This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Trial of Poor Performance Status Patients (ToPPS) (NCT00892710), a randomized phase 2 study. The primary outcome is Progression Free Survival (PFS).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00892710 |
| Phase | Phase 2 |
| Condition | Non Small Cell Lung Cancer |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 172 |
| Arms in the primary outcome | 3 |
| Lead sponsor | SCRI Development Innovations, LLC |
| Results posted | Yes |
2. Clinical Question
Population
Patients with stage IIIB/IV non-small-cell lung cancer and ECOG performance status 2 who had not previously been treated. The primary endpoint description says the analysis includes all enrolled patients, whether or not they received treatment.
Intervention
Two pemetrexed-based combination regimens were evaluated: pemetrexed with bevacizumab, and pemetrexed with bevacizumab and carboplatin. The registry lists the dosing schedules for these arms.
Comparator
Pemetrexed alone was the reference arm. The trial was randomized, open label, and used a parallel-group design.
Primary question
How did median progression-free survival compare across the three regimens? Progression-free survival was defined in relation to time from first protocol treatment until disease worsening under RECIST v1.0 criteria.
The central statistical question is descriptive as well as comparative: what median progression-free survival and associated uncertainty were recorded for each randomized treatment group? The posted medians are 2.8 months for pemetrexed, 4.0 months for pemetrexed/bevacizumab, and 4.8 months for pemetrexed/bevacizumab/carboplatin. Their 95% confidence intervals are 1.5 to 4.1 months, 2.6 to 6.0 months, and 3.1 to 6.5 months, respectively.
Those estimates concern a specific clinical population: patients with advanced non-small-cell lung cancer and performance status 2 who were previously untreated. They should not automatically be generalized to patients with other performance status, disease stages, or treatment histories. The record identifies the trial as phase II and randomized, but does not report a formal comparative estimate for the primary endpoint. A difference in the posted arm medians is not, by itself, a randomized comparison with a confidence interval or test statistic.
3. Trial Design
ToPPS was a randomized phase II trial with a parallel-group design and no masking. The registry reports an enrollment of 172 participants and a completed status. The trial dates recorded are a start in 2009-06 and primary completion in 2014-07. Its purpose was to evaluate three treatment regimens in previously untreated patients with stage IIIB/IV non-small-cell lung cancer and performance status 2.
The pemetrexed arm received pemetrexed 500 mg/m2 intravenously over 10 minutes every 21 days. The pemetrexed/bevacizumab arm added bevacizumab 15 mg/kg intravenously every 21 days. The three-drug arm also included carboplatin AUC=5 intravenously every 21 days. The registry describes these arms and doses; other treatment delivery details are not reported in the registry record.
The primary endpoint was progression-free survival, expressed as a median in months, with a 95% confidence interval. The primary endpoint timeframe is recorded as 18 months. The endpoint description specifies a population including all enrolled patients whether or not they received treatment. The arm-level primary results list 48 participants for pemetrexed, 63 for pemetrexed/bevacizumab, and 61 for the three-drug regimen.
Other listed outcomes include overall response rate, time to progression, time to treatment failure, overall survival, and 6-month and 12-month overall survival probability. The registry names these outcomes, but detailed results are not reported in the registry record except for response counts. The rationale for the enrollment target, the randomization procedure, stratification factors, and the planned statistical analysis are not reported in the registry record. The record also does not describe whether interim analyses were planned or conducted.
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: 10 patients were enrolled/randomized, but never treated due to their reqeust, physician's request or if they were deemed ineligible. 4 of these patients were on the Pemetrexed/Bevacizumab arm and 6 were on the Pemetrexed/Bevacizumab/Carboplatin arm
Overall Study
| Stage | Pemetrexed | Pemetrexed/Bevacizumab | Pemetrexed/Bevacizumab/Carboplatin |
|---|---|---|---|
| STARTED | 48 | 59 | 55 |
| COMPLETED | 0 | 0 | 0 |
| NOT COMPLETED | 48 | 59 | 55 |
Analysis population for the primary outcome, as defined in the registry: Includes all enrolled patients whether they recieved treatment or not
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: Includes all patients who were enrolled (whether they recieved treatment or not)
| Characteristic | Unit | Pemetrexed | Pemetrexed/Bevacizumab | Pemetrexed/Bevacizumab/Carboplatin | Total |
|---|---|---|---|---|---|
| Participants analysed | 48 | 63 | 61 | 172 | |
| Age, Continuous | years | 72 (51 to 84) | 72 (50 to 90) | 73 (48 to 90) | 72 (48 to 90) |
| Sex: Female, Male: Female | Participants | 18 | 27 | 27 | 72 |
| Sex: Female, Male: Male | Participants | 30 | 36 | 34 | 100 |
| Region of Enrollment: United States | participants | 48 | 63 | 61 | 172 |
6. Primary Endpoint
The registry lists the primary outcome as Progression Free Survival (PFS), measured over 18 months.
| Element | Registry entry |
|---|---|
| Result type | Median |
| Measure of spread | 95% Confidence Interval |
| Unit | months |
| Endpoint classification | Time-to-Event Analysis |
Progression-free survival measures the time from the first date of protocol treatment until disease worsening, according to the registry's description. Worsening was defined using RECIST v1.0: a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions. Results are presented as median months rather than as an average.
General statistical explanation: a median time-to-event result describes the time by which half of the analyzed group has experienced the endpoint, under the endpoint and analysis definitions used. A confidence interval communicates uncertainty around the estimated median. It is not a range containing every participant's time, and its width reflects the precision of the estimate as well as the available event and follow-up information.
Progression-free survival is used in clinical trials to summarize the time until a prespecified disease-related event. Its interpretation depends on how progression is defined, how assessments are made, and how participants without a recorded event are handled. The registry provides the RECIST-based progression definition and an all-enrolled population description, but assessment schedules, censoring rules, and missing-assessment procedures are not reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted primary endpoint results show median progression-free survival of 2.8 months in the pemetrexed arm, with a 95% confidence interval from 1.5 to 4.1 months. The pemetrexed/bevacizumab arm had a median of 4.0 months, with a 95% confidence interval from 2.6 to 6.0 months. The pemetrexed/bevacizumab/carboplatin arm had a median of 4.8 months, with a 95% confidence interval from 3.1 to 6.5 months. These estimates describe the enrolled groups under the registry's endpoint definition.
The point estimates are ordered from lower to higher across the three regimens. That ordering is descriptive, not a formal test of treatment differences. The record does not post sponsor-reported hazard ratios or other comparative analyses for progression-free survival. The displayed interval estimates are arm-specific; they do not directly quantify the uncertainty in a between-arm contrast. Overlap or non-overlap between separate arm confidence intervals is not a substitute for a prespecified comparative analysis.
The registered primary population includes all enrolled participants, whether or not they received treatment. The reported arm counts are 48, 63, and 61. The record does not explain how participants with missing progression assessments, withdrawal, or other incomplete follow-up contributed to the median estimates. Nor does it specify a censoring approach or the number of progression events. Those details matter for understanding how the observed follow-up supports each estimate.
Response counts are also posted for the secondary overall response rate outcome. In a separate unadjusted recalculation, the risk-difference comparison for pemetrexed/bevacizumab versus pemetrexed has p = 0.053, while the corresponding comparison for pemetrexed/bevacizumab/carboplatin versus pemetrexed has p = 0.001. These are not registry-reported comparative analyses. They are simple unadjusted recalculations from the posted response summaries and should be interpreted as exploratory, particularly because there are multiple arms and multiple listed outcomes.
The primary endpoint and response outcome address different aspects of the data: progression-free survival is a time-to-event measure, while response counts record whether an objective benefit was observed. A pattern across these outcomes can be informative, but it does not replace a planned analysis or establish that any regimen caused a difference. The registry does not report a sample-size justification, a multiplicity strategy, or a full statistical analysis plan. Accordingly, the posted arm estimates and unadjusted response comparisons should be read as limited evidence rather than as a complete account of comparative uncertainty.
9. Statistical Methods Explained
What does the median represent?
For a time-to-event endpoint, the median is the estimated time at which the event has occurred for half of the analyzed group, using the trial's endpoint and follow-up rules. Here the endpoint is progression-free survival, and the posted statistic is the median in months. A median is not an average, and it does not describe the experience of every participant. The registry's progression definition is based on RECIST v1.0 criteria. Details such as the timing of tumor assessments and censoring rules are not reported in the registry record.
How should a confidence interval be read?
General statistical explanation: a confidence interval expresses uncertainty in an estimate under the assumptions of the method used. The primary results give a 95% confidence interval for each arm's median. It indicates a range of values compatible with the estimate and its uncertainty under the statistical procedure; it is not a prediction interval for individual outcomes. It also does not directly answer whether two arms differ. A between-arm contrast needs its own estimate and uncertainty calculation. The registry does not post a sponsor-reported comparative analysis for the primary endpoint.
Why is a time-to-event comparison different from comparing medians?
General statistical explanation: time-to-event methods can use information about when events occur and account for participants whose event has not been observed by the end of their available follow-up. A median condenses that time distribution into one point estimate. A hazard ratio, when reported, compares event rates over follow-up under its model assumptions; it is not the same quantity as a difference between medians. The registry record does not report hazard ratios for the primary endpoint, so no such comparison can be described from the posted primary results.
What do the response recalculations represent?
Overall response rate is listed as the number of participants experiencing an objective benefit from treatment. The registry posts arm-level response counts and denominators. The risk differences and unadjusted p-values cited in the interpretation are recalculated from those posted summary statistics. They are unadjusted comparisons, not sponsor-reported analyses. They do not account for the broader set of outcomes or comparisons that may have been considered, and the registry record does not report an adjustment for multiple testing.
General statistical explanation: a risk difference compares two proportions by subtracting one from the other. A confidence interval around a risk difference describes uncertainty in that contrast. A p-value measures how incompatible the observed data are with a specified null hypothesis under the chosen test and its assumptions; it is not the probability that the null hypothesis is true. An unadjusted p-value does not account for the chance of false-positive findings that can increase when many comparisons are examined. The posted recalculations should therefore not be treated as definitive confirmatory evidence.
What do the planning illustrations mean?
The sample-size illustrations use the observed response effect as a planning reference, then consider planning for 100%, 75%, or 50% of that observed effect. They assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For the comparison of pemetrexed/bevacizumab with pemetrexed, the illustration gives 107 participants per arm for 80% power and 143 participants per arm for 90% power when planning for 100% of the observed effect; planning for 75% gives 179 and 239, and planning for 50% gives 374 and 500. For the comparison of the three-drug regimen with pemetrexed, the corresponding figures are 38 and 50 for 100%, 62 and 82 for 75%, and 126 and 168 for 50%.
These are planning illustrations, not observed power and not the trial's original design justification. They are calculated from the observed effect, which can be an optimistic basis for planning, and their assumptions may not match the trial's actual design. The registry record does not report the trial's own sample-size justification. The time-to-event endpoint is not represented by these binary-outcome illustrations.
What is not available for assessing the analysis?
The record lists no reported sponsor comparative analyses for the primary endpoint and no reported analyses for the response outcome. It does not describe the planned analysis population beyond the primary endpoint's all-enrolled wording, how missing outcomes were handled, or whether analyses were adjusted for prognostic factors. These omissions limit reconstruction of the intended statistical approach and the precision of claims that can be made from the posted summaries.
10. Multiplicity, Missing Data and Analysis Populations
The registry names one primary endpoint and several secondary outcomes, but it does not report how multiplicity was addressed. In a trial with multiple treatment comparisons and multiple endpoints, repeated testing can increase the chance of at least one result appearing notable by chance. General statistical explanation: a multiplicity strategy can define which tests are confirmatory, set an order for testing, or adjust the threshold used to interpret results. Without such a strategy in the record, unadjusted secondary p-values should be treated as exploratory rather than as proof of a confirmatory finding.
The record does not post a sponsor-reported comparative analysis for progression-free survival, and the response comparisons are unadjusted recalculations from the posted summary statistics. No analysis plan, hierarchy of endpoints, or adjustment method is reported in the registry record. It is therefore not possible to determine from the record whether the posted outcomes were intended to be tested jointly, in a fixed sequence, or as descriptive measures.
The primary endpoint description states that the population includes all enrolled patients whether or not they received treatment. This is useful information about the stated population, but the record does not explain how missing assessments, loss to follow-up, treatment discontinuation, or other incomplete data were handled. It also does not describe the rules for censoring participants whose progression status was not observed. These details can affect time-to-event estimates and their confidence intervals.
The registry does not report a separate analysis population for the secondary response outcome, nor does it explain why the response denominators differ from the primary arm counts. The record also does not provide an account of exclusions or missing response assessments. These gaps do not establish that the analyses were inappropriate; they limit the ability to reconstruct them. The sample-size justification and any interim-analysis plan are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Pemetrexed | 30 | 48 | 62.5% |
| Pemetrexed/Bevacizumab | 28 | 63 | 44.4% |
| Pemetrexed/Bevacizumab/Carboplatin | 33 | 61 | 54.1% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Pemetrexed | 48 of 48 |
| Pemetrexed/Bevacizumab | 62 of 63 |
| Pemetrexed/Bevacizumab/Carboplatin | 60 of 61 |
Most frequent serious adverse event terms
| Event term | Organ system | Pemetrexed | Pemetrexed/Bevacizumab | Pemetrexed/Bevacizumab/Carboplatin |
|---|---|---|---|---|
| Infections and infestations - Other, pneumonia | Infections and infestations | 8 of 48 | 5 of 63 | 4 of 61 |
| General disorders and administration site conditions - Other, disease progression | General disorders | 4 of 48 | 4 of 63 | 2 of 61 |
| Respiratory, thoracic and mediastinal disorders - Other, COPD exacerbation | Respiratory, thoracic and mediastinal disorders | 2 of 48 | 0 of 63 | 5 of 61 |
| Thromboembolic event | Vascular disorders | 2 of 48 | 1 of 63 | 3 of 61 |
| Dehydration | Metabolism and nutrition disorders | 2 of 48 | 1 of 63 | 2 of 61 |
| Non-cardiac chest pain | General disorders | 1 of 48 | 2 of 63 | 1 of 61 |
| Pleural Effusion | Respiratory, thoracic and mediastinal disorders | 0 of 48 | 3 of 63 | 1 of 61 |
| Respiratory Failure | Respiratory, thoracic and mediastinal disorders | 0 of 48 | 0 of 63 | 4 of 61 |
| Skin infection | Infections and infestations | 4 of 48 | 0 of 63 | 0 of 61 |
| Dyspnea | Respiratory, thoracic and mediastinal disorders | 1 of 48 | 0 of 63 | 2 of 61 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Pemetrexed | Pemetrexed/Bevacizumab | Pemetrexed/Bevacizumab/Carboplatin |
|---|---|---|---|---|
| Fatigue | General disorders | 29 of 48 | 39 of 63 | 36 of 61 |
| Nausea | Gastrointestinal disorders | 19 of 48 | 23 of 63 | 29 of 61 |
| Anemia | Blood and lymphatic system disorders | 18 of 48 | 18 of 63 | 25 of 61 |
| Dyspnea | Respiratory, thoracic and mediastinal disorders | 14 of 48 | 26 of 63 | 19 of 61 |
| Constipation | Gastrointestinal disorders | 12 of 48 | 24 of 63 | 21 of 61 |
| Anorexia | Metabolism and nutrition disorders | 15 of 48 | 26 of 63 | 14 of 61 |
| Platelet Count Decreased | Investigations | 12 of 48 | 10 of 63 | 24 of 61 |
| Neutrophil Count Decreased | Investigations | 7 of 48 | 13 of 63 | 21 of 61 |
| Edema | General disorders | 11 of 48 | 13 of 63 | 17 of 61 |
| Cough | Respiratory, thoracic and mediastinal disorders | 7 of 48 | 16 of 63 | 16 of 61 |
Serious events with the highest arm-level rate: infections and infestations - other, pneumonia (16.7%), general disorders and administration site conditions - other, disease progression (8.3%), skin infection (8.3%), respiratory, thoracic and mediastinal disorders - other, copd exacerbation (8.2%), respiratory failure (6.6%).
The registry reports serious adverse event counts for each arm: 30 participants in the pemetrexed group, 28 in the pemetrexed/bevacizumab group, and 33 in the pemetrexed/bevacizumab/carboplatin group. The corresponding numbers at risk were 48, 63, and 61. The record also reports other adverse event counts of 48, 62, and 60, respectively, with the same arm-level numbers at risk. These are counts of affected participants, not comparative estimates adjusted for follow-up or other factors.
The registry lists serious adverse event terms with percentages, including infections and infestations—other, pneumonia at 16.7%, general disorders and administration site conditions—other, disease progression at 8.3%, skin infection at 8.3%, respiratory, thoracic and mediastinal disorders—other, COPD exacerbation at 8.2%, respiratory failure at 6.6%, and thromboembolic event at 4.9%. The denominator and arm-specific distribution for these terms are not reported in the registry record.
General statistical explanation: adverse event counts depend on the definitions, observation period, and population at risk. Counts alone do not show whether an event was caused by treatment or whether rates differ reliably between arms. Death counts and further details about event timing, severity grading, and attribution are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The posted primary results provide arm-specific estimates of median progression-free survival and 95% confidence intervals in a randomized phase II trial of three regimens for previously untreated patients with stage IIIB/IV non-small-cell lung cancer and ECOG performance status 2. The medians are ordered across the arms, but the registry does not post a formal comparative analysis of the primary endpoint. The numerical ordering alone cannot establish a statistically reliable difference between treatments.
The response counts offer a separate descriptive view. Recalculated unadjusted comparisons suggest different response patterns across the arms, but those calculations are not sponsor-reported analyses and do not account for multiple outcomes or comparisons. They should not be treated as a substitute for a prespecified analysis. Other named secondary outcomes do not have detailed results in the registry record.
General statistical explanation: a confidence interval conveys uncertainty around an estimate; it does not remove uncertainty or determine whether an effect is clinically important. Statistical evidence, clinical relevance, and the quality of endpoint measurement are related but distinct considerations. The registry does not report a minimal clinically important difference for progression-free survival or a full account of how missing observations were handled.
The trial's randomized design supports comparison in principle, but interpretation still depends on the analysis methods and reporting. The record does not report a sample-size justification, a multiplicity approach, or a detailed statistical analysis plan. The planning illustrations based on observed response effects are not evidence of the trial's power and do not establish the design assumptions used when the trial was planned.
These results describe the posted record and its stated population. They should not be generalized automatically to other patient groups, and they do not on their own establish a treatment recommendation. The record offers arm-level outcome and safety summaries, but limited information about comparative methods, missing data, and other secondary endpoints.
13. Why This Trial Matters Statistically
This trial is statistically informative because it presents three randomized parallel treatment groups and a time-to-event primary endpoint in a specifically defined patient population. The arm-level medians and confidence intervals make it possible to see both the ordering of the estimates and the uncertainty around each one. That distinction is important: estimates can differ numerically without the registry providing evidence from a formal between-arm test.
The registry also illustrates why outcome labels and analysis details matter. Progression-free survival is defined using RECIST-based disease progression, while overall response rate records objective benefit as a count. The two outcomes summarize different features of trial data and cannot be treated as interchangeable. The additional named outcomes broaden the clinical questions, but detailed results are not posted for most of them.
The response recalculations and planning illustrations are useful statistical examples when their status is clear. The comparisons are unadjusted recalculations, and the sample-size values are planning illustrations based on observed effects. Neither should be mistaken for the trial's own reported inferential analysis or original design calculation. In particular, planning from an observed effect does not establish observed power.
The record's omissions are also instructive. Without a reported multiplicity strategy, missing-data rules, or full analysis plan, readers cannot reconstruct all of the decisions that shape interpretation. Reporting arm estimates is valuable, but transparent comparative methods are needed to understand how strongly the evidence supports a difference.
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 primary results are arm-specific median estimates with confidence intervals. The registry does not report a sponsor comparative analysis for progression-free survival, so the record does not provide a direct estimate and confidence interval for each between-arm contrast. The posted values therefore support descriptive reading, not a definitive comparative conclusion.
The analysis details are limited. The registry record does not report censoring rules, progression assessment schedules, handling of missing assessments, or a detailed statistical analysis plan. Although the primary endpoint description says all enrolled patients are included whether or not they received treatment, the record does not provide comparable detail for the secondary response outcome. Its denominators differ from the primary arm counts, and reasons for the differing analysis sets are not reported in the registry record.
Several secondary outcomes are named without detailed results. The record does not provide detailed estimates for time to progression, time to treatment failure, overall survival, or 6-month and 12-month overall survival probability. It also does not report a multiplicity strategy, sample-size justification, or interim-analysis plan. These omissions constrain the assessment of secondary evidence and the trial's planned inferential approach.
The response comparisons are unadjusted recalculations from posted summaries. The planning illustrations use observed effects and specified assumptions; they are not the original sample-size rationale or observed power. Safety reporting gives arm-level counts and a list of serious event terms with percentages, but the term denominator and arm-specific breakdown are not reported. These limitations do not show that the analyses or reporting were necessarily flawed; they identify what cannot be established from the registry record alone.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Trial of Poor Performance Status Patients (ToPPS) — NCT00892710.
- Registry record last updated 2015-05-15; status last verified 2015-05.
- Results first posted 2015-05-15.
- 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.
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18. Record Summary
ToPPS (NCT00892710) was a completed randomized phase II parallel-group trial with no masking. It enrolled 172 previously untreated patients with stage IIIB/IV non-small-cell lung cancer and ECOG performance status 2. The arms were pemetrexed alone, pemetrexed/bevacizumab, and pemetrexed/bevacizumab/carboplatin.
The primary endpoint was median progression-free survival in months, with a 95% confidence interval and an 18-month timeframe. Posted arm medians were 2.8, 4.0, and 4.8 months, respectively. The registry lists response rate, time to progression, time to treatment failure, overall survival, and survival probabilities as secondary outcomes, but detailed results are not reported for most of these outcomes.
The registry does not post sponsor-reported comparative analyses for the primary endpoint or response outcome. Response comparisons discussed in the statistical interpretation are unadjusted recalculations. The record does not report the trial's sample-size justification, multiplicity strategy, or detailed missing-data procedures.