BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer (NCT02379247), a non-randomized phase 1, phase 2 study. The primary outcome is Phase I: Recommended Phase II Dose (RP2D) of BYL-719 (Alpelisib) + Nab-paclitaxel to be Used in Combination to Treat Advanced HER2-negative Breast Cancer.

2. Clinical Question

The study also listed clinical benefit rate at 16 weeks, pharmacokinetic measures for both drugs, progression-free survival, and overall survival as secondary outcomes. These outcomes address different questions: clinical benefit concerns disease status at a specified time, pharmacokinetics concerns drug exposure, and survival outcomes concern time until events. The registry record does not report results for these secondary outcomes, so the clinical question that can be evaluated from the available record is primarily about the planned dose-finding objective, rather than an estimate of comparative efficacy.

3. Trial Design

The registry describes a completed Phase I/II study with non-randomized allocation, no masking, and a single-group model. Enrollment was 43. The trial evaluated BYL-719 (alpelisib) together with nab-paclitaxel in locally recurrent or metastatic HER-2 negative breast cancer. Because there was no randomized control group, the dose groups should not be read as treatment and control arms in a like-for-like comparison.

Phase I was described as a 3+3 dose-escalation design across alpelisib dose levels of 250mg, 300mg, and 350mg, given orally once daily continuously. Nab-paclitaxel was listed as 100mg/m2 intravenously on days 1, 8, and 15 of each 28 day cycle, with a window of +/- 1 day. Dose-limiting toxicities were assessed during the first treatment cycle. The registry description says escalation would stop if two or more of six patients experienced a dose-limiting toxicity, and defines the recommended Phase II dose as the next lower dose at which <1/6 subjects experienced a dose-limiting toxicity.

A dose-expansion group received the Phase I recommended Phase II dose of alpelisib with nab-paclitaxel. The actual selected dose is not reported in the registry record. The record lists a primary endpoint timeframe of 12 months, while the design description places dose-limiting toxicity assessment in the first treatment cycle; it does not clarify how these time references relate. The start date was 2015-02, primary completion was 2017-09-21, and status is completed.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Phase I: Recommended Phase II Dose (RP2D) of BYL-719 (Alpelisib) + Nab-paclitaxel to be Used in Combination to Treat Advanced HER2-negative Breast Cancer, measured over 12 months.

The primary endpoint is the recommended Phase II dose (RP2D) of BYL-719 (alpelisib) combined with nab-paclitaxel, expressed in mg. This is a dose-selection endpoint rather than a direct measure of tumor response or survival. Its purpose in a dose-escalation study is to identify a dose for further study using the dose-limiting toxicity information gathered during escalation.

In the registry description, dose-limiting toxicities were assessed during the first treatment cycle. The planned escalation used three alpelisib dose levels, and the description gives a rule for stopping escalation and selecting the next lower dose. These are the design rules, not reported findings. The registry record does not state the selected recommended Phase II dose or provide the dose-limiting toxicity observations used to determine it. Thus, although the endpoint is named and its unit is specified, its observed value cannot be interpreted from the record.

The registry lists a timeframe of 12 months for the primary endpoint. It does not explain the connection between that timeframe and the first-cycle dose-limiting toxicity assessment. A dose recommendation can guide a later study's dose choice, but by itself it is not evidence of comparative benefit, and it does not quantify clinical benefit rate, progression-free survival, or overall survival.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The key methodological distinction is between the study's planned dose-finding procedure and a reported statistical result. The registry describes a Phase I 3+3 dose-escalation design, but does not report the dose-limiting toxicity observations or the recommended Phase II dose obtained from them. A design rule specifies how investigators intend to make a decision; it is not the decision itself.

What does a 3+3 dose-escalation design do?

As a general explanation, a 3+3 design examines successive dose levels in small groups, with decisions guided by observed dose-limiting toxicities. The registry describes three alpelisib levels: 250mg, 300mg, and 350mg. It states that toxicities were assessed during the first treatment cycle and that escalation would cease if two or more of six patients experienced a dose-limiting toxicity. It defines the recommended Phase II dose as the next lower dose at which <1/6 subjects experienced a dose-limiting toxicity. These rules indicate how the design uses early safety observations to inform dose selection. The registry does not give the observations, the dose at which escalation stopped, or the resulting recommended dose.

In general, a dose-escalation rule is not the same as an estimate of treatment effect. It is designed to guide dose selection based on observed tolerability under the study conditions. It does not, on its own, estimate how the combination compares with another treatment or establish clinical benefit. The lack of a randomized control group is especially important when considering comparisons across the dose levels: dose cohorts occur within a sequential dose-finding design and are not described as randomized groups.

How should the endpoint timeframe be read?

The primary endpoint is expressed as a dose in mg and is described as the recommended Phase II dose. The registry lists its timeframe as 12 months, while its design description says dose-limiting toxicities were assessed during the first treatment cycle. Those two pieces of information refer to different time specifications, and the record does not explain their relationship. It would be inappropriate to infer a more detailed schedule or endpoint calculation than the registry states.

In general, a timeframe identifies the period in which an outcome is assessed or collected. A timeframe does not itself provide the outcome value. Here, the record names the endpoint and gives a timeframe, but does not state the selected dose. Therefore the dose-selection result cannot be evaluated from this record.

What can confidence intervals and statistical tests add?

In general, a confidence interval describes the statistical uncertainty around an estimated quantity under the model used to calculate it. A narrower interval indicates greater precision for that estimate, while a wider interval indicates less precision. A significance test addresses compatibility between observed data and a specified null hypothesis under its assumptions. Neither tool supplies information that is absent from the underlying reported result.

The registry has zero analysis entries and does not report confidence intervals, p-values, or outcome estimates for the listed endpoints. No inferential conclusion can therefore be drawn from such measures for this record. The absence of an analysis entry does not establish that no analysis was performed outside the registry; it means that statistical analysis results are not reported in the registry record.

Why does over-dispersion matter for count outcomes?

In general, count outcomes can vary more than a simple model expects. This is called over-dispersion. If a model assumes less variability than the data contain, standard errors can be too small and confidence intervals can be too narrow. Analysts may use methods that allow additional variability when the outcome and study design support them. The registry record does not report a model for count outcomes or an over-dispersion adjustment, and the named primary endpoint is a dose value rather than a count endpoint. No claim about a particular count model is warranted.

How do planning illustrations differ from trial results?

In general, sample-size calculations use assumptions about an effect, variability, allocation, and a target error rate to illustrate the amount of information a future study might need. Such calculations are planning tools; they are not observed power and do not change what the study actually found. The record describes planning illustrations based on a stated fraction of an observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also distinguishes total event counts for time-to-event illustrations from participants per arm for other outcomes.

Those assumptions describe illustrations, not this study's design: the trial itself is recorded as single-group and non-randomized. The registry does not report numerical planning outputs in the trial details. Such planning assumptions should not be interpreted as an analysis of the dose-finding endpoint or as evidence that a particular treatment effect was demonstrated.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists several secondary outcomes alongside the primary dose-selection endpoint: clinical benefit rate at 16 weeks, pharmacokinetics of BYL-719 and nab-paclitaxel when administered together, progression-free survival, and overall survival. Testing or estimating multiple outcomes can raise multiplicity concerns, because repeated statistical testing can increase the chance of at least one apparently unusual result. In general, an analysis plan may address this by defining a primary outcome, ordering tests, or adjusting inference. The registry record does not report whether any multiplicity strategy was planned or used.

Missing-data procedures and analysis populations are also not reported in the registry record. The record does not state how participants with incomplete endpoint information, treatment discontinuation, or incomplete follow-up were handled. It does not identify an intention-to-treat, per-protocol, safety, or other analysis population for outcome results. The adverse-event summaries do include at-risk counts by group, but those counts alone do not explain how the analysis population was defined or how missing observations were treated.

For the listed time-to-event outcomes, the record does not report the statistical method, censoring rules, or handling of incomplete follow-up. These details matter in general because survival estimates depend on how event times and censoring are defined. No assumptions about those procedures can be made from the outcome names alone. Since statistical analyses and endpoint results are not reported in the registry record, the uncertainty introduced by missing information cannot be assessed from this record.

11. 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 non-serious adverse event terms

The registry presents serious adverse events, other adverse events, and deaths separately for each listed group. For serious adverse events, the at-risk and affected counts are 3 and 0 in the 250mg dose group, 3 and 0 in the 300mg dose group, 7 and 0 in the 350mg dose group, and 30 and 0 in the dose-expansion group. For other adverse events, the corresponding counts are 3 and 3, 3 and 3, 7 and 7, and 30 and 28. Death counts are 3, 3, 5, and 19 in those groups, respectively.

These figures are counts, not explanations of causation. The registry does not list serious-event terms, death causes, timing, duration, or attribution to treatment. It also does not establish from these counts whether an event occurred before, during, or after treatment. The absence of affected participants in the serious adverse-event column should be read as the recorded count for that category, not as proof that no safety concerns occurred in any broader sense.

The groups are not randomized comparison arms, and their sizes differ. It is therefore not appropriate to treat the counts as a controlled comparison of safety between doses. The counts describe what the registry records for each group; they do not by themselves establish comparative risk or treatment causality.

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

The record establishes that the study was completed, was designed as a non-randomized Phase I/II study, and investigated alpelisib with nab-paclitaxel in locally recurrent or metastatic HER-2 negative breast cancer. It identifies a Phase I dose-escalation objective and describes a dose-selection rule based on dose-limiting toxicity assessment during the first treatment cycle. These details explain the study's intended question and structure.

The record does not report the recommended Phase II dose, the dose-limiting toxicity observations, or numerical results for the listed secondary outcomes. It consequently does not permit a reader to assess the reported primary endpoint value or quantify clinical benefit, pharmacokinetics, progression-free survival, or overall survival. Nor does it provide confidence intervals or statistical tests for those outcomes. The adverse-event counts are available, but without event details or attribution they cannot establish the cause of events or deaths.

In general, a single-group, non-randomized study can describe outcomes observed among its participants under the recorded treatment conditions. It cannot make the same direct treatment-versus-control comparison as a randomized study, because no control group was included. In this study, there is also no reported endpoint estimate from which to describe an outcome's magnitude or precision. Completion and enrollment do not fill that gap.

The defensible interpretation is therefore limited: the registry describes the planned dose-finding method and records safety counts by group, but it does not report the primary dose-selection result or secondary outcome results. This is a statement about the information in the registry record, not a conclusion that the study did or did not produce findings outside that record.

13. Why This Trial Matters Statistically

This study is statistically instructive because its primary question is dose selection, not a conventional randomized comparison of efficacy. The registry describes a 3+3 escalation strategy and a rule based on dose-limiting toxicities. Understanding that design helps distinguish a decision procedure from an effect estimate: identifying a dose to take forward is not the same as showing a comparative treatment benefit.

The record also illustrates why design labels matter. A single-group, non-randomized study has no control arm for a direct treatment contrast. Its dose groups arose within dose escalation and expansion, rather than through randomized allocation. Any difference across those groups would need careful interpretation even if outcome estimates were available. Here, the registry does not report those estimates or the recommended Phase II dose, so neither the dose choice nor the precision of that choice can be assessed.

Finally, the trial demonstrates that completion, enrollment, and detailed intervention descriptions are not substitutes for outcome reporting. The registry includes clinically relevant secondary outcome names and group-level safety counts, but not statistical analyses of the primary or secondary endpoints. Clear reporting of endpoint values, analysis populations, methods, and uncertainty is necessary for readers to judge what a study's data support. The distinction between recorded details and unreported results is central to interpreting this trial statistically.

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 most important trial-specific limitation for interpreting the registry record is that it does not report the primary endpoint value: the recommended Phase II dose. It also does not provide the dose-limiting toxicity observations underlying the dose-escalation decision. The design rule can be described, but whether and how it led to a dose recommendation cannot be checked from the record.

The study is non-randomized and single-group, with no separate control group. Its dose levels and dose-expansion group therefore do not provide a randomized, like-for-like comparison. The record does not report statistical results for the listed secondary outcomes, including clinical benefit rate, pharmacokinetics, progression-free survival, and overall survival. It also does not report confidence intervals, outcome analysis methods, multiplicity procedures, missing-data handling, or analysis populations.

Safety interpretation is limited by the absence of serious-event terms, causes of death, timing, and treatment attribution. The registry gives group counts, but does not supply the context needed to determine whether events were related to treatment or how they occurred over follow-up.

The primary endpoint timeframe is listed as 12 months, whereas the endpoint description says dose-limiting toxicities were assessed during the first treatment cycle. The record does not explain how these time references fit together. These limitations concern what can be concluded from the registry record; they do not establish what information may be available elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: BYL719 and Nab-Paclitaxel in Locally Recurrent or Metastatic HER-2 Negative Breast Cancer — NCT02379247.
• Registry record last updated 2022-06-07; status last verified 2022-05.
• Results first posted 2021-09-28.
• 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.

18. Record Summary

NCT02379247 is recorded as a completed Phase I/II, non-randomized, single-group study of BYL-719 (alpelisib) with nab-paclitaxel in locally recurrent or metastatic HER-2 negative breast cancer. Enrollment was 43. Phase I used alpelisib dose levels of 250mg, 300mg, and 350mg, followed by a dose-expansion group using the Phase I recommended Phase II dose.

The primary endpoint was the recommended Phase II dose, expressed in mg. The registry describes dose-limiting toxicity assessment and a 3+3 escalation rule, but the recommended dose and toxicity observations are not reported in the registry record. Secondary outcomes included clinical benefit rate, pharmacokinetics, progression-free survival, and overall survival; their results are also not reported. The record contains safety counts by group but does not provide event terms, causes of death, or treatment attribution.