgery, and outcome availability. The registry record does not provide enough information to identify such a subset for the primary or secondary outcomes. No assumptions about exclusions or missingness can be made from the posted information.

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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: kidney infection (17.6%), acute kidney injury (11.8%), diarrhea (11.8%), urinary tract infection (11.8%), febrile neutropenia (11.8%).

The registry's adverse-event summary lists 17 participants at risk in the Treatment (Pembrolizumab, aMVAC) group. It reports 6 participants affected by serious adverse events, 17 affected by other adverse events, and 3 deaths. These are participant counts in the registry summary, not calculated rates. The record does not provide a time-at-risk denominator or enough event-level detail to interpret these counts as exposure-adjusted frequencies.

Selected serious adverse-event terms are listed with percentages: Kidney Infection, 17.6%; Acute Kidney Injury, 11.8%; Diarrhea, 11.8%; Urinary Tract Infection, 11.8%; Febrile Neutropenia, 11.8%; and Fatigue, 5.9%. The record does not provide the corresponding participant counts for each term in the registry record described, nor does it clarify whether participants could appear under more than one term. These term percentages should not be added together.

Seriousness is a classification of an adverse event and is distinct from whether an event was caused by treatment. The registry figures alone do not establish causation. The record does not report detailed timing, duration, resolution, or attribution for each event, and the deaths cannot be assigned to the regimen from the summary counts alone.

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

This trial is relevant as a pilot evaluation of pembrolizumab combined with aMVAC before surgery for non-urothelial histology muscle-invasive bladder cancer. The registry documents the regimen, its single-group design, the intended pathology endpoint, and selected safety information. Those features describe what was studied, but they do not provide the missing primary response estimate.

The primary endpoint asks whether no tumor was found histologically in the cystectomy specimen under the stated ypT0N0 definition. Because the registry record does not report the number meeting that definition or the percentage, it does not support a quantitative statement about the observed pathologic complete response. The record also does not report an uncertainty interval for that outcome. The listed secondary outcomes do not have reported results in the registry record.

The trial's single-group structure also limits comparative conclusions. It does not provide a randomized estimate of the regimen's effect relative to chemotherapy alone or another treatment. The brief description discusses the rationale for combining immunotherapy and chemotherapy, but a rationale is not an outcome result. The posted information cannot establish that the combination is better, equivalent, or worse than an alternative.

The adverse-event figures describe participants recorded with serious and other adverse events and list selected serious event terms. They should be interpreted as descriptive registry summaries. They do not, by themselves, establish that the regimen caused the events, and the available information does not show event timing or duration.

Thus, the registry record supports a description of the trial and its reported safety counts, but not a conclusion about the magnitude or precision of the primary endpoint or a comparative treatment effect. The completed status does not mean that every outcome result is present in the record.

14. Why This Trial Matters Statistically

The trial addresses a population identified in the official title as having non-urothelial histology muscle-invasive bladder cancer, and evaluates a neoadjuvant combination of pembrolizumab and aMVAC followed by surgery. In statistical terms, studying a specific population and defining a pathology endpoint are useful features for understanding what the investigators intended to measure. The registry's endpoint definition ties the primary question to a finding in the cystectomy specimen.

The pilot designation and single-group design shape what can be learned. A single-group study can describe the observed experience of treated participants, but cannot provide the same direct comparative evidence as a randomized control group. That matters when interpreting any apparent outcome in relation to chemotherapy alone or other approaches. The registry record does not report a comparative effect or a primary response result.

The trial also lists safety and feasibility-related outcomes, including adverse events and the ability to undergo radical cystectomy within 10 weeks from completion of study therapy. These address aspects of treatment experience beyond pathology response. However, the registry record does not report results for the listed secondary outcomes, so those questions remain unanswered by the posted information.

For clinical researchers and biostatisticians, this record illustrates why design, endpoint definition, analysis population, and reporting completeness all matter. A defined endpoint does not convey an estimate unless the observed result and its denominator are reported. Likewise, adverse-event counts require context about ascertainment and attribution. The record gives a framework for the study, while leaving key efficacy estimates and analysis details unreported.

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 is incomplete outcome reporting in the registry record. It defines the primary pathologic complete response endpoint but does not report its observed count, percentage, or precision. It also does not report results for the listed secondary outcomes, including estimated 2-year event-free survival and ability to undergo radical cystectomy within 10 weeks from completion of study therapy.

The trial is single-group and has no randomized comparator. This prevents a direct within-trial comparison with chemotherapy alone or another regimen and limits interpretation of outcomes as treatment effects. The registry also lists no masking. Details about endpoint assessment procedures beyond the pathology definition are not reported in the registry record.

Additional trial-specific information that is not reported includes the histologic subtypes represented among enrolled participants, detailed eligibility criteria, the sample-size justification, and a statistical analysis plan. The record does not state how missing pathology assessments were handled, which analysis population was used, or how participants who did not undergo cystectomy were treated in the primary analysis. It also does not report methods for handling multiple outcomes or testing.

The adverse-event summary gives participant counts and selected term percentages, but the registry entries in the record do not include detailed timing, duration, attribution, or exposure-adjusted rates. The three reported deaths cannot be interpreted as treatment-related on the basis of these summary figures. These limitations constrain both efficacy and safety interpretation without implying that unreported results were unfavorable or favorable.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Pembrolizumab and Combination Chemotherapy Before Surgery for the Treatment of Muscle-Invasive Bladder Cancer — NCT04383743.
• Registry record last updated 2025-09-18; status last verified 2025-09.
• Results first posted 2025-09-18.
• 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

NCT04383743 is a completed phase 2 pilot trial sponsored by the University of Washington. It enrolled 17 participants and evaluated pembrolizumab with aMVAC chemotherapy before radical cystectomy for non-urothelial histology muscle-invasive bladder cancer. The registry describes a single-group design, no masking, and a primary endpoint of pathologic complete response, defined as ypT0N0 at cystectomy approximately within 10 weeks of the last neoadjuvant infusion.

The record reports selected adverse-event counts and serious adverse-event term percentages. It does not report the primary response count or rate, results for the listed secondary outcomes, or a statistical analysis plan. No randomized comparator is described, so the record does not provide a direct treatment comparison.