This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Neoadjuvant Immunotherapy in Brain Metastases (NCT04434560), a randomized phase 2 study. The primary outcome is Proportion of Patients Who Have Their Surgery Delayed by More Than 4 Days or Surgery Never Occurs as a Direct or Indirect Result of Ipilimumab and Nivolumab Treatment..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04434560 |
| Phase | Phase 2 |
| Condition | Brain Metastases, Adult |
| Allocation | Randomized |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 1 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Sarah Sammons, MD |
| Results posted | Yes |
2. Clinical Question
Population
Adults with previously untreated, surgically resectable brain metastases from solid tumors. The registry describes this population as having solid-tumor brain metastases; no further eligibility details or participant characteristics are reported in the registry record.
Intervention
A single dose of neoadjuvant nivolumab and ipilimumab, planned 7 days (± 3 days) before surgical resection. The treatment strategy also includes surgery and stereotactic radiosurgery (SRS).
Comparator
Standard care without neoadjuvant nivolumab or ipilimumab before surgery. The record describes proceeding to surgical resection in this group, and lists a standard-of-care arm and a neoadjuvant immunotherapy arm.
Primary question
Among patients assigned to neoadjuvant immunotherapy, what proportion have surgery delayed by more than 4 days or surgery never occurs as a direct or indirect result of treatment, within the stated 10-day timeframe? The registry also describes an objective to assess whether neoadjuvant treatment increases circulating T-cell proliferation relative to baseline. No participants were enrolled in the neoadjuvant group, so the primary endpoint cannot be estimated from the posted record.
The clinical question combines feasibility and biological response. The feasibility endpoint concerns whether treatment interferes with timely surgery, rather than whether tumor outcomes differ between groups. The T-cell objective concerns a change in a circulating immune measure from baseline. Exploratory objectives include progression-free survival, overall survival, local and distant intracranial progression, radiation necrosis, and immune expression profiles. The registry record does not report results for these objectives. Although the record identifies randomized allocation, it also identifies a single-group model. The listed arm descriptions and enrollment information do not resolve that inconsistency: the record reports one participant in standard care and none in the neoadjuvant group.
3. Trial Design
This is registered as a Phase II trial of surgery and stereotactic radiosurgery with neoadjuvant nivolumab and ipilimumab in patients with surgically resectable solid-tumor brain metastases. The registry records randomized allocation and no masking, while its model field identifies a single-group design. These entries do not align straightforwardly with one another or with the two arm descriptions. The record does not explain the discrepancy, so the design should be described with that qualification rather than resolved by inference.
The planned neoadjuvant strategy was a single dose of nivolumab and ipilimumab 7 days (± 3 days) before surgical resection. The standard-of-care description specifies surgery without either drug before the operation. SRS is part of the trial title and intervention context. The primary endpoint's stated timeframe is 10 days. The registry reports enrollment of 1 and identifies that participant with the standard-of-care group; it reports no participants in the neoadjuvant immunotherapy group.
The record lists a start date of 2020-11-04, a primary completion date of 2021-06-17, and a terminated status. It does not report why the trial was terminated. The registry does not report additional details about the allocation procedure, concealment, the intended number of participants, or the protocol's sample-size justification. These omissions prevent a fuller assessment of how the intended design was to be implemented. In particular, the randomized-allocation entry alone does not establish that a comparative analysis was possible: the posted enrollment contains no participant in one of the listed groups, and no analyses are reported.
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: In a Memo to File dated March 4, 2021, the removal of randomization in favor of a single-arm study in which all patients will receive neoadjuvant immunotherapy prior to their resection and SRS was proposed. One patient had already been randomized to receive standard of care surgery and SRS without neoadjuvant immunotherapy. This patient is not part of the analyses for the primary or secondary outcomes, as after the protocol amendment all patients were to receive neoadjuvant immunotherapy.
Overall Study
| Stage | Standard of Care (no Neoadjuvant Immunotherapy) | Neoadjuvant Immunotherapy |
|---|---|---|
| STARTED | 1 | 0 |
| COMPLETED | 1 | 0 |
| NOT COMPLETED | 0 | 0 |
Analysis population for the primary outcome, as defined in the registry: Outcome measure only applies to Neoadjuvant Immunotherapy; no participants were enrolled in the Neoadjuvant Immunotherapy group.
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.
Population: No participants were enrolled in the Neoadjuvant Immunotherapy group.
| Characteristic | Unit | Standard of Care (no Neoadjuvant Immunotherapy) | Neoadjuvant Immunotherapy | Total |
|---|---|---|---|---|
| Participants analysed | 1 | 0 | 1 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 1 | 0 | 1 |
| Age, Categorical: >=65 years | Participants | 0 | 0 | 0 |
| Sex: Female, Male: Female | Participants | 1 | 0 | 1 |
| Sex: Female, Male: Male | Participants | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 0 | 0 | 0 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 1 | 0 | 1 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): More than one race | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 | 0 | 0 |
| Region of Enrollment: United States | Participants | 1 | 0 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Proportion of Patients Who Have Their Surgery Delayed by More Than 4 Days or Surgery Never Occurs as a Direct or Indirect Result of Ipilimumab and Nivolumab Treatment., measured over 10 days.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint is the proportion of patients whose surgery is delayed by more than 4 days, or whose surgery never occurs, as a direct or indirect result of ipilimumab and nivolumab treatment. Its stated timeframe is 10 days, and the registry says it applies only to the neoadjuvant immunotherapy group. This endpoint addresses feasibility: it records whether giving immunotherapy before a planned operation disrupts the timing or completion of surgery.
Such an endpoint can be useful when the treatment sequence itself may affect whether a planned procedure proceeds on schedule. It focuses on a practical consequence of the neoadjuvant strategy rather than on tumor control or survival. The registry separately describes an objective concerning proliferation of circulating T-cells compared with baseline, as well as exploratory clinical outcomes. Those are not interchangeable with the surgery-timing endpoint and should not be treated as evidence about it.
The record explicitly states that no participants were enrolled in the neoadjuvant group. Because the endpoint applies only to that group, no proportion can be calculated from the posted enrollment. The record does not provide an observed endpoint value, an uncertainty interval, or a statistical test. This absence is not evidence that surgery was or was not delayed; it means the registry record contains no evaluable observations for this endpoint.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The most important interpretive fact is that the registry reports enrollment of 1 overall, with no participant in the neoadjuvant immunotherapy group. The primary outcome is restricted to that group. As a result, the posted record does not support an estimate of the proportion with surgery delayed by more than 4 days or surgery never occurring. It also does not support a comparison between the neoadjuvant and standard-of-care strategies.
The record reports no analyses. There is therefore no posted effect estimate, confidence interval, p-value, or outcome summary for the primary endpoint. The registry's other stated objectives—including circulating T-cell proliferation, progression-free survival, overall survival, intracranial progression, radiation necrosis, and immune expression profiles—also have no reported results in the registry record from the record. Without observed estimates and their uncertainty, readers cannot judge the magnitude or precision of any treatment-associated difference.
The safety information is limited as well. The standard-of-care group has one participant at risk and one participant with a serious adverse event; it also has one participant at risk and one participant with an other adverse event. The record lists no deaths. The neoadjuvant group has zero participants at risk and zero affected participants in both categories. These counts describe the posted record, not a comparative safety assessment. With no participant in the neoadjuvant group, its recorded zero affected participants must not be read as evidence that the regimen caused no adverse events.
The record's design entries require care. It labels allocation randomized and masking none, but gives the model as single group while listing two arms. It does not explain this combination. The termination status and listed dates add context about trial conduct, but the reason for termination is not reported in the registry record. Nor does the record explain whether the design or enrollment changed over time.
Overall, the posted information documents the trial's stated aims, treatment strategies, limited enrollment, and a small amount of adverse-event information. It does not provide results with which to assess feasibility, biological response, clinical outcomes, or between-group effects. Any interpretation beyond those descriptive details would go beyond what the registry record establishes.
9. Statistical Methods Explained
Statistical interpretation depends on matching an endpoint to the population actually observed and then describing both the estimated effect and its uncertainty. In this record, the primary endpoint concerns the neoadjuvant group, but no participants were enrolled in that group. That mismatch means there is no observed primary-endpoint proportion to interpret. No inferential analysis is reported, so concepts such as a treatment-effect estimate or a confidence interval cannot be applied to this endpoint using the registry record.
What does an endpoint proportion represent?
A proportion is a count of participants meeting a defined outcome divided by the number of participants who could be assessed for that outcome. For this trial, the event definition combines surgery delayed by more than 4 days with surgery never occurring as a direct or indirect result of treatment. The endpoint is restricted to the neoadjuvant group. Because the registry says there were no participants in that group, neither the event count nor an evaluable denominator is available for estimating the proportion. A zero in the group enrollment field is not an outcome rate.
Why would uncertainty matter?
In general, a confidence interval describes a range of values compatible with the observed data under a specified statistical method. It conveys precision as well as the direction and size of an estimate. An estimate based on little information will generally be less precise than one based on more information, although the exact uncertainty depends on the data and method. No confidence interval is reported for the primary endpoint, and the absence of participants in its target group prevents an interval from being estimated from the posted enrollment. No interval should be inferred from the adverse-event percentages either; the record does not report such an interval.
What can a group comparison establish?
In general, a comparative trial estimates how outcomes differ between treatment strategies, subject to the design and analysis. A randomized allocation can support a causal comparison when assignment, enrollment, outcome collection, and analysis follow the intended design. Here the registry identifies randomized allocation, but also labels the model single group and describes two arms. The registry does not explain these entries. Furthermore, the recorded enrollment is one in standard care and none in neoadjuvant immunotherapy. There is no observed outcome information in both groups to compare. The design label alone cannot supply a missing comparison.
A comparison would also require clarity about the outcome being compared, the analysis population, the time point, and the handling of incomplete observations. Those details are not reported in the registry record. The primary endpoint has a 10-day timeframe, but the record does not provide an analysis method, a precise approach to participants whose surgery timing could not be determined, or a statistical contrast between groups.
How should planning illustrations be understood?
In general, a sample-size calculation describes how many observations a study might need under stated assumptions; it does not describe how many participants were actually analyzed. The registry record's stated illustration assumptions are 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. It also specifies that time-to-event calculations use the total number of events under the Schoenfeld method, while other calculations give participants per arm. These are assumptions for a planning illustration, not evidence about the trial's achieved precision or a report of observed power.
The registry does not report its own sample-size justification. The presence of a planning framework does not establish that it was used to design or conduct this trial. In addition, a planning calculation based on an observed effect cannot be interpreted as a trial-specific result when the relevant observed effect is not reported. No planning values are stated in the registry entries used for this analysis, so no numerical sample-size conclusion can be drawn from them.
What does the absence of analyses imply?
The registry reports zero analyses. That means there are no posted statistical results to evaluate for the primary outcome or other objectives. It does not establish why analyses are absent, whether analyses were conducted outside the registry, or whether the trial was stopped before analysis. Such explanations are not reported in the registry record. The stated terminated status does not, by itself, establish a reason for termination or explain the missing results.
General statistical principles remain relevant even when results are unavailable: estimates should be read with their uncertainty, comparisons should align with the trial design, and analysis populations and missing observations should be described. In this record, those principles highlight the limits of interpretation rather than yielding an effect estimate. The available information supports descriptive statements about the registration, enrollment, and adverse-event counts, but not an estimate of efficacy, feasibility, or comparative safety.
10. Multiplicity, Missing Data and Analysis Populations
Multiplicity arises when several outcomes, comparisons, time points, or statistical tests are examined. In general, conducting many tests can increase the chance that at least one result appears statistically notable by chance. A statistical plan may prespecify a primary outcome, define secondary and exploratory analyses, or describe an approach to multiplicity. The registry lists a primary feasibility endpoint, a circulating T-cell objective, and exploratory outcomes involving survival, intracranial progression, radiation necrosis, and immune expression profiles. It does not report a multiplicity strategy or a detailed statistical analysis plan.
Missing-data methods are also not reported in the registry record. The primary endpoint concerns surgery delay or surgery not occurring, but the record does not specify how an unobserved surgery date, withdrawal, or other incomplete endpoint information would be handled. This matters in general because an analysis can depend on whether missing outcomes are excluded, modeled, or addressed through another prespecified method. No such choice can be attributed to this trial from the posted record.
Analysis populations are not reported in detail. The registry does not describe an intention-to-treat population, a per-protocol population, or another defined set for analysis. No analyses are posted, and the neoadjuvant group has no enrolled participants. The registry entries therefore do not support a conclusion about which participants would have contributed to each planned endpoint, or how deviations from the intended treatment sequence would have been handled.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Standard of Care (no Neoadjuvant Immunotherapy) | 1 | 1 | 100.0% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Standard of Care (no Neoadjuvant Immunotherapy) | 0 of 1 |
| Neoadjuvant Immunotherapy | 0 of 0 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Standard of Care (no Neoadjuvant Immunotherapy) | 1 of 1 |
| Neoadjuvant Immunotherapy | 0 of 0 |
Most frequent serious adverse event terms
| Event term | Organ system | Standard of Care (no Neoadjuvant Immunotherapy) | Neoadjuvant Immunotherapy |
|---|---|---|---|
| Pyramidal tract syndrome | Nervous system disorders | 1 of 1 | 0 of 0 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Standard of Care (no Neoadjuvant Immunotherapy) | Neoadjuvant Immunotherapy |
|---|---|---|---|
| Anemia | Blood and lymphatic system disorders | 1 of 1 | 0 of 0 |
| Hypothyroidism | Endocrine disorders | 1 of 1 | 0 of 0 |
| Lymphocyte count decreased | Investigations | 1 of 1 | 0 of 0 |
| Platelet count decreased | Investigations | 1 of 1 | 0 of 0 |
| White blood cell decreased | Investigations | 1 of 1 | 0 of 0 |
| Hyperglycemia | Metabolism and nutrition disorders | 1 of 1 | 0 of 0 |
| Hypomagnesemia | Metabolism and nutrition disorders | 1 of 1 | 0 of 0 |
| Concentration impairment | Nervous system disorders | 1 of 1 | 0 of 0 |
| Dysphasia | Nervous system disorders | 1 of 1 | 0 of 0 |
| Headache | Nervous system disorders | 1 of 1 | 0 of 0 |
Serious events with the highest arm-level rate: pyramidal tract syndrome (100.0%).
The registry lists one participant at risk for serious adverse events and one affected participant in the standard-of-care group. For other adverse events, it likewise lists one participant at risk and one affected participant. It lists zero deaths in that group. In the neoadjuvant immunotherapy group, the at-risk and affected counts are zero for both serious and other adverse events, and the death count is zero. The registry's top serious adverse-event term is Pyramidal tract syndrome, listed as 100.0%.
These figures are descriptive counts from a record with one enrollee in standard care and no enrollees in neoadjuvant immunotherapy. They do not provide a useful basis for comparing safety between strategies. In particular, zero affected participants in a group with zero participants at risk is not evidence of an absence of events among treated participants. The listed percentage should be read in the context of the very limited enrollment, not as a stable estimate of event frequency.
The registry does not report further details about event timing, severity grading beyond the serious-versus-other categories, attribution, or the relationship of the listed event to treatment. The counts therefore should not be used to draw conclusions about causation or broader safety patterns.
12. What the Result Does, and Does Not, Mean
The registry record establishes what the trial set out to study: whether neoadjuvant nivolumab and ipilimumab could be given before surgery and SRS while maintaining the planned surgical course, alongside an objective concerning circulating T-cell proliferation. It also records exploratory clinical outcomes and a standard-of-care arm description. These details identify the research questions, but they are not themselves evidence that an outcome occurred.
The posted enrollment is one participant in standard care and none in the neoadjuvant group. Consequently, the primary feasibility endpoint has no enrolled participants in its applicable group. The record does not report an outcome estimate, a confidence interval, or an analysis for that endpoint. It likewise does not report analyses for the immune or exploratory outcomes. The absence of a posted estimate cannot be interpreted as a favorable or unfavorable result.
The safety counts are similarly limited. They describe one participant in the standard-of-care group and no participants in the neoadjuvant group. They cannot establish comparative safety, and the zero counts in the empty neoadjuvant group cannot establish that no adverse events would occur with treatment. The record's serious adverse-event term and percentage are descriptive registry entries, not a general estimate of risk.
The design information also needs qualification: randomized allocation is recorded, but the model is listed as single group despite two arm descriptions. The record does not explain the discrepancy. The terminated status is documented, while the reason for termination is not reported in the registry record. Without further information, neither the design inconsistency nor the termination should be assigned an explanation.
Thus, the record can be read as a limited account of trial intent, design labels, enrollment, and safety counts. It cannot answer whether the neoadjuvant strategy met its feasibility objective, changed T-cell proliferation, or affected clinical outcomes. Those conclusions require outcome data and analyses that are not reported.
13. Why This Trial Matters Statistically
This trial raises a statistically important distinction between a clearly stated research question and an estimable answer. The primary endpoint has a direct operational definition—surgery delayed by more than 4 days or not occurring because of treatment—and a stated 10-day timeframe. Yet it applies only to the neoadjuvant group, which has no enrolled participants in the registry record. A well-defined endpoint cannot yield an estimate without observations in its target population.
The record also illustrates why design metadata need to be read together. Randomized allocation appears alongside a single-group model and descriptions of two arms. Each entry conveys a different aspect of the registered design, but the record does not reconcile them. Enrollment adds another essential part of the interpretation: one person is listed in standard care and none in the neoadjuvant group. Taken together, these registry entries do not support a treatment comparison, regardless of the allocation label.
Statistical reporting is more than a statement of whether a result is significant. Useful interpretation ordinarily depends on estimates, uncertainty, defined analysis populations, and transparent handling of missing information. None of these analytic results is posted for the primary endpoint. The example emphasizes that a registry's aims and design can inform readers about what investigators intended to assess, while still leaving the central statistical questions unanswered.
Finally, sparse safety counts illustrate why percentages and zero counts require context. The listed serious adverse-event percentage is based on a very small recorded group, while the neoadjuvant group has no participants at risk. The record supports reporting those details, not generalizing them into comparative risk estimates. This distinction between descriptive entries and inferential evidence is central to responsible reading of small or incomplete trial records.
14. 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 main limitation is the lack of enrolled participants in the group to which the primary endpoint applies. With no neoadjuvant participants, the registry cannot provide an observed feasibility proportion for surgery delay or failure to proceed. The single participant in standard care does not fill that gap, because the endpoint is explicitly limited to the neoadjuvant group.
No analyses are reported, and the registry record does not include estimates, uncertainty intervals, or results for the primary or other stated objectives. It therefore cannot establish findings about circulating T-cell proliferation, progression-free survival, overall survival, local or distant intracranial progression, radiation necrosis, or immune expression profiles. The small enrollment also sharply limits what can be learned from the adverse-event counts; in particular, the neoadjuvant group's zeros reflect no recorded participants at risk.
The record contains design metadata that are not reconciled: allocation is identified as randomized, the model as single group, and two arm descriptions are listed. The reason for this mismatch is not reported. The record also does not provide a reason for the terminated status, details of the analysis populations, a statistical analysis plan, missing-data procedures, or the trial's own sample-size justification. These are registry-record limitations; they do not establish what may or may not have been documented elsewhere.
Finally, the posted information does not explain whether enrollment or procedures changed during the study, nor why the trial ended. Interpretation should therefore remain bounded to the stated objectives, recorded design entries, enrollment, and adverse-event counts.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Neoadjuvant Immunotherapy in Brain Metastases — NCT04434560.
- Registry record last updated 2022-07-26; status last verified 2022-07.
- Results first posted 2022-07-26.
- 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.
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18. Record Summary
The registry describes a Phase II study of neoadjuvant nivolumab and ipilimumab before surgery and SRS for surgically resectable solid-tumor brain metastases. Its primary endpoint concerns surgery delayed by more than 4 days or not occurring as a direct or indirect result of treatment, within a 10-day timeframe. The record also lists a circulating T-cell objective and exploratory clinical outcomes.
Allocation is identified as randomized, masking as none, and the model as single group, while two arms are described. Enrollment is 1: one participant in standard care and none in neoadjuvant immunotherapy. The status is terminated. No analyses are reported, and the primary endpoint has no enrolled participants in its applicable group. The registry lists one serious and one other adverse-event participant in standard care, zero deaths, and no participants at risk in the neoadjuvant group. The reason for termination and any outcome analyses are not reported in the registry record.