Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients (NCT00418886), a randomized phase 3 study. The primary outcome is Progression-Free Survival (PFS) in the Overall Population.

2. Clinical Question

The registry describes the study as an investigation of whether adding vandetanib to pemetrexed was more effective than pemetrexed alone. Its stated rationale was that vandetanib inhibits VEGFR and EGFR signalling; the registry summary presents blocking tumour blood supply and cancer-cell division as the proposed rationale for studying the drug. These are explanations of the study rationale, not findings established by the posted outcome figures.

The main statistical question concerns time to progression or qualifying death, rather than response alone. The registry also lists overall survival, objective response, disease control, response duration, and symptom-related outcomes among the secondary outcomes. The reported results therefore address several different aspects of disease and symptoms, but the registry record does not provide results for every listed outcome.

3. Trial Design

This was a phase III, randomized, double-blinded, parallel-group, multi-centre study. The registry labels masking as quadruple; it does not identify which roles were masked. The comparison was between vandetanib plus pemetrexed and placebo plus pemetrexed, so both groups received pemetrexed and the randomized contrast concerned adding vandetanib rather than replacing pemetrexed.

The registry lists enrollment as 698 and status as completed. The recorded study start is 2007-01 and the primary completion is 2008-09. These dates describe the registry record and do not, on their own, explain the timing or completeness of follow-up for each outcome. The primary endpoint’s assessment schedule is described as RECIST tumour assessments every 6 weeks (+/- 3 days) from randomization until objective progression.

The primary endpoint population is defined as the full analysis set, including all randomized participants. The posted arm-specific endpoint figures list 256.0 participants for vandetanib plus pemetrexed and 278.0 for placebo plus pemetrexed. The registry does not explain how the arm figures relate to the enrollment figure, or whether endpoint availability differed by participant. Details of randomization procedures, allocation concealment, treatment adherence, and the specific people included in the masking designation are not reported in the registry record.

The study title and summary focus on patients with locally advanced or metastatic non-small cell lung cancer, and the title describes a second-line setting. The registry lists non-small cell lung cancer and lung cancer as conditions. It does not report further eligibility details in the information used for these results, so the degree to which participants represented particular clinical subgroups cannot be assessed from this record alone.

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: A total of 534 participants were randomized in the study.

Randomized Period

Reasons for not completing this period:

Survival Follow-up Period

Analysis population for the primary outcome, as defined in the registry: The full analysis set included all randomized participants.

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: The full analysis set included all randomized participants.

6. Primary Endpoint

The registry lists the primary outcome as Progression-Free Survival (PFS) in the Overall Population, measured over RECIST tumour assessments carried out every 6 weeks (+/- 3 days) from randomization until objective progression.

The primary endpoint was progression-free survival in the overall population, reported as a median time in weeks. It measures the time from randomization until objective disease progression or death from any cause in the absence of objective progression, provided that death occurred within 3 months from the last evaluable RECIST assessment. Tumour assessments were scheduled every 6 weeks (+/- 3 days) from randomization until objective progression.

Time-to-event outcomes are used when the question concerns how long participants remain free of a defined event. A median gives the point in the observed time-to-event distribution at which half of the relevant event-time experience lies on either side; it does not describe every participant’s course or the average duration. This is a general explanation of the statistic. The registry reports a 95% confidence interval for each arm’s median, which conveys uncertainty around that arm-specific estimate.

Progression-free survival combines progression and qualifying death into one endpoint. It is not the same outcome as overall survival, which the registry lists separately as a secondary outcome. The endpoint definition also makes death eligibility depend on timing relative to the last evaluable RECIST assessment. The registry does not provide event counts, a hazard ratio, or a sponsor-reported inferential comparison for this primary endpoint in the posted results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Progression-free survival is a time-to-event endpoint. Each participant’s relevant time begins at randomization and ends at the first event that meets the endpoint definition. In this study, an event was objective disease progression or death from any cause without objective progression, subject to the requirement that death be within 3 months from the last evaluable RECIST assessment. This combines two kinds of events under one endpoint rule. It does not mean that progression and death are interchangeable clinical outcomes; it means the analysis treats either qualifying event as the endpoint event.

What does the median represent?

The median is a location measure for the event-time distribution. It identifies the time by which half of the event-time distribution has occurred, under the analysis used. It is not an arithmetic average, and it does not state how long any particular participant remained progression-free. In time-to-event analyses, some participants may not have had a recorded event by the end of their available observation. Their data are generally handled through censoring methods, but the registry record does not describe the censoring rules or the analysis used to obtain these medians. That explanation of censoring is general statistical background.

The reported medians are 17.6 weeks for vandetanib plus pemetrexed and 11.9 weeks for placebo plus pemetrexed. Each is accompanied by a 95% confidence interval: 13.4 to 18.9 weeks and 11.4 to 15.9 weeks, respectively. A confidence interval conveys uncertainty about an estimate under the assumptions of its method. It is not a range expected to contain every participant’s progression-free time, nor does it provide a direct confidence interval for the difference between arms.

Why is a direct comparison not reconstructed from the medians?

A time-to-event comparison usually uses the distribution of event times and information about censoring across follow-up. The two arm medians alone do not retain all of that information. A hazard ratio, for example, is a comparative summary based on event experience over time and has its own assumptions and interpretation. The registry record does not post a sponsor-reported hazard ratio or other inferential comparison for the primary endpoint. No recalculated comparison is presented for this median-time endpoint because the record’s posted summary statistics do not support one. A comparison based only on the two medians would not be a substitute for the sponsor’s analysis.

Confidence intervals for separate arms also should not be used as a shortcut for a formal between-arm test. Their overlap is not itself a p-value or a confidence interval for a treatment contrast. The posted intervals describe the arm-specific median estimates. Without a reported comparative analysis, readers cannot determine from these figures alone the precision of the contrast under the trial’s analysis plan.

What do the secondary comparisons add?

For the binary secondary outcomes, recalculated risk differences compare the proportions in the two groups using the posted participant counts and response counts. The risk difference is an absolute contrast in proportions. Recalculated relative risks and odds ratios are also listed for those comparisons, but they describe relative rather than absolute contrasts. For the symptom score, the posted least-squares means and standard errors are accompanied by a recalculated mean difference and an approximate confidence interval. These secondary comparisons are explicitly unadjusted recalculations from posted summary statistics; they are not a substitute for the sponsor’s own analyses, which take precedence when available. The registry reports no sponsor analyses for these outcomes.

Unadjusted p-values address each comparison separately. When several outcomes are examined, the chance of obtaining at least one apparently unusual result can rise if no multiplicity approach is applied. Whether an adjustment was planned or used is not reported in the registry record. Therefore the recalculated secondary p-values should not be read as if they were adjusted for all the outcomes or analyses considered in the study.

How should planning illustrations be read?

The posted sample-size illustrations are hypothetical planning calculations based on the observed effects, not the trial’s own design calculations and not observed power. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation; the planning target is a stated fraction of the observed effect. The binary-outcome and symptom-score illustrations give participants per arm for 80% or 90% power under those assumptions. They show how planning requirements would vary if a future study targeted the full observed effect or a smaller fraction of it. They do not establish that the trial was adequately powered, and they do not account for all possible design features.

No comparable planning illustration is available for the primary time-to-event endpoint in the posted results. The record does not report the assumptions used to design the original study, any interim analyses, or the sponsor’s statistical analysis plan. Those items should not be inferred from the endpoint estimates or the secondary planning illustrations.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists multiple secondary outcomes, including overall survival, response, disease control, response duration, symptom deterioration, and longitudinal symptom measures. It also reports more than one safety period. The record does not state how the study handled multiplicity across outcomes, time points, or analyses. It does not report whether any secondary outcome was designated as confirmatory or whether a hierarchy of testing was used. These details are not reported in the registry record and should not be inferred from the order in which outcomes are listed.

The recalculated p-values for objective response, disease control, and the longitudinal symptom score are unadjusted. Each addresses its own comparison, rather than controlling the chance of false-positive findings across the family of outcomes. This is a general statistical distinction. Their interpretation therefore depends on the broader analysis plan, which is not reported. The posted results also list no sponsor-reported analyses for these secondary endpoints.

The primary endpoint population is described as the full analysis set, including all randomized participants. However, the registry does not provide a detailed account of the analysis population used for each secondary endpoint, missing outcome data, exclusions after randomization, or imputation methods. The primary endpoint’s death rule is stated, but handling of other incomplete or unevaluable RECIST assessments is not described. Assessment frequency is specified as every 6 weeks (+/- 3 days), but actual adherence to that schedule is not reported.

These omissions prevent a detailed assessment of whether missingness could have affected the estimates or whether analyses followed a prespecified plan. They do not show that missing data or multiplicity problems occurred; they mean that the registry record does not provide the information needed to evaluate those issues. Interim-analysis procedures, stopping rules, and the statistical analysis plan are likewise not reported in the registry 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (3.7%), dyspnoea (3.7%), pyrexia (2.7%), anaemia (2.6%), vomiting (2.2%).

The registry reports serious adverse events and other adverse events for the randomized period and for a separate survival follow-up period. During the randomized period, serious adverse events affected 84 of 260 participants in the vandetanib plus pemetrexed group and 94 of 273 in the placebo plus pemetrexed group. The corresponding counts for other adverse events were 234 of 260 and 242 of 273. During survival follow-up, serious adverse events affected 7 of 124 and 3 of 110, while other adverse events affected 22 of 124 and 19 of 110, respectively. Deaths are also listed by group and period.

These period-specific figures should be read separately. The registry record does not explain whether participants could contribute to both periods or how the safety observation windows were defined beyond their labels, so the counts should not be combined. The listed serious-event terms include pneumonia and dyspnoea at 3.7% each, pyrexia at 2.7%, anaemia at 2.6%, and vomiting and fatigue at 2.2% each. The registry does not report a causal assessment for these terms. Counts and percentages describe reported events; they do not by themselves establish that a treatment caused an event or provide a complete comparative safety analysis.

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

The posted results answer part of the study’s comparative question by giving arm-specific median progression-free survival estimates and confidence intervals. They also give selected secondary outcome values and period-specific adverse-event counts. They do not provide a sponsor-reported comparative statistic for the primary endpoint, such as a hazard ratio, or a reported inferential test for that endpoint. The medians alone therefore do not provide a complete statistical comparison.

The registry reports a randomized comparison, but the figures should be interpreted in the context of what is and is not documented. The primary population is defined, and the endpoint rule is described, yet details about the primary analysis method, censoring, missing data, and the original statistical plan are not reported. The record also does not report numerical results for every listed secondary outcome. These gaps limit what can be concluded from the registry results about the consistency and precision of the overall evidence.

The secondary results concern distinct questions. Response and disease control describe categorical tumour outcomes, whereas the symptom score reflects a different type of measure. The unadjusted recalculations are not equivalent to a complete sponsor analysis or a multiplicity-adjusted assessment. Safety counts likewise describe event reporting over separate periods and should not be interpreted as causal effects without further analysis.

These results do not establish that vandetanib caused any observed difference, nor do they demonstrate that the combination does or does not work. They are a record of particular estimates and event counts in this study, accompanied by limited information about the analyses that produced them. Interpretation should remain tied to those specific measures and to the uncertainty and reporting limitations.

13. Why This Trial Matters Statistically

This trial is statistically informative because it uses a randomized, masked, parallel-group comparison in which both groups received pemetrexed and the added treatment differed. That design makes the between-group contrast the central quantity of interest. The primary endpoint is time-to-event, which can incorporate event timing rather than reducing follow-up to a simple event proportion. These design features clarify the question the study set out to address.

At the same time, the registry illustrates why endpoint estimates and comparative evidence are not interchangeable. Arm-specific medians with confidence intervals describe each group, but they do not provide the same information as a reported time-to-event contrast. The absence of a posted hazard ratio or other sponsor-reported primary comparison leaves an important part of the inferential picture unavailable in this record. Readers should distinguish the available descriptive estimates from a complete analysis of the primary question.

The registry also includes several types of secondary outcomes, from response and disease control to symptom measures and safety events. Their variety makes it important to consider multiplicity and the outcome-specific analysis methods. The posted unadjusted recalculations are useful descriptive comparisons, but they cannot stand in for a prespecified analysis plan or adjustment strategy. The trial therefore highlights the value of reporting analysis populations, missing-data procedures, censoring, endpoint comparisons, and multiplicity methods alongside outcome estimates.

Finally, the planning illustrations based on observed effects show why sample-size calculations must be interpreted as conditional design scenarios rather than evidence of the study’s power. They do not reveal the original design assumptions. Separating design information, observed results, and post hoc planning illustrations is essential for a transparent statistical reading.

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 registry record leaves several trial-specific uncertainties. Although it describes a quadruple-masked study, it does not identify which participants, investigators, assessors, or other roles were masked. It does not provide details of the randomization method or allocation concealment. These omissions limit assessment of how the design was implemented, even though the study is labeled randomized and masked.

For the primary endpoint, the record gives arm-specific medians and confidence intervals but no event counts, hazard ratio, p-value, or sponsor-reported comparative analysis. It does not describe censoring rules, the statistical method used to estimate medians, or the handling of unevaluable scans and other missing data. The endpoint definition specifies a timing condition for deaths without objective progression, but the record does not explain how that rule was operationalized in the analysis.

The registry lists several secondary outcomes, while numerical results are posted for only selected measures. It does not report results for overall survival, duration of response, the listed symptom-deterioration outcomes, or every longitudinal symptom analysis. The available secondary comparisons are unadjusted recalculations, and a multiplicity strategy is not reported. Their methods and missing-data handling are also not detailed.

Safety information is separated into randomized and survival follow-up periods, but the record does not provide enough detail to establish how observation windows overlap or how events were attributed. The listed event counts should therefore remain period-specific. Finally, the original sample-size assumptions, interim analyses, stopping rules, and statistical analysis plan are not reported. These limitations identify what cannot be evaluated from the registry record; they do not establish that the unreported procedures were inadequate.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Efficacy Study Comparing ZD6474 in Combination With Pemetrexed and Pemetrexed Alone in 2nd Line NSCLC Patients — NCT00418886.
• Registry record last updated 2024-12-31; status last verified 2024-12.
• Results first posted 2012-03-26.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT00418886 is a completed phase III randomized, quadruple-masked, parallel-group study of vandetanib plus pemetrexed versus placebo plus pemetrexed in locally advanced or metastatic non-small cell lung cancer. The registry lists enrollment as 698, with a study start of 2007-01 and primary completion of 2008-09.

The primary outcome was median progression-free survival in the overall population. The posted medians were 17.6 weeks for vandetanib plus pemetrexed and 11.9 weeks for placebo plus pemetrexed, with arm-specific 95% confidence intervals. A sponsor-reported comparative analysis for this primary endpoint is not reported in the registry record.

Selected secondary results include objective response, disease control, and a longitudinal symptom score. Their recalculated comparisons are unadjusted. The record also reports adverse-event counts for the randomized and survival follow-up periods. Analysis-plan, missing-data, and multiplicity details are not reported in the registry record.