A Study to Assess Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab and Vinorelbine in Participants With Metastatic or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Assess Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab and Vinorelbine in Participants With Metastatic or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer (NCT01565083), a non-randomized phase 2 study. The primary outcome is Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).

2. Clinical Question

3. Trial Design

This was a phase II, two-cohort, open-label, multicenter trial with a parallel model and non-randomized allocation. The study was designed to assess the efficacy and safety of pertuzumab given with trastuzumab and vinorelbine in first-line participants with HER2-positive advanced breast cancer, defined as metastatic or locally advanced disease. The registry lists 213 enrolled participants and a completed status.

The two groups were labelled Pertuzumab + Trastuzumab + Vinorelbine: Separate Infusion and Pertuzumab + Trastuzumab + Vinorelbine: Single Infusion. Both labels include the same three drugs; the labels distinguish the infusion approaches under study. The registry’s descriptions include separate intravenous infusions and different administration arrangements. It does not report enough detail to infer more about how the approaches were implemented beyond those descriptions.

Because allocation was not randomized, differences between groups could reflect participant characteristics, treatment delivery or other factors, as well as any difference associated with the infusion approach. Open-label conduct also means treatment assignment was not masked. These design features matter when interpreting a comparison: the groups are not equivalent to randomized arms, and a numerical contrast would not by itself identify a causal treatment effect.

The primary endpoint was investigator-assessed best overall response according to RECIST v1.1. The endpoint was based on confirmed complete or partial responses. The registry also lists secondary outcomes concerning response timing and duration, progression, progression-free survival, time to progression and overall survival. Although the record lists 11 outcome measures, it contains zero analysis entries. Primary response estimates and estimates for the secondary outcomes are not reported in the registry record.

The registry lists a start date of 2012-04 and a primary completion date of 2015-10. The primary endpoint assessment schedule began at baseline, continued every 3 cycles up to 36 months, and then every 6 cycles for participants who remained progression free after 36 months. Further assessments were planned 28 days after end of treatment and every 3 months thereafter, to a maximum of approximately 3.5 years.

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: Due to non-randomized nature of the study (single infusion cohort started enrollment only after separate infusion cohort recruitment was completed) and different baseline characteristics of participants, the comparison between the 2 cohorts was not performed. Hence, the efficacy and safety results for the 2 cohorts should be considered separately.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: ITT population. Only participants with measurable disease at baseline were included in the 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.

Population: Intent-to-treat (ITT) population included all participants enrolled into the study.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Best Overall Response (BOR) as Assessed by Investigator According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), measured over Baseline, every 3 cycles up to 36 months, and every 6 cycles thereafter if progression free after 36 months, 28 days after end of treatment, every 3 months thereafter (maximum up to approximately 3.5 years).

The primary endpoint was the percentage of participants whose best overall response was a confirmed complete response or partial response, as assessed by an investigator using RECIST v1.1. It summarizes whether a participant experienced tumor shrinkage meeting the specified response criteria at some point during assessment. It is a binary outcome at the participant level: each participant either met the confirmed-response definition or did not.

The registry describes how measurable disease was established. Investigators identified target lesions at baseline, measured them, and recorded a baseline sum of diameters. Complete response required disappearance of all target lesions and reduction of nodal short axis to less than 10 mm. Partial response required a decrease of at least 30 percent in the sum of target-lesion diameters relative to baseline. A response had to be confirmed at two consecutive tumor assessments at least 4 weeks apart.

This endpoint is used to give a defined measure of tumor response under a prespecified assessment framework. Requiring confirmation makes the endpoint depend on repeated assessments rather than a single observation. The registry specifies a 95% confidence interval calculated using the Clopper-Pearson approach. However, it does not report the response count, percentage or interval estimate. The endpoint definition is available, but the observed primary result and its precision are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record defines a binary primary endpoint: whether each participant achieved a confirmed complete response or partial response. The primary summary is the percentage of participants meeting either response category. For a binary endpoint, the underlying information is a count of participants meeting the definition and a denominator of participants included in the analysis. Neither the response count nor the resulting percentage is reported in the registry record.

What does the confidence interval describe?

The registry specifies a 95% confidence interval calculated by the Clopper-Pearson approach. In general, a confidence interval expresses uncertainty around an estimated quantity under a stated statistical method. For a response percentage, it communicates how much uncertainty remains about the underlying response frequency given the observed data and the method’s assumptions. It does not guarantee that a particular interval contains the true value, and it does not show whether a result is clinically important.

The Clopper-Pearson method is an exact binomial interval procedure. It is designed for a proportion based on a count of events among a defined number of participants. Its use does not remove uncertainty or compensate for limitations in the study design. Since the registry record contains neither the response count nor the interval limits, the magnitude of the response and the interval’s precision cannot be evaluated from the record.

How was response defined?

Investigators assessed tumors using RECIST v1.1. Target lesions were identified and measured at baseline; the registry describes a maximum of 2 lesions per organ and 5 lesions in total, or pathological nodes with short axis of at least 15 mm. The sum of diameters was based on the longest diameter for non-nodal lesions and the short axis for nodal lesions. Other lesions or disease sites were designated non-target lesions.

A complete response required disappearance of all target lesions and a short-axis reduction to less than 10 mm for nodal target lesions or non-target lesions. A partial response required a decrease of at least 30 percent in the sum of target-lesion diameters, using baseline as the reference. The registry required confirmation at two consecutive tumor assessments at least 4 weeks apart. These rules create an operational definition for the endpoint, but do not tell the reader how many participants met it.

Who was included in the primary analysis?

The registry identifies the ITT population and states that only participants with measurable disease at baseline were included in the primary analysis. This qualification matters because the analysis denominator is not necessarily all enrolled participants. The registry record does not report the number included in the primary response analysis, the number excluded for lack of measurable disease, or how participants with missing assessments were handled. Those details are needed to understand the analysis denominator and the potential effect of missing observations.

What does non-randomized allocation mean?

Randomization is a general method for assigning participants to groups in a way intended to balance both measured and unmeasured characteristics on average. This trial was non-randomized, so that protection does not apply. Group differences in outcomes could be associated with differences in participant characteristics or other factors, rather than the infusion approach itself. Since the registry explicitly says the arms are not a like-for-like control comparison, a direct numerical contrast should be read descriptively rather than as a randomized estimate of causal effect.

The study was open-label, with no masking. In general, knowledge of treatment assignment can affect aspects of care, reporting or assessment. The primary endpoint was investigator-assessed, so lack of masking is relevant when considering possible influences on outcome assessment. The registry record does not report additional procedures intended to limit such influences.

What can be learned from the planning assumptions?

The registry describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between groups and a normal approximation. For binary outcomes, those assumptions are used to illustrate participant requirements per arm for a specified power and effect size. Such calculations are planning aids: they do not show the power actually achieved, and they do not turn an observed estimate into a randomized comparison.

The registry record does not report the trial’s own sample-size justification, and it does not provide a numerical observed effect for interpreting an effect-based planning illustration. Any such illustration should be read as conditional on its assumptions, not as evidence that the study was adequately sized or that an effect was present. The calculation also cannot correct for non-randomized allocation, missing outcome data or differences between the analysis population and enrollment.

What is not reported?

The registry contains zero analysis entries. It does not report the primary response results, outcome-specific estimates for the secondary measures, or a detailed statistical analysis plan. The choice of interval method is stated for the primary endpoint, but the handling of missing data, any multiplicity strategy, any interim analyses and any adjustment for covariates are not reported in the registry record. These omissions limit the ability to reconstruct or evaluate the full analysis from the registry alone.

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("Pertuzumab + Trastuzumab + Vinorelbine: Separate I", "Pertuzumab + Trastuzumab + Vinorelbine: Single Inf")
n      <- c(89, 91)
events <- c(66, 58)
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  Pertuzumab + Trastuzumab + Vinorelbine: Separate I  89  66  74.2  63.8  82.9  64.2  82.1  64.2  82.1
ARM  Pertuzumab + Trastuzumab + Vinorelbine: Single Inf  91  58  63.7  53.0  73.6  53.5  72.9  53.5  72.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary response endpoint and secondary outcomes that include time to response, duration of response, progression, progression-free survival, time to progression, death and overall survival. Testing or estimating multiple outcomes raises a general multiplicity issue: when many statistical questions are considered, the interpretation of individual significance tests may require a plan for controlling or contextualizing the overall error rate. The registry record does not report a multiplicity strategy, an allocation of significance levels across outcomes, or which secondary outcomes were treated as confirmatory rather than descriptive.

The record identifies the primary endpoint’s confidence interval method but contains zero analysis entries. It does not report whether interim analyses were planned or conducted, or whether any formal stopping rules were used. Those details are not reported in the registry record and should not be inferred from the phase or duration of the trial.

The primary analysis population is described as ITT, with only participants who had measurable disease at baseline included. The registry does not give the number of participants in that analysis or explain how missing tumor assessments, incomplete follow-up, or participants without evaluable response information were handled. In general, missing outcomes can affect a percentage estimate if the likelihood of missingness is related to response or participant characteristics. Without the missing-data approach and analysis denominators, that possibility cannot be assessed.

The analysis population wording also leaves a practical distinction between enrollment and endpoint eligibility. The study enrolled 213 participants, but the primary analysis was restricted to those with measurable disease at baseline. The registry does not report the count meeting that restriction. As a result, the enrolled total should not be assumed to be the primary endpoint denominator. The record does not provide enough information to judge the impact of missing or excluded observations on the reported efficacy results, which themselves are not reported.

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: febrile neutropenia (5.7%), pyrexia (5.6%), hypersensitivity (4.7%), pneumonia (3.7%), neutropenia (2.8%).

The safety record lists 106 participants at risk in the Separate Infusion group and 107 in the Single Infusion group. Serious adverse events affected 32 participants in the Separate Infusion group and 44 in the Single Infusion group. Other adverse events affected 103 and 106 participants, respectively. These are group-specific counts as recorded; they should not be interpreted as evidence that one infusion approach caused more or fewer events than the other, because allocation was non-randomized and the arms are not a like-for-like control comparison.

The registry also lists the following serious adverse event terms and percentages: Febrile neutropenia, 5.7%; Pyrexia, 5.6%; Hypersensitivity, 4.7%; Pneumonia, 3.7%; Neutropenia, 2.8%; and Abdominal pain, 1.9%. The record does not clarify in this summary whether these percentages apply to each group separately or to a combined population, so they should not be assigned to a particular group.

The deaths field has no reported count. Deaths are therefore not reported in the registry record. The adverse-event counts are descriptive summaries; the registry record does not provide enough information to infer causation, compare risk under randomized conditions, or determine the timing and duration of the events.

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

The trial record establishes that a phase II study evaluated pertuzumab, trastuzumab and vinorelbine in first-line participants with HER2-positive metastatic or locally advanced breast cancer. It defines an investigator-assessed response endpoint under RECIST v1.1 and describes two infusion-labelled groups. It also records group-level counts of participants affected by serious and other adverse events.

It does not report the primary response percentages, response counts or confidence intervals. It therefore cannot show how frequently participants met the confirmed response definition or how precisely that frequency was estimated. The registry lists secondary outcomes, but their numerical results are also not reported in the registry record. Listing an endpoint is not the same as reporting its result.

The design does not establish a randomized comparison between the groups. Non-randomized allocation can leave group differences that affect outcomes, while open-label conduct and investigator assessment are relevant features when judging the response findings. A contrast between the groups, if available elsewhere, would not by itself establish that an infusion approach caused the contrast.

The safety counts indicate how many participants in each group were recorded as affected, using the registry’s at-risk group sizes. They do not, by themselves, explain why events occurred or establish comparative safety. The listed serious adverse event percentages add descriptive information, but their group attribution is not specified in this summary. Death counts are not reported in the registry record.

Overall, the registry record supports a description of the study question, endpoint definitions, design and selected safety counts. It does not support a conclusion about the size of the observed efficacy effect, its statistical precision, or a causal difference between the two groups. Those limits are important when distinguishing what the trial set out to assess from what its posted record actually reports.

14. Why This Trial Matters Statistically

This trial illustrates why study design and outcome reporting both matter in biostatistical interpretation. A clearly defined endpoint does not, on its own, reveal the result. The registry describes a confirmed response endpoint, its RECIST v1.1 criteria and its confidence interval method, but does not report the response estimate or interval. Readers can understand what would count as a response without being able to determine how often it occurred.

The two-cohort structure also illustrates the limits of non-randomized comparisons. Similar treatment components across groups do not make the groups interchangeable: allocation was not random, and the registry explicitly warns that they are not a like-for-like control comparison. An observed difference, if reported, would need cautious interpretation because group characteristics or other influences could contribute.

The distinction between enrollment and the endpoint population is another statistical consideration. Although 213 participants were enrolled, the primary analysis was restricted to participants with measurable disease at baseline. The analysis denominator and missing-data handling are not reported in the registry record. Without them, the link between enrollment and the response estimate cannot be assessed.

Finally, the record separates outcome definitions from outcome findings. It lists response, progression and survival outcomes, but contains zero analysis entries. The safety record supplies selected event counts, while deaths are not reported. This makes the record useful for understanding the design and the limits of the available evidence, but not for quantifying the primary response result or establishing a comparative treatment effect.

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 most direct limitation of the registry record is that it does not report primary efficacy estimates. No response counts, percentages or confidence interval limits are available, despite the endpoint definition and method being described. Numerical results for the listed secondary outcomes are also not reported in the registry record. This prevents readers from assessing the observed outcome levels or their precision.

The study was non-randomized and open-label. The registry explicitly cautions that the arms are not a like-for-like control comparison. Accordingly, group differences cannot be interpreted as an unbiased causal contrast on the basis of the design described. Investigator assessment of the primary endpoint is also relevant in an unmasked study.

The primary analysis was limited to the ITT population with measurable disease at baseline, but the number meeting that criterion is not reported. The registry does not describe the handling of missing assessments, incomplete follow-up or other exclusions. It also does not report a detailed statistical analysis plan, multiplicity approach, interim analyses, or the trial’s own sample-size justification. These details are not reported in the registry record.

The safety summary has its own limits. It reports affected-participant counts by group and a list of serious adverse event terms with percentages, but the summary does not clarify the group attribution of those percentages. The deaths field contains no count. The posted safety information is therefore descriptive and incomplete for a detailed comparative assessment.

Finally, the record lists an endpoint assessment schedule extending to approximately 3.5 years, but it does not provide the corresponding outcome results or follow-up completeness. The schedule alone cannot establish how much information was collected for each endpoint or how missing observations may have affected analyses.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Assess Efficacy and Safety of Pertuzumab Given in Combination With Trastuzumab and Vinorelbine in Participants With Metastatic or Locally Advanced Human Epidermal Growth Factor Receptor (HER) 2-Positive Breast Cancer — NCT01565083.
• Registry record last updated 2016-11-22; status last verified 2016-09.
• Results first posted 2016-11-22.
• 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

NCT01565083 is a completed, open-label, non-randomized, multicenter phase II trial with a parallel, two-cohort design. It enrolled 213 participants with first-line HER2-positive metastatic or locally advanced breast cancer. The groups were labelled for pertuzumab, trastuzumab and vinorelbine given by separate-infusion or single-infusion approaches.

The primary endpoint was the percentage of participants with confirmed complete or partial response by investigator assessment according to RECIST v1.1, with a 95% confidence interval specified using the Clopper-Pearson approach. The primary analysis was restricted to participants with measurable disease at baseline. The registry lists secondary response, progression and survival outcomes, but contains zero analysis entries and does not report efficacy estimates.

Serious adverse events affected 32 of 106 participants in the Separate Infusion group and 44 of 107 in the Single Infusion group. Other adverse events affected 103 and 106 participants, respectively. The deaths field has no reported count. Because allocation was non-randomized, the groups are not a like-for-like control comparison.