Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer (NCT01111825), a na phase 1, phase 2 study. The primary outcome is Objective Response Rate (ORR) (Phase II).

2. Clinical Question

The clinical question combines dose-finding and activity assessment. In Phase I, the stated aim was to determine the maximum tolerated dose of temsirolimus with daily neratinib. In Phase II, the primary endpoint was objective response rate, defined using confirmed complete and partial responses. The registry also lists clinical benefit rate, duration of response, progression-free survival, and overall survival as secondary outcomes.

This is a question about outcomes observed among people receiving the combination, not about a randomized treatment contrast. Without a control group, the study cannot isolate the combination’s effect from the natural course of disease, patient characteristics, prior treatment, or other influences. The population is also disease-specific: the record identifies trastuzumab-refractory HER2-amplified disease and triple-negative disease, rather than all breast cancer. The registry record does not report the primary endpoint result, so the response proportion cannot be described from the available record.

3. Trial Design

The registry describes an open-label, single-group, multicenter, multinational Phase I/II study. Its stated objectives were to determine the maximum tolerated dose of temsirolimus with daily neratinib and to assess the safety and efficacy of the combination in advanced breast carcinoma. The record lists an enrollment of 99 and a status of completed. The recorded study start is 2010-04, and primary completion is recorded as 2016-07.

Phase I and Phase II have different roles. Dose escalation in Phase I is intended to explore tolerability across dose levels and identify a dose for further study. Phase II evaluates outcomes such as tumor response. The registry states that Phase I data were not included in the efficacy analysis. The Phase II primary endpoint population is described as the intent-to-treat population, comprising all enrolled subjects in Phase II. The record does not give a separate analyzed count for that population.

There was no random allocation and no masking: allocation is recorded as not applicable, masking as none, and the model as single group. Consequently, the Phase I and Phase II categories and the listed disease groups should not be read as randomized treatment arms or as like-for-like control groups. Differences between groups could reflect differences in patient populations, dose level, or study phase rather than an effect attributable to treatment.

The registry record does not report the operational details of dose escalation, the specific dose levels, the selected dose, or a separate statistical analysis plan. It also does not report a sample-size justification. The study is completed, but completion status by itself does not establish that every planned outcome has a posted result.

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: Intent to Treat (ITT) population (all enrolled subjects) for the Phase II portion of the study. Per protocol, Phase I data was not included in 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 Response Rate (ORR) (Phase II), measured over From enrollment date to first documented response, or last tumor assessment, assessed up to two years.

The primary Phase II endpoint is objective response rate (ORR), measured as a count of participants who achieved a confirmed complete response or partial response under RECIST v1.1. A complete response is defined as disappearance of all target lesions. A partial response requires at least a 30% decrease in the sum of the longest diameters of target lesions. The record says a response must be confirmed no less than 4-weeks after response criteria are first met. The stated assessment period runs from enrollment to first documented response, or last tumor assessment, and is assessed up to two years.

ORR is used to describe the proportion of participants meeting a defined tumor-response threshold during a specified assessment period. It translates imaging-based changes into a participant-level endpoint, rather than treating each lesion as an independent observation. Requiring confirmation is intended to distinguish a response that persists on reassessment from an initial measurement that may not be sustained. The exact criteria and confirmation rule are important because response classification depends on both the measurement definition and the assessment schedule.

ORR does not by itself describe how long a response lasts, whether disease remains stable without meeting response criteria, or how long participants live without progression or overall. The registry lists duration of response, clinical benefit rate, progression-free survival, and overall survival as secondary outcomes, but the primary endpoint remains response. The registry record does not report the observed number of responders or the ORR estimate, so no response proportion or precision estimate can be stated.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods below explain general statistical ideas relevant to the design and endpoints recorded for this study. They do not imply that a particular model, adjustment, or analysis was used unless the registry record says so.

What does a single-group design estimate?

In a single-group study, outcomes are observed among participants receiving the study regimen. For a binary endpoint such as objective response, the basic summary is the number meeting the response definition relative to the relevant analysis population. That summary describes the observed group. It does not, by itself, estimate what would have happened to the same participants under another treatment or without the study regimen. A randomized concurrent control group is one way to support a treatment comparison; this study is not described as randomized and has no such control group.

Open-label means masking was absent. Knowledge of treatment can influence care, assessments, and reporting, depending on how outcomes are collected. RECIST v1.1 provides structured response criteria, and the confirmation requirement further standardizes classification, but the record does not describe independent review, blinded imaging assessment, or other procedures that might reduce assessment bias. Those details are not reported in the registry record.

How is a binary response endpoint read?

ORR is a binary participant-level outcome: a participant either meets the confirmed complete- or partial-response definition within the specified assessment period or does not. The response proportion is an estimate of the frequency of that outcome in the defined population. It depends on a clear numerator and denominator. Here the stated efficacy population is all enrolled Phase II subjects, while the record does not give the actual number in that population or the observed response count. Thus the registry description alone cannot establish the estimate.

General explanation: a confidence interval conveys uncertainty around an estimated proportion. Its width depends in part on the amount of information available and on the number of observed responses. A narrow interval indicates greater statistical precision than a wide interval, but precision is not the same as freedom from bias. Because no ORR estimate or interval is reported in the registry record, neither its magnitude nor its statistical precision can be evaluated from that record.

Why do response criteria and timing matter?

RECIST v1.1 defines how target-lesion measurements are classified. The record specifies complete response as disappearance of all target lesions and partial response as at least a 30% decrease in the sum of the longest diameters of target lesions. It also requires response confirmation no less than 4-weeks after the criteria are initially met. These rules reduce ambiguity in deciding which observations count as response. The timeframe begins at enrollment and continues to first documented response or last tumor assessment, assessed up to two years. Interpretation still depends on assessment frequency, missing scans, and the analysis rules for participants who do not complete assessment; those details are not reported in the registry record.

What does dose escalation add?

General explanation: dose-escalation designs use observations at successive dose levels to learn about tolerability and guide selection of a dose for later evaluation. A maximum tolerated dose is a dose-finding concept, not an efficacy outcome. Estimates from early dose-finding cohorts can be sensitive to the design rules and the number of participants treated at each level. The registry calls the study adaptive and dose-escalation, and states that determining the maximum tolerated dose was an aim. The specific escalation algorithm, dose levels, stopping rules, and selected dose are not reported in the registry record, so the method cannot be reconstructed from the description.

How should the secondary outcomes be understood?

The listed secondary outcomes are clinical benefit rate, duration of response, progression-free survival, and overall survival. These outcomes address different aspects of disease course. Clinical benefit rate is a broader response-related concept than ORR, while duration of response concerns the period following response. Progression-free survival and overall survival are time-to-event outcomes, where the timing of an event and follow-up are central. The registry record does not provide their results, definitions beyond their names, censoring rules, or analysis methods. They should not be assumed to use a particular model or time origin beyond what is explicitly stated for the primary endpoint.

What do the sample-size illustrations mean?

General explanation: a sample-size calculation for a future study asks how many participants or events would be needed under stated assumptions to detect a chosen effect with a specified probability, while controlling a stated significance level. Such figures depend on the assumed effect, allocation, endpoint type, and statistical approximation. They are planning illustrations, not observed trial outcomes and not a measure of the probability that the study found a real effect. The registry’s stated illustration assumptions use 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 fraction of the observed effect. Time-to-event illustrations are described in total events, while other illustrations are described as participants per arm. Those assumptions do not turn this single-group trial into a randomized comparison. The registry record does not state that these illustrations were the trial’s own design justification.

The registry lists zero analyses, and it does not report an inferential model for ORR, a confidence interval, a hypothesis test, or an adjustment strategy. It would therefore be inappropriate to attribute a particular statistical test or model to the trial. General concepts can clarify what such methods would do, but they cannot substitute for an analysis specification or posted result.

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("Phase 2 Triple -ve", "Phase 2 HER2+", "Phase 2 HER2+ Dose Esc")
n      <- c(6, 37, 48)
events <- c(0, 5, 14)
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  Phase 2 Triple -ve  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Phase 2 HER2+  37  5  13.5  4.5  28.8  5.9  28.0  6.0  28.1
ARM  Phase 2 HER2+ Dose Esc  48  14  29.2  17.0  44.1  18.2  43.2  18.3  43.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists ORR as the primary Phase II outcome and names clinical benefit rate, duration of response, progression-free survival, and overall survival as secondary outcomes. When a study examines several outcomes or performs multiple comparisons, the chance of at least one apparently notable result can increase. Statistical approaches to multiplicity can control or describe that issue, but they require a prespecified analysis plan and decisions about which outcomes and contrasts are included.

The registry record does not report a multiplicity adjustment, a hierarchy among the secondary outcomes, or an analysis plan describing how multiple tests were handled. It lists zero analyses. No claim about adjusted or unadjusted significance can therefore be made from the record. The primary outcome’s designation does not establish that a particular statistical test was performed.

Missing-data handling is also not reported in the registry record. The efficacy population is described as all enrolled subjects in Phase II, but there is no reported rule for participants who lack an evaluable scan, withdraw, or have an unconfirmed initial response. The definition of the analysis population does not, on its own, specify how missing endpoint status was classified or whether any imputation was used. A complete accounting would ordinarily identify the number assessed and the reasons participants were not assessed.

The record says Phase I data were excluded from efficacy analysis. It does not give the number enrolled in Phase II or the analyzed denominator for ORR. The overall enrollment of 99 should not be treated as the Phase II efficacy sample size. Without the denominator, endpoint count, missing-data rules, and multiplicity plan, the reported endpoint definition cannot be converted into a complete efficacy analysis.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: dyspnoea (33.3%), chest pain (16.7%), cough (16.7%), eyelid oedema (12.5%), empyema (12.5%).

The registry separates serious adverse event reporting into Phase 1, Phase 2 Triple -ve, Phase 2 HER2+, and Phase 2 HER2+ Dose Esc groups. For each group it reports participants at risk and participants affected by serious events and by other events. The counts are, respectively, 8 and 3 serious-event participants in Phase 1; 6 and 2 in Phase 2 Triple -ve; 37 and 12 in Phase 2 HER2+; and 48 and 20 in Phase 2 HER2+ Dose Esc. The record also lists other-event counts of 8, 6, 37, and 48 for those groups, respectively.

The serious-event terms listed most prominently are Dyspnoea at 33.3%, Chest pain at 16.7%, Cough at 16.7%, Eyelid oedema at 12.5%, Empyema at 12.5%, and Spinal cord compression at 12.5%. These are registry-reported term percentages; the record does not explain their calculation or establish whether a participant could contribute to more than one term. The death counts are not reported in the registry record.

These figures describe reported safety events within the listed groups; they do not compare the regimen with a control. The group sizes and populations differ, and the study was not randomized. Do not treat the group counts as evidence that one dose or disease group has greater risk than another. Serious adverse event counts also do not convey event severity beyond the registry’s serious classification, timing, duration, relatedness, or outcome. Those details are not reported in the registry record.

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

The study record identifies a clinical question: whether participants in the Phase II population experienced confirmed tumor responses while receiving temsirolimus with daily neratinib. It defines the response criteria and names additional outcomes addressing clinical benefit, response duration, progression-free survival, and overall survival. It also records a separate Phase I dose-finding objective and summarizes serious adverse event reporting across study groups.

However, the registry record does not report the primary ORR result. It gives no responder count, response proportion, or uncertainty interval. As a result, the available record does not establish how frequently confirmed responses occurred or how precisely a response estimate could be made. Completion status and the presence of a detailed endpoint definition do not supply those results.

Even if an outcome estimate were available, the single-group, open-label design would describe outcomes among participants treated in this study rather than provide a randomized comparison with another treatment. It would not by itself show what would have happened to a comparable group receiving an alternative. Likewise, the listed Phase I and Phase II categories are not control arms. The registry explicitly notes that the arms are not a like-for-like control comparison.

General interpretation: statistical evidence and clinical meaning are related but distinct. An estimate describes the observed data; uncertainty describes how imprecisely that estimate is measured; design determines which causal conclusions are supported. A defined response threshold can make an outcome reproducible, but it cannot remove limitations from an uncontrolled design or absent result reporting. The safety counts similarly document reported events but cannot establish comparative risk.

The record therefore supports conclusions about study design, eligibility focus, outcome definitions, and the existence of safety reporting. It does not support a conclusion about the size of the response rate, whether the regimen changed outcomes relative to another option, or the comparative balance of benefit and harm. Those questions would require complete results and, for comparative effects, an appropriate comparison design.

14. Why This Trial Matters Statistically

This study illustrates why statistical interpretation begins with the design and the estimand—the quantity an analysis is intended to describe. Its Phase I objective concerns dose finding, while its Phase II primary endpoint concerns confirmed response. These questions require different summaries and should not be blended into a single claim about efficacy. The record’s statement that Phase I data were excluded from efficacy analysis is important when identifying which participants belong in the primary endpoint population.

The study also illustrates the limits of interpreting a response rate without a control group. A response proportion can be clinically informative as a description of observed outcomes, but it is not automatically a comparative treatment effect. The absence of random allocation means that comparisons across disease categories or dose-escalation groups can be affected by differences in who entered each group. Treating such categories as if they were randomized arms would overstate what the design can establish.

Outcome definitions matter too. RECIST v1.1 thresholds and a confirmation requirement make the endpoint more explicit than a vague assessment of improvement. Yet readers still need the observed counts, denominator, assessment completeness, and uncertainty interval to judge the numerical result. Here, the registry record specifies the endpoint but does not report its observed result. This distinction between a well-defined outcome and a reported outcome is central to evidence appraisal.

Finally, safety counts need the same attention to denominators and design. Reporting participants affected by serious events and listing event terms is useful descriptive information, but it does not create a controlled safety comparison. The record’s group structure, missing outcome details, and absent efficacy analysis show why a registry entry can document important methods and monitoring while still leaving major statistical questions unanswered.

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 limitations are specific to the information recorded for this study. The design is single-group, open-label, and nonrandomized, so there is no concurrent control for interpreting efficacy or safety differences. The record explicitly cautions that the arms are not a like-for-like control comparison. Results across Phase I, Phase II triple-negative, HER2+, and HER2+ dose-escalation groups cannot be read as randomized contrasts.

The record reports overall enrollment of 99, but does not state the Phase II efficacy denominator or the number with evaluable response assessments. Because Phase I participants were excluded from efficacy analysis, overall enrollment is not a substitute for the primary endpoint population size. The primary ORR count, estimate, and confidence interval are not reported in the registry record. The registry lists zero analyses, leaving the analysis method and inferential results unavailable.

Important implementation details are also absent from the registry record: the specific dose-escalation rules and dose levels, the selected dose, the schedule of tumor assessments, handling of unconfirmed responses, missing-data rules, and multiplicity strategy. The record names secondary outcomes but does not provide their results or analysis details. These omissions limit assessment of both the efficacy analysis and the precision of any estimates.

Safety information is presented as grouped counts and selected serious-event terms. The record does not provide the death counts, event timing, relatedness, duration, or a detailed account of how term percentages were calculated. The group data should therefore be treated as descriptive reporting, not as a basis for comparative risk estimates. These limitations concern what can be interpreted from the registry record and do not establish that information was absent from other study materials.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Temsirolimus Plus Neratinib for Patients With Metastatic HER2-Amplified or Triple Negative Breast Cancer — NCT01111825.
• Registry record last updated 2018-09-26; status last verified 2018-08.
• Results first posted 2017-11-07.
• 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 describes NCT01111825, a completed, open-label, single-group Phase I/II study of temsirolimus plus daily neratinib in advanced breast carcinoma. Its stated aims were to determine the maximum tolerated dose and assess safety and efficacy in trastuzumab-refractory HER2-amplified or triple-negative disease. Enrollment is recorded as 99; the recorded start is 2010-04 and primary completion is 2016-07.

The Phase II primary outcome is confirmed objective response under RECIST v1.1 in the intent-to-treat population of enrolled Phase II subjects. Phase I data were excluded from efficacy analysis. The registry lists four secondary outcomes: clinical benefit rate, duration of response, progression-free survival, and overall survival.

The registry record does not report the primary efficacy result, an analysis method, or an inferential analysis. It reports serious adverse event counts by study group and selected serious-event terms. Because there is no randomized control group, these results are descriptive rather than controlled treatment comparisons.