Trial of Vinflunine Versus Alkylating Agent in Metastatic Breast Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Trial of Vinflunine Versus Alkylating Agent in Metastatic Breast Cancer (NCT01091168), a randomized phase 3 study. The primary outcome is Overall Survival.

2. Clinical Question

The clinical question concerns a population described as having few therapeutic options after exposure to, or resistance to, several major drug classes. The trial compares vinflunine with an active-treatment comparator rather than with no treatment. Because the comparator could be selected by the physician, the control treatment was not necessarily the same alkylating agent for every participant.

The registry identifies overall survival as the primary endpoint. Disease Control Rate and Progression Free Survival are listed as secondary outcomes. These measures address different aspects of the clinical course: overall survival concerns time to death, while disease control and progression-free survival concern disease status or progression. They should not be treated as interchangeable measures.

3. Trial Design

The registry describes a randomized, phase III, parallel-group trial with no masking. The record reports enrollment of 594 participants and a completed status. The start date is 2009-07, and primary completion is dated 2012-08-27. The registry identifies Pierre Fabre Medicament as the sponsor.

Participants were allocated to vinflunine or an alkylating agent of physician choice. In the vinflunine arm, the described regimen was 280 mg/m² intravenously on day 1 of each cycle, with cycles repeated every 3 weeks. In the comparator arm, the selected alkylating agent was used as a single agent and had to be available at the investigational center and approved for cancer treatment in the country. The registry does not identify a single common alkylating drug for all participants.

The primary endpoint was overall survival in the ITT population, defined as time from randomisation to death or last follow-up. The record states that survival for participants who had not died would be censored at the date of last contact, last follow-up or last news. The primary outcome timeframe is described as baseline up to 3 years 1 month.

Randomization supports a comparison between assigned groups, while the absence of masking means the trial was open-label. The registry record does not report details of the randomization sequence, allocation concealment, stratification factors or masking of outcome assessment. It also does not report the original sample-size justification or the trial's original design assumptions. Those omissions limit how fully the planned design can be reconstructed from the record.

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: ITT population

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 Overall Survival, measured over From baseline up to 3 years 1 month.

Overall survival measures the time from randomisation until death, with follow-up time censored for participants not known to have died by their last contact or follow-up. The registry describes this as the trial's main endpoint and specifies analysis in the ITT population. ITT refers generally to analyzing participants according to their randomized group; the registry record does not give further operational detail about the population beyond naming it.

Overall survival is a time-to-event outcome. It uses information about both whether an event occurred and when it occurred, while allowing participants with incomplete follow-up to contribute information up to their censoring time. General statistical explanation: censoring is a way to represent that the event time is not observed during the available follow-up, rather than treating the last known contact as the event itself.

The endpoint is relevant to a comparison of treatment strategies because death is an event that can be dated. The registry reports median overall survival for each arm and a hazard ratio for the between-arm comparison. A median describes the time by which the estimated survival experience has reached its midpoint; it is not the same quantity as a hazard ratio. The hazard ratio summarizes the relative event rate over follow-up under the model or analysis used. Neither summary, by itself, describes every participant's experience or establishes a causal mechanism.

7. Results Posted in the Registry

• Vinflunine vs Alkylating Agent: hazard ratio 1.04 (95% CI 0.86–1.25), reported p = 0.673 (as reported in the registry).

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Disease Control Rate (DCR)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Alkylating Agent: 35.5% (105/296) versus 43.6% (130/298) on control; risk difference -8.2 percentage points (95% CI -16.0 to -0.3), risk ratio 0.81 (0.67–0.99); unadjusted two-proportion z-test p = 0.042.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Alkylating Agent than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Progression Free Survival (PFS)

• Endpoint type: Time to event: compared as a hazard ratio.
• Test: Hazard ratio as reported by the sponsor (Log Rank); it was not recalculated.
• Result:
  • Vinflunine vs Alkylating Agent: hazard ratio 0.94 (95% CI 0.80–1.12), reported p = 0.493 (as reported in the registry).
• Interpretation:
  • The 95% confidence interval includes no difference (a ratio of 1), so these data do not show a statistically significant difference between Vinflunine vs Alkylating Agent and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes give a mixed pattern rather than a uniform confirmation of the primary result. Disease Control Rate has an unadjusted comparison with p = 0.042, while the Progression Free Survival hazard ratio has a confidence interval that includes 1 and a reported p-value of 0.493. These measures address different outcomes, so a finding in one does not automatically imply a similar finding in another.

Overall survival remains the primary outcome and its reported comparison has p = 0.673. The registry record does not describe a confirmatory hierarchy that would make the secondary outcomes substitutes for the primary result. Their role is therefore supportive or exploratory in interpretation, rather than a basis for replacing the primary endpoint's result.

General statistical explanation: when researchers examine several outcomes, an apparently unusual result can occur even when there is no underlying difference, simply because many comparisons are being made. A multiplicity strategy can control this risk by specifying how evidence across outcomes will be assessed. The registry record does not report such an adjustment or a prespecified testing sequence. The unadjusted Disease Control Rate result should therefore carry less weight than a result from a prespecified, multiplicity-controlled analysis.

The secondary outcomes also differ in measurement and analysis. Disease Control Rate is a percentage outcome, while Progression Free Survival is time-to-event. Their estimates and p-values answer different questions and have different sources of uncertainty. Together they provide context for the overall survival finding, but the record does not support treating them as a single combined measure of benefit.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Disease Control Rate (DCR)
• Progression Free Survival (PFS)

9. Statistical Interpretation

10. Statistical Methods Explained

What does the hazard ratio describe?

The primary comparison is reported as a hazard ratio for vinflunine versus an alkylating agent. General statistical explanation: a hazard is the instantaneous event rate among participants who have not yet had the event, conditional on the analysis framework. A hazard ratio compares those rates across groups over follow-up. It is not a ratio of median survival times, and it does not directly state how much longer an individual participant will live. The reported estimate is 1.04, with a 95% confidence interval of 0.86 to 1.25.

The registry lists the Cochran-Mantel-Haenszel method for the primary reported analysis. The registry record does not describe the precise implementation, any stratification variables, or model diagnostics. The hazard ratio and p-value should therefore be read as the sponsor-reported comparison rather than as a fully reproducible analysis specification.

How should the p-value be read?

The primary p-value is 0.673. General statistical explanation: a p-value measures how incompatible the observed data, or more extreme data, are with a specified null model, assuming that model and the test's assumptions hold. It is not the probability that the null hypothesis is true, and it does not measure the probability that the result arose “by chance.” The p-value should be read alongside the effect estimate and confidence interval, not as a stand-alone verdict.

The primary comparison is labelled as a superiority analysis in the registry. A non-significant superiority test does not demonstrate equivalence or non-inferiority. The registry record does not report a non-inferiority margin or an equivalence margin.

What do the medians and confidence intervals convey?

The reported medians are 9.1 months for vinflunine and 9.3 months for the alkylating agent. Each median is accompanied by a 95% confidence interval. General statistical explanation: a confidence interval represents uncertainty in an estimated quantity under the method used. It is not a range containing a known proportion of individual survival times. The intervals around arm-specific medians answer a different question from the interval around the hazard ratio, which addresses the comparative estimate.

For time-to-event outcomes, follow-up can be incomplete because participants may not experience the event before their last recorded contact. The primary endpoint definition specifies censoring at last contact, last follow-up or last news for participants not known to have died. General statistical explanation: standard time-to-event analyses rely on assumptions about censoring; if censoring is related to future event risk in ways not handled by the analysis, estimates can be affected. The registry record does not report diagnostic assessments of these assumptions.

How do the secondary outcome methods differ?

Disease Control Rate is reported as a percentage with a 95% confidence interval for each arm. A recalculated unadjusted comparison based on the posted summary counts gives a risk difference, with an unadjusted p-value of 0.042. The registry's own analysis reports p = 0.042 using a Log Rank method. These are not identical analysis descriptions or exactly the same p-value, so they should not be treated as the same calculation. The registry record does not explain the Log Rank analysis for this outcome.

Progression Free Survival is a time-to-event outcome. The reported medians are 2.5 months for vinflunine and 1.9 months for the alkylating agent. The reported hazard ratio is 0.94, with a 95% confidence interval of 0.8 to 1.12 and p = 0.493, using the Log Rank method. General statistical explanation: the log-rank test compares event-time patterns between groups while accounting for censoring under its assumptions. The registry record does not provide further detail on the test implementation or assumptions.

Over-dispersion is a general concern when count data vary more than a simple model assumes; it can make standard errors too small if ignored. The posted outcomes are survival and binary percentage measures, and the registry record does not report a count-model analysis or an over-dispersion assessment. Such a concern should not be invoked as an explanation for the posted results without relevant model details.

The record includes no reported adjustment for multiple testing across the primary and secondary outcomes. General statistical explanation: testing several outcomes can increase the chance of at least one apparently unusual result, so secondary p-values are usually interpreted with caution unless a testing strategy is specified. No such strategy is reported in the registry record.

11. Confidence Intervals and Precision

The primary hazard ratio is 1.04, and its 95% confidence interval extends from 0.86 to 1.25. General statistical explanation: the interval describes the range of effect estimates compatible with the data under the analysis method and its assumptions. Because this interval includes 1, it is compatible with no relative hazard difference as well as with values on either side of that reference. The estimate is therefore not precise enough to establish a clear direction of the relative hazard.

The arm-specific median overall survival estimates also have uncertainty: 9.1 months, with a 95% confidence interval of 7.7 to 10.4 months, for vinflunine; and 9.3 months, with a 95% confidence interval of 7.5 to 10.9 months, for the alkylating agent. These intervals quantify uncertainty around each arm's median, not directly around a difference between medians.

The p-value of 0.673 is consistent with the confidence interval's inclusion of the null hazard ratio. Neither the p-value nor the confidence interval proves that the true effect is exactly absent. Conversely, the confidence interval does not show that every value in its range is equally plausible; estimates near the point estimate are generally more compatible with the data under the model than estimates near the limits.

Precision depends on the amount and distribution of information available for analysis, including event occurrence and follow-up. Although the record reports enrollment and arm-level outcome estimates, it does not report the number of deaths used in the primary analysis or detailed follow-up distribution. Those omissions restrict a fuller assessment of how the precision arose.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on the observed effect, not the trial's original design calculations. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The trial's own original sample-size assumptions are not reported in the registry record.

For Disease Control Rate, the figures are participants per arm. The time-to-event planning figures for overall survival and Progression Free Survival are total events, not participants per arm. This difference matters: event targets for survival outcomes are not enrollment targets, because not every participant necessarily contributes an event during follow-up.

The 80% power column describes the planning number associated with an 80% chance of detecting the specified effect under the stated assumptions if that effect is real. The 90% power column uses a higher target chance of detection and consequently requires a larger planning number for the same effect. The rows use 100% of the observed effect, 75% of the observed effect and 50% of the observed effect. Smaller effects need more participants or events to detect under the same assumptions.

These figures are not observed power. They are hypothetical planning quantities calculated from the observed effect and stated assumptions, not evidence about the probability that the completed trial detected an effect. The large event totals in the survival illustrations should not be read as the trial's achieved event counts or as proof that the trial was designed to those targets. The registry record does not report the original design justification.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 1.040, so ln(HR) = 0.0392.
2. d = 4 × (1.96 + 0.842)² / [ln(1.040)]² = 20,409.7, rounded up to 20,410 events in total for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
hr <- 1.04                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(1091168)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 20,410 (80% power), 27,323 (90% power)
 75% of observed effect: events = 36,284 (80% power), 48,574 (90% power)
 50% of observed effect: events = 81,639 (80% power), 109,292 (90% power)
Simulated power with 20,410 events: 0.800 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

14. Analyses Reported by the Sponsor

The primary result is reported by the sponsor as a hazard ratio of 1.04, with a 95% confidence interval of 0.86 to 1.25 and p = 0.673 using the Cochran-Mantel-Haenszel method. The posted analysis does not flag a discrepancy between the sponsor's reported result and the recalculated summary. For time-to-event outcomes, the interpretation uses the sponsor-reported hazard ratio rather than deriving a new hazard ratio from arm-level medians.

For Disease Control Rate, the unadjusted recalculation uses posted group counts and gives an unadjusted p-value of 0.042. The sponsor-reported analysis lists p = 0.042 and a Log Rank method. Because the analysis descriptions differ and the registry record does not explain that method for this outcome, the two values should be distinguished rather than treated as exact reproductions of one another.

Recalculations from summary statistics are limited: they cannot recreate an analysis that depends on participant-level data, censoring patterns, stratification or model details absent from the record. The sponsor's reported methods and estimates remain the direct record of the trial analysis; the unadjusted calculations offer a separate, simpler view of the posted summary data.

15. Multiplicity, Missing Data and Analysis Populations

The registry identifies overall survival as the primary endpoint and lists Disease Control Rate and Progression Free Survival as secondary outcomes. It reports separate analyses, but a multiplicity adjustment, a testing hierarchy, or a strategy for controlling the overall type I error is not reported in the registry record. Without that information, secondary p-values should not be interpreted as if each were an isolated, prespecified confirmatory test.

The primary analysis population is identified as ITT. The registry record does not report detailed rules for population membership, handling of protocol deviations, or whether any additional analysis populations were used. It also does not report the extent or handling of missing endpoint data, withdrawals, or loss to follow-up beyond describing censoring for overall survival. This limits assessment of how missing information may have affected estimates.

For overall survival, participants who had not died were to be censored at last contact, last follow-up or last news. The record does not describe the amount of censoring, whether censoring differed by arm, or checks of censoring assumptions. General statistical explanation: censoring is not inherently a missing event, but interpretation depends on whether the available follow-up is informative about future event risk under the analysis approach.

The registry also does not report interim analyses, stopping rules, a detailed statistical analysis plan, or the original sample-size justification. These omissions do not establish that such plans or procedures were absent; they mean that they are not reported in the registry record. As a result, the published summary supports interpretation of the posted estimates but not a full audit of the study's prespecification or missing-data procedures.

16. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: malignant neoplasm progression (14.8%), neutropenia (2.0%), anaemia (2.0%), vomiting (2.0%), dyspnoea (2.0%).

The serious adverse event summaries report 82 affected participants among 297 at risk in the vinflunine group and 66 affected among 290 at risk in the alkylating-agent group. The record also reports deaths of 276 in the vinflunine group and 274 in the alkylating-agent group. These are descriptive counts; they do not, by themselves, establish that a treatment caused an event or explain the timing and cause of deaths.

For the vinflunine group, the most frequently listed serious term is malignant neoplasm progression at 14.8%. Neutropenia, anaemia, vomiting and dyspnoea are each listed at 2.0%, and constipation at 1.7%. The registry's serious-event listing should be read separately from its broader other-adverse-event counts, which report 197 affected among 297 at risk for vinflunine and 262 among 290 at risk for the alkylating agent.

The registry record does not provide a detailed causal assessment, event timing, exposure-adjusted rates or a complete comparative safety analysis in the registry record reported. The counts therefore describe reported safety experience rather than providing a definitive estimate of comparative risk.

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

The posted primary result describes overall survival in the randomized groups as analyzed in the registry record. The hazard ratio is 1.04, its 95% confidence interval is 0.86 to 1.25, and the reported p-value is 0.673. The estimate is close to the null reference, while the interval includes values on either side. This is not evidence establishing equivalence, and it does not prove that the treatments have identical effects.

The median overall survival estimates are 9.1 months for vinflunine and 9.3 months for the alkylating agent. These arm-specific medians do not capture the full distribution of survival times, and comparing medians alone is not a substitute for the reported time-to-event comparison. The confidence intervals show uncertainty in each median and in the comparative hazard estimate.

The secondary outcomes do not transform the primary result into a definitive conclusion about overall survival. Disease Control Rate has an unadjusted comparison, whereas the Progression Free Survival result has a reported interval that includes 1. Because the record does not report multiplicity control or a confirmatory hierarchy, secondary findings warrant caution.

These results apply to the trial population and comparator strategy described in the registry: patients with metastatic breast cancer previously treated with or resistant to several drug classes, compared with an alkylating agent selected by a physician. The record does not establish how results would apply to other populations, treatment settings or comparator regimens. It also does not establish the causes of observed outcomes or provide individual treatment predictions. Statistical estimates describe uncertainty in group-level comparisons, not certainty about what will happen to a particular patient.

18. Why This Trial Matters Statistically

This trial illustrates why a primary endpoint and its comparative estimate should guide interpretation. The arm-specific medians are easy to read, but the hazard ratio and its confidence interval address the randomized comparison over follow-up. Here, the reported hazard ratio is close to 1 and the interval includes 1, so the data do not provide a precise estimate establishing a directional overall-survival difference.

It also illustrates the distinction between failure to demonstrate superiority and demonstration of equivalence. The registry labels the analysis as superiority, and the primary p-value is 0.673. That result is not a formal equivalence finding; such a conclusion would require a suitable design and margin, which are not reported in the registry record.

The record provides a further lesson in interpreting secondary outcomes. A nominally unusual unadjusted secondary comparison should be considered in light of multiple outcomes and differences in outcome type. Disease Control Rate and Progression Free Survival are not interchangeable with overall survival, and the registry does not report a strategy that assigns confirmatory status to the secondary tests.

Finally, physician choice of alkylating agent creates a comparator strategy that may reflect clinical practice but is not a single uniform drug. Alongside the open-label design, this feature matters when assessing what the comparison represents and how far the results can be generalized. Clear reporting of analysis plans, missing-data handling and multiplicity would help readers assess these issues more fully.

19. 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 comparator is an alkylating agent of physician choice, rather than a single named drug. The registry specifies that the agent was used alone, available at the investigational center and approved for cancer treatment in the country, but does not report which agents were used or how often. This means the comparison is between vinflunine and a physician-choice treatment strategy, not necessarily between vinflunine and one uniform drug.

The trial was randomized but had no masking. Open-label conduct can matter particularly for outcomes involving clinical assessment or decisions, although the registry record does not provide information about outcome-assessor masking. Overall survival is defined through death or censoring, but detailed follow-up patterns and censoring diagnostics are not reported.

The record identifies an ITT primary population but does not give additional detail about analysis-population definitions, missing-data procedures, protocol deviations, or the number of deaths included in the primary analysis. The original sample-size justification and interim-analysis procedures are also not reported in the registry record. The planning illustrations based on observed effects cannot fill those gaps.

The secondary analyses are reported without a described multiplicity strategy, and the Disease Control Rate sponsor analysis is listed with a Log Rank method without further explanation. These reporting gaps limit reconstruction of the complete statistical plan. They do not demonstrate that procedures were not conducted; they limit what can be concluded from the registry record alone.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Trial of Vinflunine Versus Alkylating Agent in Metastatic Breast Cancer — NCT01091168.
• Registry record last updated 2019-09-16; status last verified 2019-08.
• Results first posted 2019-09-16.
• 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.

23. Record Summary

NCT01091168 is a completed randomized phase III parallel-group trial with no masking, comparing intravenous vinflunine with an alkylating agent selected by the physician in metastatic breast cancer after prior treatment with, or resistance to, an anthracycline, a taxane, an antimetabolite and a vinca-alkaloid. The registry reports enrollment of 594 participants.

Overall survival was the primary endpoint in the ITT population. Median overall survival was 9.1 months for vinflunine and 9.3 months for the alkylating agent; the reported hazard ratio was 1.04, with a 95% confidence interval of 0.86 to 1.25 and p = 0.673. Disease Control Rate and Progression Free Survival were secondary outcomes.

The primary comparison does not establish a clear overall-survival difference or equivalence. Interpretation of secondary findings is limited by the absence of a reported multiplicity strategy. The registry record also leaves important design and analysis details, including original sample-size justification and missing-data procedures, unreported.