Vemurafenib and Cobimetinib in Treating Patients With BRAF V600E Mutation Positive Craniopharyngioma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Vemurafenib and Cobimetinib in Treating Patients With BRAF V600E Mutation Positive Craniopharyngioma (NCT03224767), a na phase 2 study. The primary outcome is Response Rate.

2. Clinical Question

3. Trial Design

This is a phase II trial sponsored by the Alliance for Clinical Trials in Oncology. Its official title describes a study of BRAF/MEK inhibitors in papillary craniopharyngiomas. The registry lists the model as single group, allocation as not applicable, and masking as none. These features describe a nonrandomized, unmasked treatment study rather than a randomized comparison against a control group. Although Arm A and Arm B are named in the safety record, the registry does not describe them as randomized arms or provide a basis for comparing them as equivalent groups.

The registry lists enrollment as 24. The study began on 2018-01-05, and its primary completion date is listed as 2023-09-22. Its current status is active, not recruiting. These registry entries describe the study record; they do not establish how many participants were ultimately evaluable for the primary endpoint.

The treatment description specifies vemurafenib by mouth twice daily on days 1–28 and cobimetinib by mouth once daily on days 1–21. Treatment repeats every 28 days for up to 5 courses in the absence of disease progression or unacceptable toxicity. The description also lists radiation therapy, surgery, or continued treatment as possible subsequent options, but the registry record does not report the complete details of those options in the available treatment text.

The primary endpoint is response rate, with a timeframe of up to 5 years. Secondary outcomes listed are progression-free survival and overall survival. Laboratory biomarker analysis and quality-of-life assessment are also listed as interventions or study activities. The registry record does not report the full assessment schedule or the analysis results for these outcomes.

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 Response Rate, measured over Up to 5 years.

The primary endpoint is response rate, expressed as a percentage of participants. The registry defines it as the number of responses achieved during treatment with BRAF and MEK inhibitors divided by the total number of evaluable patients. Response is assessed using contrast-enhanced magnetic resonance imaging or computed tomography, and the stated timeframe is up to 5 years.

Response rate is used to describe how often a prespecified tumor response is observed in the evaluable population. In a single-group study, it can characterize activity during treatment, but by itself it does not establish what would have happened to similar patients without that treatment or under another treatment. Interpretation therefore depends on the response definition, the evaluable population, the completeness of follow-up, and the precision of the estimate.

The registry description says response-rate point estimates will be generated within each cohort, with corresponding 95% binomial confidence intervals. It does not provide the response definition’s full criteria, the number of evaluable patients, the number of responses, or the resulting estimate and interval. Consequently, the posted registry record does not support a numerical assessment of the observed primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods description includes planned response-rate estimation and a design feature intended to assess futility. It does not report numerical primary-outcome results, so the statistical methods can be explained as planned approaches rather than as analyses whose findings are available in the registry record.

What does a response-rate estimate describe?

A response rate is a proportion: responses form the numerator, and evaluable patients form the denominator. The registry specifies this general definition and says responses will be assessed with contrast-enhanced magnetic resonance imaging or computed tomography. Restricting the denominator to evaluable patients makes the definition of evaluability important. If some enrolled participants do not have an assessable outcome, the estimated rate among evaluable patients may not describe the experience of everyone who entered the study. The criteria for evaluability and the handling of participants without an assessment are not reported in the registry record.

A point estimate gives one summary of the observed response proportion. A confidence interval describes statistical uncertainty around that estimate under the assumptions of the interval method. A 95% binomial confidence interval is planned for response rates within each cohort. In general, an interval is not a guarantee that the true rate falls within its endpoints; rather, it reflects the uncertainty associated with estimating a proportion from observations under a specified statistical procedure. The registry record does not provide the calculated intervals, so their width and the resulting precision cannot be assessed.

Why use a binomial method?

For a binary outcome such as response or no response, the binomial framework models the count of responses among the patients included in the analysis. The corresponding interval quantifies uncertainty in the underlying response probability, subject to the method’s assumptions and the definition of the analysis population. The planned approach is appropriate to describe a response proportion, but it does not address all sources of uncertainty. For example, the interval alone does not correct a poorly defined response assessment, missing evaluations, selection into the evaluable population, or lack of a control group.

What does the two-stage design contribute?

The endpoint description states that Simon's two-stage design will be applied to evaluate response rate within each cohort, with one interim analysis for futility. In general, a two-stage design allows an early assessment of whether continuing a study is unlikely to meet a prespecified activity criterion. A futility assessment concerns whether the accumulating evidence is sufficiently unpromising to stop under the design rules; it is not, by itself, proof that an intervention has no effect. The registry record does not report the design’s decision thresholds, the timing or results of the interim assessment, or whether the planned stages were completed. Those details should not be inferred from the design label.

How should the planning illustrations be read?

The planning assumptions associated with the posted sample-size material are described as illustrations computed from the observed effect, not as the trial’s own design. They specify a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is expressed as a stated fraction of the observed effect. For time-to-event outcomes, the illustration reports the total number of events using the Schoenfeld approach; other illustrations report participants per arm. These assumptions describe hypothetical planning calculations, not observed power for this study and not evidence that the trial was designed with those assumptions.

In general, a planning illustration estimates the amount of information a future study might need under chosen assumptions. Its result depends on the effect size used, the desired power, the significance level, allocation, and the statistical approximation. Because the registry record is described as a single-group study, a hypothetical equal-allocation illustration should not be mistaken for the trial’s actual treatment allocation or design. No numerical planning estimates are stated in the registry information.

What do over-dispersion and time-to-event methods mean?

For a binary response proportion, the binomial model assumes a common underlying probability for the observations represented by that model. More general settings may show over-dispersion, meaning the observed variability exceeds what the assumed model allows; in that case, uncertainty estimates based on the simpler model can be too narrow. The registry record does not report an over-dispersion assessment or a method for adjusting for it, and there is no basis to assert that over-dispersion occurred.

Progression-free survival and overall survival are listed as secondary outcomes. In general, time-to-event methods account for both the timing of an event and the fact that some participants may not yet have experienced it by the end of observation. The planning note refers to a Schoenfeld approach for total event counts in time-to-event illustrations. That planning reference does not report the trial’s observed survival events, follow-up distribution, censoring, or analysis model. Those results and methods are not 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("Arm A", "Arm B")
n      <- c(16, 5)
events <- c(15, 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  Arm A  16  15  93.8  69.8  99.8  71.7  98.9  71.3  98.5
ARM  Arm B  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists response rate as the primary outcome and progression-free survival and overall survival as secondary outcomes. It also describes response-rate estimation within each cohort. When several endpoints or cohort-specific analyses are considered, multiplicity can arise: the more questions analyzed, the more opportunities there may be for an apparently notable result by chance. The record does not report whether multiplicity adjustments were planned, how the primary and secondary outcomes were prioritized for formal testing, or how any cohort-level inferences were to be combined.

The primary-endpoint description specifies 95% binomial confidence intervals and a Simon's two-stage design with one interim analysis for futility within each cohort. It does not report the detailed decision rules, type I error control across cohorts, or any adjustment related to multiple outcomes. Those features should not be assumed from the general design description.

The response-rate denominator is defined as evaluable patients, but the registry record does not report the criteria used to determine evaluability or how missing imaging assessments were handled. It also does not report whether the primary analysis was based on all enrolled participants, a treated population, or another analysis population. Without those definitions and the observed numerator and denominator, the response-rate result cannot be reconstructed or evaluated for sensitivity to missing outcomes.

The record lists 3 outcome measures and no analysis results. It does not report imputation, sensitivity analyses, or other procedures for missing data. The absence of these details in the registry record does not establish that such procedures were or were not used elsewhere; it means they cannot be evaluated from the registry 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: eye disorders - other, specify (20.0%), edema limbs (20.0%), fever (20.0%), inj, pois and proced complic - oth spec (20.0%), myositis (20.0%).

The safety record separates serious adverse events from other adverse events and gives counts at risk and affected for Arm A and Arm B. For serious events, Arm A lists 17 participants at risk and 10 affected, while Arm B lists 5 at risk and 3 affected. For other events, Arm A lists 17 at risk and 16 affected, while Arm B lists 5 at risk and 5 affected. Deaths are listed as 0 in each group.

These are descriptive registry counts, not a randomized treatment comparison. The trial model is single group, and the record does not establish Arm A and Arm B as like-for-like control groups. The counts should therefore be read within the reporting structure, rather than used to claim that one group had greater or lesser safety risk. The record does not report exposure-adjusted event rates, event duration, severity breakdowns beyond the serious-event classification, or the timing of events.

The listed serious-event terms are each accompanied by 20.0%. Since the corresponding term-specific counts and denominators are not reported in the registry information, the percentages cannot be converted into participant counts from this record alone. These summaries also do not indicate whether events were judged related to treatment.

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

The registry record identifies a phase II study of vemurafenib and cobimetinib in papillary craniopharyngioma with a BRAF V600E mutation. It describes a planned primary response-rate analysis, the imaging methods used to assess response, and a confidence-interval approach. It also reports selected safety counts. These details clarify what the study set out to assess and what safety information is recorded.

They do not provide an observed response-rate estimate. The registry record does not report the number of responses, the evaluable denominator, or a confidence interval. Nor does it report results for the listed secondary outcomes of progression-free survival and overall survival. Without these outcome results, the record cannot show the magnitude or precision of any observed response or survival finding.

The study’s single-group design also limits what can be concluded from outcomes observed during treatment. Without a randomized control group, a treatment-period response rate alone cannot separate the treatment’s contribution from other possible influences on observed outcomes. The safety labels do not establish a control comparison, and the reported counts should not be interpreted as proof of a difference between arms.

The reported safety counts can describe how many participants in the registry’s safety groups were listed as affected, but they do not establish the cause of an event or provide a complete account of its severity, timing, or duration. The serious-event term percentages likewise lack the term-level counts and denominators needed for a fuller interpretation.

Accordingly, the registry record supports a description of the study design, planned endpoint, and selected safety reporting. It does not support a conclusion about treatment effectiveness, comparative benefit, or the balance of benefit and harm. Such conclusions would require outcome analyses and supporting details that are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial is statistically notable because it studies a defined molecular and disease population using a single-group phase II design and a response-rate endpoint. The registry specifies that response will be assessed by contrast-enhanced magnetic resonance imaging or computed tomography, and that response-rate estimates will be generated within each cohort with 95% binomial confidence intervals. These details make clear that the intended analysis focuses on estimating response proportions, rather than on a randomized treatment contrast.

The planned Simon's two-stage design with an interim futility analysis illustrates how an early decision rule can be incorporated into a phase II study. In general, such a rule can limit continued study when interim evidence does not meet a prespecified activity criterion. The registry record does not include the thresholds or interim findings, so the practical consequences of the design cannot be evaluated from the available record.

The distinction between planned methods and reported results is central. The registry gives an endpoint definition and some safety counts, but does not report response results or analyses for progression-free survival and overall survival. A clearly specified endpoint is useful for understanding what evidence was intended to be collected; it is not a substitute for the observed data, analysis population, and uncertainty estimates needed to interpret findings.

Finally, the single-group structure matters when interpreting any future or separately reported response estimate. A proportion observed during treatment can describe outcomes in the studied population, but does not by itself provide a randomized estimate of what treatment changed relative to an alternative. This makes transparent reporting of evaluability, missing outcomes, follow-up, and the full analysis especially important.

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.

Several trial-specific details needed to interpret outcomes are not reported in the registry record. Although enrollment is listed as 24, the record does not state the number evaluable for response, the number of observed responses, or the primary endpoint estimate. Without the numerator, denominator, and confidence interval, response-rate precision cannot be assessed.

The primary endpoint is described as being assessed within each cohort, but the cohort definitions and their relationship to the Arm A and Arm B labels in the safety record are not established in the available information. Those safety labels should not be assumed to correspond to particular treatment regimens or to randomized groups. The treatment description also does not provide the complete details of the listed post-course options.

The registry record does not report response-evaluability criteria, missing-imaging procedures, the analysis population, or sensitivity analyses. It does not report the detailed rules or results for the planned futility analysis. For the secondary time-to-event outcomes, it does not provide event counts, follow-up summaries, censoring details, or analysis estimates.

The safety information is limited to counts at risk and affected, deaths, and selected serious-event terms with percentages. It does not provide exposure-adjusted rates or enough term-specific information to reconstruct counts. Because the design is single group, the Arm A and Arm B safety figures do not constitute a like-for-like randomized comparison. These limitations restrict interpretation of both the planned efficacy endpoint and the available safety summary.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Vemurafenib and Cobimetinib in Treating Patients With BRAF V600E Mutation Positive Craniopharyngioma — NCT03224767.
• Registry record last updated 2026-10-07; status last verified 2026-06.
• Results first posted 2026-06-10.
• 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 registry record describes NCT03224767, a phase II study sponsored by the Alliance for Clinical Trials in Oncology. It evaluates vemurafenib and cobimetinib in patients with BRAF V600E mutation-positive papillary craniopharyngioma. The design is listed as single group, with no masking and allocation not applicable. Enrollment is 24, and the record lists the status as active, not recruiting.

The primary outcome is response rate, defined using responses among evaluable patients and assessed by contrast-enhanced magnetic resonance imaging or computed tomography. The planned analysis includes 95% binomial confidence intervals and a Simon's two-stage design with one interim analysis for futility within each cohort. Progression-free survival and overall survival are listed as secondary outcomes.

The registry includes selected adverse-event counts but no outcome analysis results. Response, survival, analysis-population, and missing-data details are not reported in the registry record, limiting assessment of efficacy and the precision of any clinical outcome.