A Study to Evaluate the Efficacy and Safety of Bintrafusp Alfa (M7824) Monotherapy in Metastatic or Locally Advanced Urothelial Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Efficacy and Safety of Bintrafusp Alfa (M7824) Monotherapy in Metastatic or Locally Advanced Urothelial Cancer (NCT04349280), a na phase 1 study. The primary outcome is Confirmed Overall Response Rate (ORR) Assessed by Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

2. Clinical Question

3. Trial Design

This was a Phase Ib, single-group study of bintrafusp alfa monotherapy. The study title and official title describe people with metastatic or locally advanced urothelial cancer, including locally advanced/unresectable disease, after progression or recurrence following platinum treatment. The registry lists 25 participants as the enrollment. It lists one intervention, bintrafusp alfa, and an arm description in which participants receive bintrafusp alfa.

The record lists the allocation as not applicable, the model as single group, and masking as none. These design features mean the record does not describe random assignment or blinded treatment allocation. It is not a randomized comparison, and there is no like-for-like control arm. The findings therefore need to be read as outcomes recorded within the treated group, not as estimates of a relative treatment effect against another group.

The study start date is 2020-10-15, and the primary completion date is 2022-08-15. The registry status is terminated. A reason for termination is not reported in the registry record, so the status alone does not explain why the study ended or whether the planned enrollment, follow-up, or analyses were completed.

The primary outcome was confirmed overall response rate assessed by investigator using RECIST version 1.1, with a timeframe of up to approximately 22 months. The secondary outcomes concerned treatment-emergent adverse events, treatment-emergent serious adverse events, and the worst grade of treatment-emergent adverse events. The registry record lists three outcome measures but does not report analysis results for the primary response endpoint. It also does not report a statistical analysis plan, interim analysis details, or a reason for stopping the study.

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.

Main Study (Up to Approx. 95 Weeks)

Reasons for not completing this period:

PACT Phase (Up to Approx. 56 Weeks)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety population included all participants who were administered at least 1 infusion of bintrafusp alfa.

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 Confirmed Overall Response Rate (ORR) Assessed by Investigator Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1, measured over Up to approximately 22 months.

The primary endpoint is confirmed overall response rate (ORR), expressed as the percentage of participants with a confirmed complete response or confirmed partial response under investigator assessment using RECIST version 1.1. A partial response requires at least a 30% decrease in the sum of the diameters of target lesions relative to the baseline sum. A complete response requires disappearance of all target lesions. The description also specifies that pathological lymph nodes, whether target or non-target, must have a short axis below 10 millimeters.

ORR is a binary participant-level endpoint: each participant either meets the stated response definition or does not. In general, this type of measure gives a direct description of the fraction of an analysis population meeting a prespecified response criterion. It does not, by itself, describe how long a response lasts, whether symptoms changed, or how outcomes compare with what would have happened under another treatment.

The registry record names a 95% confidence interval as the dispersion measure and gives a timeframe of up to approximately 22 months. In general, a confidence interval expresses statistical uncertainty around an estimated response proportion; it does not guarantee that the true value lies within the interval. The registry record does not report the observed number of confirmed responses, the estimated percentage, or its confidence interval, so the magnitude and precision of the primary endpoint result cannot be assessed from this entry.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary endpoint count?

The endpoint is a binary outcome for each participant: a confirmed complete or partial response is counted as a response, and other outcomes are not counted as responses under the stated definition. The study reports the endpoint as a percentage of participants. For that percentage to be interpretable, the analysis population and the response-assessment rules must be clear. The record defines the safety population as all participants given at least one infusion, but does not report the observed response count or percentage. It also does not state how participants without an assessable scan or without confirmation of an initial response were handled.

RECIST version 1.1 supplies the response criteria named in the registry. The description specifies the lesion changes required for partial and complete response. In general, standardized criteria reduce ambiguity in classifying outcomes, although they do not eliminate differences in assessment or missing measurements. The record identifies investigator assessment; independent central review is not reported in the registry record.

What does a confidence interval communicate?

The stated dispersion measure is a 95% confidence interval. In general, a confidence interval reflects uncertainty in an estimated quantity, here an ORR percentage. A narrower interval indicates greater statistical precision under the method used; a wider interval indicates less precision. An interval is not a measure of clinical importance, and it does not make an estimate causal. The registry record does not give the interval or the method used to construct it, so neither its width nor the specific interval procedure can be assessed.

Why does the study design matter?

In a single-group study, the outcomes are observed in participants who received the study intervention. Without a randomized comparator, an observed response proportion cannot be interpreted as a treatment-versus-control difference. General explanations for outcomes could include the intervention, features of the enrolled participants, the natural course of disease, other care, or assessment processes. The registry record does not provide information that would separate those possibilities. The lack of masking is also recorded; the record does not describe blinded endpoint review.

Allocation is listed as not applicable, consistent with the single-group model. This is not a head-to-head trial. The registry explicitly flags that the arms are not a like-for-like control comparison. The additional PACT phase group listed in the safety information is not identified as a randomized control group, and it should not be treated as one.

How should event percentages be read?

The primary endpoint is a percentage of participants with an event, where the event is response. The safety information also uses participant counts for adverse events. In general, participant-level event summaries count whether a participant experienced an event, rather than counting every occurrence of that event. The registry entry provides participant denominators for the listed safety groups, but does not give event timing, duration, recurrence, or a complete description of how each category was assigned.

For serious adverse events, the main study group lists 17 affected participants among 25 at risk. For other adverse events, it lists 21 among 25. The PACT phase group lists 1 among 1 for serious events and 0 among 1 for other events. These counts should be read within their respective registry groups and not combined or used to form a comparison. The meaning of the term-level percentages is not fully specified by the record; in particular, the denominator for the listed serious-event terms is not reported.

What do the planning assumptions mean?

General sample-size calculations ask how much information a future design might need under specified assumptions. The registry material describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation, and a normal approximation; the target effect is described as a stated fraction of the observed effect. Such illustrations are planning scenarios, not observed power and not evidence that the trial was designed or conducted with those assumptions. The record does not report the trial's own sample-size justification, and no planning output values are included in the record summarized for this analysis.

In general, power depends on assumptions about the effect, variability, analysis, and design. A planning estimate is sensitive to those inputs and cannot repair the absence of a reported endpoint result. The registry record does not report a formal statistical analysis plan, the approach to multiplicity, interim analyses, or the methods for missing data. Those methods should not be inferred from the endpoint label or from the existence of planning assumptions.

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("Main Study - Bintrafusp Alfa")
n      <- c(25)
events <- c(5)
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  Main Study - Bintrafusp Alfa  25  5  20.0  6.8  40.7  8.9  39.1  9.0  39.4

11. Multiplicity, Missing Data and Analysis Populations

The registry record identifies one primary outcome and three outcome measures in total. It does not report a multiplicity strategy for testing or interpreting multiple outcomes. In general, when several outcomes or comparisons are assessed, multiplicity procedures can address the increased chance of false-positive findings across tests. No such adjustment, testing hierarchy, or distinction between confirmatory and exploratory analyses is reported in the registry record. Because the primary result is also not reported, the record does not permit assessment of how the primary endpoint related to any other outcome analyses.

Missing-data methods are not reported in the registry record. The endpoint description names the safety population as participants who received at least one infusion, but does not explain whether participants without an evaluable response assessment were excluded, treated as nonresponders, or handled by another method. The number of participants with missing or unevaluable response data is not reported. Therefore, the response denominator and the effect of missing outcome information cannot be determined.

The record lists no analyses in the posted outcome information. It does not provide a statistical analysis plan, details of prespecified analysis populations beyond the safety-population definition, or information about interim analyses. The reason the study was terminated is also not reported in the registry record. These omissions limit the ability to distinguish planned analyses from analyses completed after study conduct or to judge whether outcome reporting is complete.

In general, analysis-population definitions and missing-data assumptions can influence an estimated response percentage. The posted entry does not supply enough information to evaluate those choices for this trial. No particular method should be presumed.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: acute kidney injury (100.0%), urinary tract infection (16.0%), pyrexia (8.0%), anaemia (4.0%), colitis (4.0%).

The registry lists safety counts for two named groups. For the Main Study - Bintrafusp Alfa group, serious adverse events were recorded for 17 of 25 participants at risk, other adverse events for 21 of 25, and 12 deaths. For the PACT Phase - Bintrafusp Alfa group, the corresponding figures are 1 of 1 for serious adverse events, 0 of 1 for other adverse events, and 0 deaths. These are descriptive counts within the groups, not comparative treatment effects.

The record also lists serious adverse-event terms: acute kidney injury at 100.0%, urinary tract infection at 16.0%, pyrexia at 8.0%, anaemia at 4.0%, colitis at 4.0%, and general physical health deterioration at 4.0%. The denominator and counting rule for these term-specific percentages are not reported in the registry record. The 100.0% entry should therefore not be read as applying to all participants in the main study group. The record does not report whether events were judged related to bintrafusp alfa, their timing or duration, or the causes of deaths. In general, safety counts describe reported events; without attribution and comparison information, they do not establish causation.

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

The registry record establishes that this was a single-group Phase Ib evaluation of bintrafusp alfa monotherapy in participants with metastatic or locally advanced urothelial cancer after progression or recurrence following platinum treatment. It also specifies the primary response endpoint: confirmed complete or partial response under investigator assessment using RECIST version 1.1. Those design and definition details clarify what the study set out to measure.

The record does not report the observed ORR, response count, or 95% confidence interval. It therefore does not show the frequency of confirmed responses in the analysis population or how precisely that frequency was estimated. The stated endpoint definition cannot substitute for the missing result. Nor can the safety counts be used to infer the primary response outcome.

Even if a response estimate were available, the single-group design would make it descriptive rather than a randomized estimate of benefit relative to a comparator. The registry does not identify a like-for-like control group. It therefore cannot establish that an outcome was caused by bintrafusp alfa or show how outcomes would compare under another treatment.

The safety figures indicate that serious and other adverse events were recorded in the named groups, and that deaths were listed for the main study group. They do not establish that treatment caused an event or death. The registry does not report event attribution or causes of death, and the denominator for term-specific serious-event percentages is not stated.

The status is terminated, but the reason is not reported in the registry record. Details about missing assessments, analysis methods, and the study's statistical plan are also not reported. These limits prevent a full evaluation of the completeness and analysis of the trial results. The defensible interpretation is that the registry describes the intended endpoint and some safety counts, but does not provide the primary efficacy result needed to quantify the observed response pattern.

14. Why This Trial Matters Statistically

Statistically, the record illustrates the difference between a clearly defined endpoint and a reported endpoint result. The response measure is specified using investigator-assessed RECIST version 1.1, including the criteria for complete and partial response. That tells a reader what the study intended to classify. However, without the response count, percentage, and confidence interval, the endpoint definition cannot answer how often responses were observed or how uncertain the estimate was.

The single-group design is also central to interpretation. It can describe outcomes among participants who received bintrafusp alfa, but it does not supply a concurrent randomized comparison. That distinction matters because a percentage observed in a treated group is not the same as an estimate of the difference caused by treatment. The registry record itself identifies the absence of a like-for-like control comparison.

The entry also demonstrates why denominators and analysis populations matter. The response endpoint names the safety population, while the registry gives enrollment and separate safety-group counts. It does not report the response denominator or missing-assessment handling. In general, an outcome proportion cannot be fully interpreted without knowing who was included and how unavailable outcomes were treated.

Finally, safety counts and term-specific percentages require context. The record reports counts for serious and other adverse events, but does not report event attribution or the denominator for the serious-event term percentages. These details are necessary to avoid treating descriptive safety summaries as causal findings. The stated terminated status, without a reason or analysis account, adds another uncertainty about the completeness of the reported 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 primary limitation for interpreting efficacy is that the registry record does not report the primary outcome result. The confirmed ORR count, estimated percentage, and 95% confidence interval are absent. Consequently, the response frequency and its precision cannot be assessed from this record.

The study had a single-group design, with no randomized comparator and no like-for-like control comparison. The results, if fully reported, would describe outcomes in the treated group rather than provide a randomized estimate of comparative effect. Masking is listed as none, and the record does not report independent central response review.

The record does not report the analysis plan, missing-data method, number of evaluable response assessments, or response denominator. It is therefore not possible to determine from the registry entry how participants without assessable or confirmed responses were handled. The reason for termination and the effect, if any, on follow-up and outcome collection are not reported.

Safety interpretation is also limited. Although counts are listed for serious events, other events, and deaths, the record does not report causes of death or whether events were judged related to treatment. The denominator and counting rule for serious-event term percentages are not reported. The registry does not provide enough detail to evaluate event timing, duration, or recurrence.

Finally, the stated planning assumptions do not establish the study's actual design justification or statistical plan. The record does not report a sample-size justification, multiplicity approach, or interim analysis details. These omissions constrain interpretation without supporting assumptions about what the investigators planned or why the study ended.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Evaluate the Efficacy and Safety of Bintrafusp Alfa (M7824) Monotherapy in Metastatic or Locally Advanced Urothelial Cancer — NCT04349280.
• Registry record last updated 2024-04-18; status last verified 2024-04.
• Results first posted 2024-04-18.
• 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

NCT04349280 is a Phase Ib, single-group study of bintrafusp alfa monotherapy in metastatic or locally advanced/unresectable urothelial cancer following progression or recurrence after platinum treatment. The registry lists enrollment of 25, no masking, and a terminated status. The start date is 2020-10-15, and the primary completion date is 2022-08-15.

The primary endpoint is confirmed investigator-assessed ORR under RECIST version 1.1, with a timeframe of up to approximately 22 months. The registry record does not report the response count, percentage, or confidence interval. It lists serious and other adverse-event counts for the Main Study and PACT Phase groups, as well as deaths, but does not provide event attribution or causes of death. The reason for termination, missing-data methods, and statistical analysis plan are not reported in the registry record.