Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy (NCT01198158), a randomized phase 3 study. The primary outcome is Overall Survival (OS).

2. Clinical Question

The trial addressed whether adding bevacizumab to everolimus was associated with a different overall-survival pattern than everolimus alone in this specific treatment setting. It was registered as a randomized phase III study with a parallel-group design and double masking. The registry record lists enrollment of 77.

The posted primary results give a Kaplan-Meier median and 95% confidence interval for each arm, alongside a log-rank comparison. These statistics answer related but distinct questions: the median describes the time by which the estimated survival curve reaches its midpoint, while the log-rank test evaluates evidence of a difference across the observed survival curves. Neither statistic alone describes every feature of the curves or establishes why any difference might occur.

The clinical question is therefore about the comparative survival experience recorded in this trial, not about all patients with kidney cancer or all possible treatment sequences. The registry record does not report the reason the trial was terminated, nor does it report details of the analysis population or the method used to address missing outcome data.

3. Trial Design

This was a randomized, double-masked, parallel-group phase III trial sponsored by the National Cancer Institute. The registry record gives enrollment as 77 and lists a start date of 2010-09-15 and primary completion on 2017-12-15. Its current status is terminated; the reason for termination is not reported in the registry record.

One arm received everolimus alone, described as oral once-daily treatment on days 1-28. The other received the same everolimus regimen together with bevacizumab, administered intravenously over 30-90 minutes on days 1 and 15. These are the registered regimen descriptions; additional information about treatment delivery, adherence, dose changes or discontinuation is not reported in the registry record.

Random allocation is useful because, in expectation, it reduces systematic differences between treatment groups at the start of a study. It does not guarantee that all characteristics will be balanced, particularly in a trial with limited enrollment. Double masking can reduce some influences of treatment knowledge on care and assessment, but the registry record does not describe who was masked or how masking was maintained.

The primary outcome was overall survival, defined from randomization to death due to any cause and assessed up to 5.5 years. The registry also lists progression-free survival, objective response rate and toxicities as secondary outcomes. The record describes Kaplan-Meier estimation for the primary endpoint and reports a log-rank comparison. It does not report the randomization ratio, eligibility criteria in full, planned sample-size justification, interim-analysis procedures, or a detailed statistical analysis plan. Those omissions limit assessment of how the trial was intended to operate beyond the design features explicitly recorded.

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 Overall Survival (OS), measured over The time from date of randomization to date of death due to any cause, assessed up to 5.5 years.

Overall survival measures the time from randomization until death from any cause. Because it includes death regardless of cause, it is a broad endpoint that does not require a judgement about whether a death was related to kidney cancer or treatment. In this trial, the registry record states that overall survival was assessed up to 5.5 years.

The reported summary is the median survival time estimated with the Kaplan-Meier method. The median is the time at which the estimated survival probability reaches its midpoint. It is a compact description of the survival curve, but it does not capture the full curve: two groups can have similar medians while differing at other times, or the same median while having different patterns before or after that point.

The 95% confidence interval communicates uncertainty around each estimated median. A confidence interval is a range of values that reflects the precision of an estimate under the statistical method used; a wider interval indicates less precision. The intervals are not a guarantee that the true value lies within a particular range for this one trial.

The registry record also reports a log-rank test comparing the groups. That test uses information across the follow-up period rather than comparing only the two medians. Overall survival is therefore useful as a time-to-event outcome, while interpretation should consider both the curve-based comparison and the precision of the arm-specific estimates. The registry record does not provide details about censoring or the completeness of follow-up.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Overall survival is a time-to-event outcome: each participant contributes information about how long they were observed before death or the end of their available follow-up. Some participants may not have died by the time their follow-up ends. Their time is still informative up to the last point at which their status is known, after which their survival time is censored. The registry record does not describe the censoring rules or the amount of censoring in this trial.

What does Kaplan-Meier estimation do?

The Kaplan-Meier estimator estimates survival over time while accounting for participants whose observed follow-up ends before death. It updates the estimated probability of remaining alive at observed event times, using the participants still under observation at each time. This makes it suited to outcomes where follow-up lengths can differ. The reported median is obtained from the estimated survival curve, at the point where the curve reaches its midpoint. If the data do not support locating that point, a median may not be estimable; the posted record does report medians for both arms.

The median is an interpretable summary, but it compresses a curve into one value. It does not show the pattern of deaths over the entire follow-up period or indicate whether any difference is concentrated at a particular time. The registry record does not post a hazard ratio for overall survival, so the relative rate of events over time cannot be assessed from a reported hazard ratio in this record.

What do the confidence intervals convey?

A 95% confidence interval describes uncertainty in an estimate under the assumptions of its statistical procedure. In repeated use of the same procedure under the relevant assumptions, intervals constructed this way would cover the underlying value at the stated rate. For an individual trial, the interval is a measure of precision, not a probability statement about where the fixed true value lies. The primary-outcome intervals are broad, indicating that the median estimates are not highly precise.

Each arm's interval concerns that arm's median. It is not the confidence interval for the difference between arms. The registry record does not provide an interval for a treatment contrast in overall survival. Comparing the locations or overlap of the two arm-specific intervals is not a substitute for a formal comparison test, because the uncertainty of a contrast depends on the joint comparison and its method.

What does the log-rank test assess?

The log-rank test compares the observed event pattern between groups across follow-up, taking account of the risk sets at event times. Its p-value summarizes how compatible the observed group separation is with a null model of no difference, under the test's assumptions. It is not an effect-size estimate, and a p-value alone does not tell how large or clinically important a difference might be. The registry reports a log-rank p-value of 0.739 for the primary comparison, but does not report a test statistic or additional comparison details.

The log-rank test is commonly used for time-to-event comparisons. Its interpretation can be affected by the pattern of differences over time; if group effects vary substantially over follow-up, a single summary test may not describe that pattern fully. This is a general statistical consideration, not a claim that such variation occurred in this trial. The registry record does not report an assessment of whether the test's assumptions were met.

How should the secondary binary comparison be read?

Objective response rate is a binary outcome, recording whether a participant met the response definition. The posted arm estimates are percentages with 95% confidence intervals. A recalculated risk difference is an unadjusted comparison based on the posted response counts and group sizes; it is not an adjusted analysis and does not replace a sponsor-reported analysis. No sponsor-reported comparison for this secondary outcome is listed in the registry record.

For binary outcomes, the risk difference expresses the contrast in the probability of the outcome between groups. Confidence intervals around a contrast show the range of effects that remain compatible with the data and method. When the interval includes values on both sides of no difference, the estimate is compatible with a range of possible directions. The posted intervals are wide, so the secondary comparison is imprecise. The recalculated p-value is unadjusted and should not be treated as confirmatory evidence, especially when multiple outcomes are considered.

What does over-dispersion mean in general?

Over-dispersion occurs when observed variability is greater than a statistical model expects. In general, failing to account for it can make standard errors too small and confidence intervals too narrow. The registry results use Kaplan-Meier estimation and a log-rank test for overall survival; the record does not report a model-based count analysis or an assessment of over-dispersion. This general concept therefore does not establish a limitation specific to the posted primary analysis.

The planning illustration associated with the secondary binary comparison is not observed power. It uses the observed effect and stated fractions of that effect under the stated assumptions: a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such figures illustrate how planning requirements can change with the target effect and power; they do not show the probability that this completed trial detected an effect. The registry record does not report that these assumptions were used to design the trial.

10. Analyses Reported by the Sponsor

The primary comparison reported by the sponsor is a log-rank test, with p=0.739. That is the appropriate sponsor-reported inferential result for the registered overall-survival comparison. The registry record also reports Kaplan-Meier medians and 95% confidence intervals by arm. No sponsor-reported hazard ratio or confidence interval for a relative overall-survival effect is listed.

The recalculated comparisons available for the secondary binary outcome are simple, unadjusted calculations from posted summary statistics. They are not a substitute for the sponsor's primary time-to-event analysis and do not provide an adjusted estimate. The registry record lists no sponsor-reported analysis for objective response rate. Accordingly, the recalculation can serve only as a descriptive statistical check of the posted binary summaries, not as evidence that supersedes or extends the sponsor's primary analysis.

The registry record indicates no discrepancy between the posted results and the recalculated results. Even so, the primary endpoint has no recalculated time-to-event contrast in the posted results; the sponsor's log-rank analysis remains the reported inferential comparison. The absence of a reported hazard ratio means that the comparative effect's relative magnitude and precision cannot be fully characterized from the primary results listed in the registry.

For the secondary outcome, the recalculated p-value is unadjusted. It does not account for the consideration of multiple outcomes and should not be read as a planned confirmatory test. The record does not report a multiplicity strategy or a statistical analysis plan that would establish how secondary analyses were intended to support the primary conclusion.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary endpoint and several secondary outcomes, but does not report a multiplicity strategy. When a study examines multiple outcomes or comparisons, the chance of at least one apparently notable result due to chance can increase. Methods such as adjusted significance thresholds or a prespecified testing hierarchy can address that issue, but no such approach is reported in the registry record. The unadjusted secondary comparison should therefore be interpreted as exploratory or descriptive, not as a stand-alone confirmatory finding.

The record does not report interim-analysis procedures. It is not possible to determine whether planned looks at accumulating data occurred, how they might have been accounted for, or whether no interim analyses were planned. Nor does the registry record provide the full statistical analysis plan, so details about model choices, analysis timing, covariate adjustment or sensitivity analyses cannot be established.

Missing-data methods and the completeness of outcome follow-up are also not reported in the registry record. For a time-to-event outcome, participants may be censored when their status is no longer observed, but the record does not specify censoring procedures or describe losses to follow-up. For secondary outcomes, the record does not explain how missing response or safety assessments were handled. These omissions make it harder to assess whether missing information could affect the estimates.

The analysis populations are not reported in the registry record. The primary-outcome arm sizes are listed as 41 and 36, while safety denominators are separately listed for each arm. The record does not explain the relationship between these sets of denominators, or whether analyses followed intention-to-treat, per-protocol or another population definition. The randomized design is reported, but the analysis approach needed to understand how participants were included in each outcome is not specified.

The registry lists enrollment of 77 and status as terminated, but it does not state why the study ended or whether termination changed planned analyses. A sample-size justification and planned target enrollment are not reported. Consequently, the precision and limitations of the posted results can be described, but the adequacy of enrollment relative to the original design cannot be assessed from the registry record.

12. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anemia (24.2%), fatigue (18.4%), creatinine increased (18.2%), hyperglycemia (13.2%), platelet count decreased (12.1%).

The safety record lists serious adverse events among participants at risk: 9 of 38 in the everolimus arm and 11 of 33 in the everolimus-with-bevacizumab arm. It separately lists other adverse events affecting 32 of 38 and 32 of 33 participants, respectively. Deaths are recorded as 33 and 28. These figures are descriptive counts with the denominators recorded for each safety group; they are not estimates of a causal treatment effect.

The record also lists serious adverse-event terms with percentages, including anemia, fatigue, creatinine increased, hyperglycemia, platelet count decreased and hypertriglyceridemia. It does not identify an arm for each listed percentage in the posted terms, so those percentages should not be attributed to a particular group. The adverse-event summary does not provide enough information to compare event timing, duration, severity distribution or attribution between arms.

The safety denominators differ from the primary-outcome group sizes, and the registry record does not explain the difference. The safety figures should therefore be interpreted using their own stated denominators rather than assumed to represent the same analysis population as overall survival. They describe what was recorded, but do not by themselves establish whether an event was caused by treatment or whether the groups differed beyond chance.

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

The posted results describe a randomized comparison of everolimus alone with everolimus plus bevacizumab among patients with advanced renal cell carcinoma after tyrosine kinase inhibitor treatment. The primary outcome is overall survival. The two arm-specific median estimates and the log-rank result summarize the available comparison, while the confidence intervals communicate substantial uncertainty in those estimates.

The log-rank p-value of 0.739 does not indicate a clear separation of the survival curves in this trial. It does not prove the regimens are equivalent, and it does not rule out differences that the available data estimate imprecisely. The registry record does not provide a hazard ratio or a confidence interval for a relative overall-survival effect, so the magnitude of a relative effect cannot be stated from the posted primary results.

The findings apply to the enrolled trial population and the registered regimens. They do not establish results for other kidney cancer populations, other treatment sequences or different dosing approaches. The record's listed conditions and treatment setting define the context; the study does not answer every question about advanced renal cell carcinoma.

The posted secondary information is limited. Objective response is recorded, but its unadjusted comparison is not a substitute for the primary endpoint. Progression-free survival results are not reported in the registry record, and multiplicity procedures are also not reported. The safety counts describe events in their recorded denominators, but do not on their own prove that treatment caused or prevented an event.

Overall, the trial record supports a cautious description: it reports survival estimates and a comparison that do not establish a clear difference, with considerable uncertainty and important analysis details unavailable. It should not be translated into medical advice or a general claim that either regimen works or does not work.

14. Why This Trial Matters Statistically

This trial illustrates why a time-to-event result needs more than a single median. The median offers a direct summary of survival time, but the log-rank test compares the survival experience across follow-up. The confidence intervals show that the arm-specific medians are not precisely estimated, and the absence of a reported hazard ratio leaves an important aspect of the comparative effect unavailable.

It also demonstrates the difference between failing to establish a difference and establishing equivalence. A log-rank p-value of 0.739 does not show that the groups are the same. A study can yield an inconclusive result because the data are compatible with a range of effects; precision and design information are essential when interpreting that uncertainty. Here, the registry record does not report a sample-size justification or the reason for termination, which prevents a fuller assessment of the planned evidentiary strength.

The trial also shows why outcome families need to be read together but not conflated. Overall survival, response, progression-free survival and adverse events describe distinct outcomes. A secondary comparison cannot replace the primary endpoint, especially when the registry record does not report a multiplicity plan and some secondary results are unavailable.

Finally, differences in analysis denominators matter. The survival group sizes and safety denominators are recorded separately, but the registry does not explain their relationship. Careful interpretation requires keeping each outcome tied to its own population and analysis rather than assuming every figure uses the same participants. These are practical lessons in reading trial results, not conclusions about treatment choice.

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 registry record reports a terminated study but does not state the reason for termination. Without that information, it is not possible to judge whether recruitment, follow-up or planned analyses were affected. The record lists enrollment of 77, but provides no planned target or sample-size justification, so the adequacy of enrollment relative to the original design cannot be assessed.

The primary survival estimates have broad confidence intervals, and no hazard ratio or confidence interval for a relative effect is reported. The log-rank p-value supplies a comparison test but not an estimate of effect magnitude. The registry record also does not describe the number or timing of deaths beyond the separately listed safety death counts, which should not be assumed to provide the primary endpoint event information.

Important analysis details are unavailable: the analysis populations, missing-data handling, censoring rules, randomization ratio, interim-analysis procedures and full statistical analysis plan are not reported in the registry record. The record does not explain why the primary-outcome group sizes differ from the safety denominators. These gaps limit assessment of how participants and events entered each analysis.

Secondary evidence is incomplete. The record names progression-free survival but does not report its results, and no sponsor-reported analysis is listed for objective response. The multiplicity approach is not reported, so the inferential status of secondary comparisons is uncertain. Safety terms are listed with percentages, but the record does not identify an arm for each percentage or provide further detail about event timing and attribution.

These are limitations of what the registry record makes available. They should not be mistaken for evidence that a particular method was or was not used, or that a missing result was unfavorable. The reason for each omission is not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Everolimus With or Without Bevacizumab in Treating Patients With Advanced Kidney Cancer That Progressed After First-Line Therapy — NCT01198158.
• Registry record last updated 2019-03-06; status last verified 2019-03.
• Results first posted 2019-03-06.
• 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

NCT01198158 is a randomized, double-masked, parallel-group phase III trial sponsored by the National Cancer Institute. It compared everolimus alone with everolimus plus bevacizumab for advanced renal cell carcinoma progressing after tyrosine kinase inhibitor treatment. The registry lists enrollment of 77, a start date of 2010-09-15, primary completion on 2017-12-15 and status as terminated.

Overall survival was the primary endpoint, defined as time from randomization to death from any cause and assessed up to 5.5 years. The record reports Kaplan-Meier medians with 95% confidence intervals and a log-rank comparison. The sponsor-reported p-value is 0.739; the posted estimates do not establish a clear survival difference, and uncertainty remains substantial.

The registry lists progression-free survival, objective response rate and toxicities as secondary outcomes. Secondary analysis and safety details are incomplete, and key information about multiplicity, missing data, analysis populations and the reason for termination is not reported in the registry record.