Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma (NCT04225039), a non-randomized phase 2 study. The primary outcome is Objective Radiographic Response (ORR).

2. Clinical Question

In practical terms, the primary question is whether participants included in the specified Cohort A efficacy population had a complete or partial radiographic response under the stated assessment criteria. A complete response is defined as disappearance of all target lesions. A partial response is defined as a >=50% decrease in the sum of the products of the perpendicular diameters of target lesions. Overall response is the combination of complete and partial responses.

The study’s brief summary says the investigators hypothesize that the regimen will be safe, stimulate an anti-tumor immune response, and result in improved tumor responses. That statement describes the investigators’ rationale; it is not a numerical finding. The registry record does not report a numerical objective response result, its confidence interval, or an analysis comparing response with a control group. Overall survival, progression-free survival, and treatment-emergent adverse events are listed as secondary outcomes, but their numerical results are not reported in the registry record.

3. Trial Design

This is a phase II, non-randomized, parallel study of a treatment combination for recurrent glioblastoma. The listed enrollment is 39. The study is sponsored by the University of Pennsylvania. Its start date is 2020-06-23, its primary completion date is 2022-09-08, and its status is active, not recruiting. These registry entries describe the study record and do not establish that all posted outcomes are complete or available.

The Cohort A description lists N=16 and specifies a priming dose of INCMGA00012 and INCAGN01876 before stereotactic radiosurgery. The described radiation schedule is 8 Gy x 3 fractions. After radiosurgery, both drugs are resumed on the schedules stated in the arm description. The description ends before its treatment-continuation details are complete, so the full regimen duration is not reported in the registry record.

Cohort B is divided into sub-arm #1 and sub-arm #2, each described as N=8. In sub-arm #1, neoadjuvant INCMGA00012 and INCAGN01876 are given with stereotactic radiosurgery before surgery. In sub-arm #2, the two drugs are given before surgery without stereotactic radiosurgery. Both descriptions state that the immunotherapy combination is resumed after surgery, but the treatment-duration wording is incomplete. The registry lists brain surgery as an intervention.

Because allocation is non-randomized and masking is absent, the study does not assign participants by chance to masked treatment groups. The registry record does not report how treatment assignment was determined, whether the cohorts were intended to support a formal comparative analysis, or whether differences between participants were adjusted for statistically. The arm descriptions therefore support a description of the treatment approaches, not an assumption that observed differences between arms would be caused by the treatment differences.

The efficacy population is described separately from the overall enrollment: only eligible Cohort A participants meeting the treatment-exposure criteria were prespecified for the primary efficacy analysis. The record also notes that two participants were excluded from efficacy analysis because of a protocol deviation. It does not report the final number analyzed for the primary endpoint or give a participant flow accounting for all enrolled participants.

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:

Analysis population for the primary outcome, as defined in the registry: Per protocol, it was pre-specified to only include subjects in Cohort A and the subject must have received at least one dose of BOTH study drugs AND has received at least one fraction of SRS. Because of a protocol deviation, the data of 2 subjects is not included for efficacy analysis.

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 Objective Radiographic Response (ORR), measured over 26 months.

The primary endpoint is objective radiographic response, expressed as the percentage of participants with a response. Response is assessed by MRI using modified response assessment in neuro-oncology criteria for target lesions. The registry defines complete response as disappearance of all target lesions and partial response as a >=50% decrease in the sum of the products of the perpendicular diameters of target lesions. Overall response combines complete and partial responses. The assessment timeframe is 26 months.

As a general statistical concept, a binary response endpoint classifies each participant according to whether the stated response criterion was met. Reporting a percentage can make the frequency of response easier to interpret than reporting a count alone, while the count and analysis denominator remain important for understanding how much information supports that percentage. A confidence interval conveys the uncertainty around an estimated response percentage; it does not guarantee that the true response rate lies within the interval.

The registry identifies a 95% confidence interval as the endpoint’s dispersion measure, but it does not post the response estimate or its interval bounds. The numerical response result is therefore not reported in the registry record. The endpoint’s definition and assessment timeframe are available, but they are not a substitute for the missing result. The response criterion also concerns radiographic change in target lesions; it should not be interpreted as a complete account of other outcomes such as survival, progression, symptoms, or safety.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a binary response percentage represent?

As a general statistical concept, a binary endpoint assigns each participant to one of two outcome categories: the specified event occurred, or it did not. For objective radiographic response, the event is meeting the registry’s definition of complete or partial response. A percentage summarizes how frequent that event was in the analysis population. To interpret it, readers need both the event count and the number of participants assessed. The response percentage and its denominator are not reported in the registry record.

Using a stated response definition makes the endpoint more reproducible than a subjective judgment without specified criteria. Here, the record identifies MRI assessment, modified response assessment in neuro-oncology criteria, target lesions, and the definitions of complete and partial response. The timeframe is 26 months. The record does not describe details such as the review process, whether assessment was independent, or how disagreements were handled; those details are not reported in the registry record.

How should a confidence interval be understood?

As a general statistical concept, a confidence interval expresses uncertainty around an estimate. For a response percentage, a narrower interval generally indicates greater statistical precision, while a wider interval indicates more uncertainty. The interval’s width depends on the amount of information and the observed outcome pattern, as well as the method used to calculate it. A confidence interval does not establish that a treatment caused an outcome, and it does not replace consideration of study design or possible bias.

The registry names a 95% confidence interval as the dispersion measure for the primary endpoint. However, the interval limits and the underlying response estimate are not reported in the registry record. The method used to calculate the interval is also not reported in the registry record. No conclusion about the endpoint’s precision can be drawn from the stated confidence level alone.

What does non-randomized allocation mean for interpretation?

As a general statistical concept, random allocation is used to balance measured and unmeasured participant characteristics across treatment groups on average. In a non-randomized study, treatment groups may differ for reasons related to eligibility, clinical decisions, participant characteristics, or the treatment pathway. Statistical adjustment can sometimes address measured differences, but cannot automatically remove bias from unmeasured differences.

This study is explicitly non-randomized and unmasked. The registry does not report a statistical adjustment strategy or an analysis comparing treatment groups. The two Cohort B sub-arms differ in whether stereotactic radiosurgery is included, and the treatment sequence also differs from Cohort A. Comparisons among these groups would therefore be descriptive unless a suitable analysis and its assumptions were reported. No such analysis is reported in the registry record.

What do the planning assumptions say?

The record describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. For time-to-event outcomes, the illustration concerns the total number of events; for other outcomes, it concerns participants per arm. The calculated planning values and the numerical observed effect are not reported in the registry record.

As a general statistical concept, a planning calculation asks how much information a study would need under specified assumptions. It is not an observed outcome and is not a retrospective measure of whether a completed study had adequate power. The record characterizes this illustration as planning based on the observed effect, not as the trial’s own design. Its assumptions should not be mistaken for a reported protocol justification. The trial’s own sample-size justification is not reported in the registry record.

What can be concluded about multiplicity and interim analysis?

As a general statistical concept, multiplicity arises when several outcomes, groups, time points, or statistical tests are considered. Repeated testing can increase the chance of finding an apparently notable result by chance, so analysis plans sometimes specify how such testing will be handled. The registry lists a primary endpoint and secondary outcomes, but does not report a multiplicity strategy or the statistical analyses for those outcomes. The number of analyses recorded is 0. Interim analyses are not reported in the registry record.

The registry record also does not report the statistical test used for the primary endpoint, the handling of missing endpoint data, or a full analysis-population definition beyond the stated Cohort A eligibility criteria. These omissions limit reproducibility and make it difficult to determine how any eventual result should be interpreted. General statistical principles can explain what such methods would address, but cannot establish which methods were used in this study.

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("GITR + PD1, SRS (Cohort A)")
n      <- c(16)
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  GITR + PD1, SRS (Cohort A)  16  0  0.0  0.0  20.6  0.0  19.4  0.1  19.5

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies objective radiographic response as the primary endpoint and lists treatment-emergent adverse events, overall survival, and progression-free survival as secondary outcomes. It does not report a multiplicity strategy describing how inference across these outcomes would be handled. It also records 0 analyses. The statistical methods used for the outcomes, including any hypothesis tests or adjustment procedures, are not reported in the registry record.

The primary efficacy population is described as Cohort A participants who received at least one dose of both study drugs and at least one fraction of stereotactic radiosurgery. The record states that two participants were excluded from efficacy analysis because of a protocol deviation. It does not report the final number included in the primary analysis, the number with missing response assessments, or how missing outcomes were treated. The reasons for the protocol deviation and the consequences for analysis are not reported in the registry record.

As a general statistical concept, the analysis population matters because estimates can change depending on which participants are included. A per-protocol population focused on participants meeting treatment criteria may answer a different question from an analysis including everyone enrolled or assigned to a treatment approach. Missing outcomes can also affect estimates if the participants without assessments differ from those assessed. These issues cannot be evaluated fully without participant-flow and missing-data details.

The record does not report an intention-to-treat analysis, a sensitivity analysis for missing data, or a prespecified hierarchy for primary and secondary outcomes. It is not appropriate to infer that these methods were or were not used outside the registry record. Their status is not reported in the registry record.

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: cognitive disturbance (20.0%), colonic obstruction (12.5%), encephalitis infection (12.5%), upper respiratory infection (12.5%), fall (12.5%).

The safety summary reports, for Cohort A, 8 of 18 participants with serious adverse events, 18 of 18 with other adverse events, and 12 deaths. For Cohort B Sub-arm #1, it reports 5 of 8 with serious adverse events, 8 of 8 with other adverse events, and 0 deaths. For Cohort B Sub-arm #2, it reports 5 of 8 with serious adverse events, 8 of 8 with other adverse events, and 6 deaths. For participants listed as ineligible or having withdrawn consent, it reports 1 of 5 with serious adverse events, 0 of 5 with other adverse events, and 4 deaths.

These are descriptive group summaries. The record does not provide a randomized comparison, adjusted safety analyses, or enough information to attribute differences across groups to treatment. The safety denominators also do not always align with the arm descriptions: Cohort A is listed as N=16 in its arm description but 18 at risk in the safety summary. The registry does not explain the difference.

The listed serious-event terms include cognitive disturbance at 20.0%, and colonic obstruction, encephalitis infection, upper respiratory infection, fall, and shunt malfunction at 12.5% each. The registry record does not explain the denominator or calculation underlying these term percentages. They should not be interpreted as rates for a specific treatment group without that information. The summary does not establish whether events are related to treatment.

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

The registry record establishes that a phase II, non-randomized study was designed to assess a combination of INCAGN01876, INCMGA00012, and stereotactic radiosurgery in recurrent glioblastoma. It defines objective radiographic response as the primary endpoint, describes the response criteria, and specifies a 26-month timeframe. It also lists safety, overall survival, and progression-free survival as secondary outcomes.

Those design details do not establish what response rate was observed. The numerical primary endpoint result and its confidence interval are not reported in the registry record. Numerical results for overall survival and progression-free survival are also not reported. The safety summary gives group counts, but the record does not include a randomized control comparison or an adjusted analysis supporting causal claims about differences between treatment approaches.

As a general statistical concept, a point estimate describes the observed result in the analyzed group, while its uncertainty reflects how precisely that result has been estimated. Neither can be inferred from an endpoint definition or a confidence level alone. Likewise, a study hypothesis is not an outcome, and a planning illustration is not evidence that a treatment effect was demonstrated. The record’s stated planning assumptions do not supply missing response results or establish observed power.

The non-randomized design and the restricted efficacy population also matter. Participants meeting the Cohort A treatment criteria may differ from those in the other groups or from participants excluded from efficacy analysis. Without the final analysis denominator, missing-data details, and a reported comparative method, the posted record cannot resolve how these factors affect an estimate.

Accordingly, the record supports a description of the study design, endpoint definitions, and posted safety counts. It does not support a conclusion about the size or precision of the primary response result, a comparison of efficacy among groups, or a causal claim about treatment effects. The absence of a result in the registry record should be distinguished from evidence that an outcome did or did not occur.

14. Why This Trial Matters Statistically

This study raises statistical questions that are important when interpreting early-phase, non-randomized research. The primary endpoint is clearly framed as an objective radiographic response percentage with a 95% confidence interval, but the numerical estimate and interval are not reported in the registry record. Without those values, readers cannot evaluate the observed frequency of response or the precision of the estimate. Defining an endpoint is necessary for interpretation, but it is not equivalent to reporting its result.

The registry’s description of the efficacy population also highlights why analysis denominators matter. Efficacy was prespecified for Cohort A participants who received both drugs and at least one fraction of stereotactic radiosurgery, and two participants were excluded after a protocol deviation. Yet the final analysis denominator and details of the deviation are not reported. Those details would help readers understand which participants contributed to the primary estimate and how exclusions might affect its interpretation.

The non-randomized, parallel design makes comparisons across treatment approaches especially difficult. Cohort B sub-arms differ in the use of stereotactic radiosurgery and include surgery, while Cohort A follows a different sequence. Without randomized assignment or a reported adjusted comparison, arm-level differences cannot be attributed to one component of treatment. This is a design limitation, not a finding about whether any regimen is beneficial.

The posted safety counts add descriptive information but also expose a reporting issue: Cohort A’s arm description lists N=16, whereas its safety summary lists 18 participants at risk. The record does not reconcile these values. Transparent participant flow and consistent denominators are important for interpreting both safety and efficacy summaries.

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 registry record does not report a numerical objective response result, its 95% confidence interval, or the method used to calculate that interval. It also does not report numerical results for overall survival or progression-free survival. As a result, the posted information cannot establish the observed efficacy outcomes or their precision.

The study is non-randomized and unmasked. The record does not describe how participants entered the different cohorts, whether treatment assignment depended on clinical or participant factors, or whether statistical adjustment was planned or performed. The Cohort B sub-arms differ in use of stereotactic radiosurgery, and the treatment pathways include surgery. The groups therefore cannot be assumed to be interchangeable comparators.

The primary efficacy population is restricted to eligible Cohort A participants who received both study drugs and at least one fraction of stereotactic radiosurgery. Two participants were excluded from efficacy analysis because of a protocol deviation. The nature of the deviation, final analysis denominator, participant flow, and handling of missing response assessments are not reported in the registry record.

The registry lists Cohort A as N=16 in its arm description but lists 18 participants at risk in its safety summary. It does not explain this difference. Safety counts and the percentages attached to serious-event terms are descriptive, and the denominator for the term percentages is not reported. The record also does not report whether events were judged related to treatment.

The treatment descriptions end before all continuation details are specified. The registry does not report the trial’s own sample-size justification, statistical analysis plan, multiplicity approach, or interim analyses. These limitations concern the information available in the registry record and do not establish what may have been specified or analyzed elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Anti-GITR/Anti-PD1/Stereotactic Radiosurgery, in Recurrent Glioblastoma — NCT04225039.
• Registry record last updated 2026-06-23; status last verified 2026-06.
• Results first posted 2023-09-15.
• 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

NCT04225039 is a phase II, non-randomized, parallel study of INCAGN01876 and INCMGA00012 with treatment approaches involving stereotactic radiosurgery for recurrent glioblastoma. The listed enrollment is 39. The sponsor is the University of Pennsylvania. The record lists a start date of 2020-06-23, a primary completion date of 2022-09-08, and a status of active, not recruiting.

The primary endpoint is objective radiographic response by MRI under modified response assessment in neuro-oncology criteria, with a timeframe of 26 months. The efficacy population is restricted to specified Cohort A participants; two participants were excluded because of a protocol deviation. Secondary outcomes include treatment-emergent adverse events, overall survival, and progression-free survival.

The registry record posts group-level safety counts but does not report the numerical primary response outcome, its confidence interval, or numerical survival results. It also does not report the statistical analysis plan, the final efficacy denominator, or an explanation for the difference between the Cohort A arm-description count and safety at-risk count.