This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record.
1. Trial at a Glance
IMpower133 was a randomized, double-blind, parallel phase 3 trial comparing atezolizumab plus carboplatin and etoposide with placebo plus carboplatin and etoposide in participants with untreated extensive-stage small cell lung cancer.
| Feature | IMpower133 |
|---|---|
| Trial name | IMpower133 |
| NCT identifier | NCT02763579 |
| Phase | Phase 3 |
| Condition | Small Cell Lung Carcinoma |
| Design | Randomized, parallel, double-blind |
| Allocation | Randomized |
| Primary purpose | Treatment |
| Enrollment | 503 |
| Primary endpoints | Duration of Progression-Free Survival and Duration of Overall Survival |
| Primary endpoint type | Time-to-event |
| Primary hypothesis type | Superiority |
| Lead sponsor | Hoffmann-La Roche |
| Sponsor type | Industry |
| Status | Completed |
2. Clinical Question
The central statistical question was whether adding atezolizumab to carboplatin and etoposide produced a different time-to-event outcome from placebo plus carboplatin and etoposide in participants with untreated extensive-stage small cell lung cancer.
Population
Participants with untreated extensive-stage small cell lung cancer, corresponding to the registered condition of small cell lung carcinoma.
Intervention
Atezolizumab, an engineered anti-PD-L1 antibody, given with carboplatin and etoposide.
Comparator
Placebo given with carboplatin and etoposide.
Primary question
Under a superiority framework, how does the randomized comparison differ with respect to progression-free survival and overall survival?
3. Trial Design
Atezolizumab combination
- Atezolizumab
- Carboplatin
- Etoposide
Placebo combination
- Placebo
- Carboplatin
- Etoposide
The registry records 503 participants and two treatment arms. The statistical analyses reported for the primary endpoints use the intention-to-treat population, defined as all randomized participants regardless of whether the participant received the assigned treatment.
4. Endpoints
| Endpoint | Registered definition / time frame | Type |
|---|---|---|
| Duration of Progression-Free Survival (PFS) | Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population. Baseline until PD or death, whichever occurs first (up to approximately 23 months). | Time-to-event |
| Duration of Overall Survival (OS) | Duration of Overall Survival (OS) in the Global Population. Baseline until death from any cause (up to approximately 23 months). | Time-to-event |
Progression-Free Survival definition
The registered definition states that progression is defined using Response Evaluation Criteria In Solid Tumors Criteria, with at least 20% increase in the sum of the longest diameter of target lesions compared with baseline, or unequivocal progression in non-target lesion(s), or the appearance of new lesion(s).
Overall Survival definition
Overall survival is defined as the time from randomization to death from any cause.
5. Primary Results: Progression-Free Survival
The registry reports a formal primary-endpoint analysis of progression-free survival using the intention-to-treat population and a log-rank test. The reported effect measure is a stratified hazard ratio.
Stratified hazard ratio for PFS
95% CI: 0.62–0.96 · P = 0.0170
Comparison: Placebo + Carboplatin + Etoposide vs Atezolizumab + Carboplatin + Etoposide
| Feature | Reported PFS analysis |
|---|---|
| Endpoint | Duration of Progression-Free Survival (PFS) as Assessed by the Investigator Using RECIST v1.1 in the Global Population |
| Time frame | Baseline until PD or death, whichever occurs first (up to approximately 23 months) |
| Analysis population | ITT population: all randomized participants, regardless of whether the participant received the assigned treatment |
| Groups compared | Placebo + Carboplatin + Etoposide vs Atezolizumab + Carboplatin + Etoposide |
| Method | Log Rank |
| Effect measure | Stratified Hazard Ratio |
| Estimate | 0.77 |
| 95% CI | 0.62–0.96 |
| P-value | 0.0170 |
| Hypothesis | Superiority |
The reported stratified hazard ratio is 0.77 for the listed comparison of placebo plus carboplatin and etoposide versus atezolizumab plus carboplatin and etoposide. Numerically, a hazard ratio of 0.77 means that the estimated instantaneous event rate for the first-listed group is 0.77 times that of the second-listed group under the reported time-to-event analysis, corresponding to a 23% lower estimated hazard for the first-listed group.
This is a statement about the estimated relative hazard over follow-up; it is not a statement that 23% of participants avoided progression, nor does it imply that every individual participant experienced a 23% reduction in risk.
The 95% confidence interval of 0.62–0.96 describes statistical uncertainty around the estimated hazard ratio. It does not describe the range of individual patient outcomes. The interval is entirely below 1, which is consistent with a difference between the randomized groups under the reported superiority analysis.
The P-value of 0.0170 addresses evidence against the relevant null hypothesis under the stated testing framework. It does not measure the size of the treatment effect, clinical importance, or the probability that either treatment is effective.
Because the endpoint is time-to-event and the effect measure is a hazard ratio, interpretation also depends on the underlying survival-analysis framework and the assumptions associated with representing the treatment contrast using a single hazard ratio. The registry does not provide a separate proportional-hazards diagnostic in the ClinicalTrials.gov record.
6. Primary Results: Overall Survival
Overall survival was the second registered primary endpoint. The registry reports an intention-to-treat analysis using a log-rank test and a stratified hazard ratio.
Stratified hazard ratio for OS
95% CI: 0.54–0.91 · P = 0.0069
Comparison: Placebo + Carboplatin + Etoposide vs Atezolizumab + Carboplatin + Etoposide
| Feature | Reported OS analysis |
|---|---|
| Endpoint | Duration of Overall Survival (OS) in the Global Population |
| Time frame | Baseline until death from any cause (up to approximately 23 months) |
| Analysis population | ITT population: all randomized participants, regardless of whether the participant received the assigned treatment |
| Groups compared | Placebo + Carboplatin + Etoposide vs Atezolizumab + Carboplatin + Etoposide |
| Method | Log Rank |
| Effect measure | Stratified Hazard Ratio |
| Estimate | 0.70 |
| 95% CI | 0.54–0.91 |
| P-value | 0.0069 |
| Hypothesis | Superiority |
The reported stratified hazard ratio is 0.70 for the listed comparison of placebo plus carboplatin and etoposide versus atezolizumab plus carboplatin and etoposide. Numerically, this corresponds to an estimated instantaneous death rate for the first-listed group that is 0.70 times that of the second-listed group under the reported time-to-event model, or a 30% lower estimated hazard for the first-listed group.
The hazard ratio does not mean that 30% of participants survived, that 30% of participants were protected from death, or that each participant's probability of death was reduced by exactly 30%.
The 95% confidence interval of 0.54–0.91 quantifies uncertainty around the estimated hazard ratio. Because the interval remains below 1, the reported interval is consistent with a difference between the randomized groups under the stated superiority framework.
The P-value of 0.0069 is evidence against the relevant null hypothesis under the analysis framework. It is not an effect-size measure and should not be interpreted as the probability that the null hypothesis is true or false.
As with PFS, OS is subject to censoring and is summarized through a time-to-event framework. A single hazard ratio is a relative summary and does not replace reporting absolute survival probabilities or other time-specific measures when those are available.
7. Secondary Endpoint Results
The registry contains nine posted secondary statistical analyses in addition to the two primary analyses represented above. These analyses include objective response rate, duration of response, PFS rates at specified time points, OS rates at specified time points, and time to deterioration for selected symptoms.
Objective Response Rate
Odds ratio for objective response
95% CI: 0.55–1.37
Comparison: Placebo + Carboplatin + Etoposide vs Atezolizumab + Carboplatin + Etoposide
| Feature | Reported analysis |
|---|---|
| Endpoint | Percentage of Participants With Objective Response Rate (ORR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population |
| Time frame | Baseline until partial response (PR) or complete response (CR), whichever occurs first (up to approximately 23 months) |
| Endpoint type | Binary |
| Analysis population | ITT population |
| Method | Not reported |
| Effect measure | Odds Ratio (OR) |
| Estimate | 0.87 |
| 95% CI | 0.55–1.37 |
| Hypothesis | Superiority |
Duration of Response
Hazard ratio for duration of response
95% CI: 0.562–0.911 · P = 0.0063
| Feature | Reported analysis |
|---|---|
| Endpoint | Duration of Response (DOR) as Assessed by the Investigator Using RECIST v1.1 in the Global Population |
| Time frame | First occurrence of PR or CR until PD or death, whichever occurs first (up to approximately 23 months) |
| Endpoint type | Time-to-event |
| Method | Log Rank |
| Effect measure | Hazard Ratio (HR) |
| Estimate | 0.715 |
| 95% CI | 0.562–0.911 |
| P-value | 0.0063 |
Because duration of response is measured from the first occurrence of partial or complete response until progression or death, it is a time-to-event endpoint among participants for whom a response is observed. The registry analysis reports a log-rank test and hazard ratio for this endpoint.
PFS Rates
| Time point | Effect measure | Estimate | 95% CI | P-value |
|---|---|---|---|---|
| 6 months | Difference in Event Free Rate | 8.47 | -0.33–17.27 | 0.0593 |
| 1 year | Difference in Event Free Rate | 7.27 | 1.52–13.02 | 0.0133 |
Both analyses concern the registered endpoint "PFS Rate at 6 Months and at 1 Year in Global Population." The registry reports a Z-test, normalized as a Wald / z-test, and gives the effect measure as a difference in event-free rate. The analysis population is the ITT population.
OS Rate
| Time point | Effect measure | Estimate | 95% CI | P-value |
|---|---|---|---|---|
| 1 year | Difference in Event Free Rate | 13.46 | 3.29–23.64 | 0.0095 |
The registry endpoint is "OS Rate at 1 Year and 2 Years in the Global Population." The posted analysis represented in the ClinicalTrials.gov record is specifically annotated as the OS Rate at 1 year. The method is a Z-test, normalized as a Wald / z-test, with the ITT population used for the comparison.
Time to Deterioration
| Symptom subscale | HR | 95% CI | P-value |
|---|---|---|---|
| Cough | 1.221 | 0.795–1.874 | 0.3604 |
| Pain in Chest | 1.058 | 0.722–1.553 | 0.7712 |
| Pain in Arm or Shoulder | 1.077 | 0.747–1.552 | 0.6922 |
| Dyspnea | 0.748 | 0.549–1.019 | 0.0650 |
These analyses are part of the registered "Time to Deterioration (TTD) Per European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) Core 30 (C30) and Supplemental Lung Cancer Module (QLQ-LC13) in the Global Population." The time frame is baseline until deterioration per symptom subscale, up to approximately 23 months. The registry reports log-rank analyses and hazard ratios.
The registry specifies that these TTD analyses are stratified and identifies sex (male vs female) and ECOG (0 vs 1) as the stratification factors. The ClinicalTrials.gov record does not provide additional detail about how the individual symptom-scale deterioration events were constructed beyond the registered endpoint description.
8. Statistical Methodology
Intention-to-treat analysis
The primary and secondary efficacy analyses reported here use the ITT population. The registry defines this population as all randomized participants, regardless of whether the participant received the assigned treatment.
The ITT principle keeps participants associated with the treatment assignment generated by randomization. This preserves the treatment comparison created by random allocation and avoids redefining the primary comparison solely according to treatment actually received.
For IMpower133, the registry definition explicitly states that all randomized participants are included regardless of whether they received the assigned treatment.
Log-rank test
The log-rank test is the reported method for both primary time-to-event endpoints and for duration of response and time-to-deterioration analyses. It compares the event-time experience of the groups across follow-up while accounting for the timing of events and censoring.
The registry identifies the method as "Log Rank" for the primary PFS and OS analyses and for the reported DOR and TTD analyses.
Hazard ratio
The primary endpoints use a stratified hazard ratio as the effect measure. A hazard ratio is a relative time-to-event measure: values below 1 indicate a lower estimated hazard for the first-listed group in the reported comparison, while values above 1 indicate a higher estimated hazard for the first-listed group.
For the primary analyses reported here, the first-listed group is placebo + carboplatin + etoposide and the second-listed group is atezolizumab + carboplatin + etoposide.
Wald / z-test
The registry reports a Z-test for PFS rates at 6 months and 1 year and for OS rates at 1 year and 2 years. The statistical method is Wald / z-test, with the effect measure reported as a difference in event-free rate.
For these binary time-point summaries, the effect measure is an absolute difference rather than a hazard ratio. That distinction matters: a difference in event-free rate describes separation at a particular time point, whereas a hazard ratio summarizes relative instantaneous event rates across follow-up under the time-to-event model.
Odds ratio
Objective response rate is a binary endpoint, and the registry reports an odds ratio of 0.87 with a 95% confidence interval of 0.55–1.37. The registry does not report the formal statistical method in the ClinicalTrials.gov record.
An odds ratio compares the odds of the specified binary outcome between groups. It is not the same as a risk ratio or a difference in response probabilities, and its interpretation depends on which group is placed in the numerator.
Confidence intervals
The registry reports two-sided 95% confidence intervals for the primary hazard ratios and for the posted secondary effect estimates. A confidence interval communicates the statistical precision of an estimate under the relevant estimation framework; it is not a range containing a specified percentage of individual patient effects.
9. Statistical Methods Explained
Why was a log-rank test used?
Both registered primary endpoints are time-to-event outcomes. Participants can experience the event at different times, and some observations can be censored. A log-rank test is designed for comparing survival-type event-time distributions between groups rather than reducing the endpoint to a simple yes/no outcome at a single arbitrary time.
What does a hazard ratio of 0.70 mean?
For the reported OS comparison, the hazard ratio is 0.70 for placebo plus carboplatin and etoposide relative to atezolizumab plus carboplatin and etoposide. Numerically, this means the estimated instantaneous death rate for the first-listed group is 70% of that of the second-listed group under the reported model. It does not mean that 70% of participants died or that each participant experienced a 30% reduction in individual risk.
Why does the confidence interval matter?
The estimate is only one summary of the observed data. The 95% confidence interval provides information about the statistical precision of that estimate. For the OS analysis, the interval is 0.54–0.91; for PFS, it is 0.62–0.96. These intervals show that the reported estimates are not being presented as exact quantities.
Why does the P-value not measure effect size?
A P-value evaluates the compatibility of the observed data with a specified null hypothesis under the statistical testing framework. It depends on both the observed effect and the amount of information in the analysis. A small P-value does not tell us how large the treatment effect is; the hazard ratio and its confidence interval address that question more directly.
Why is ITT important here?
The primary analyses were conducted in the ITT population, defined as all randomized participants regardless of whether they received the assigned treatment. This preserves the original randomized comparison rather than restricting the primary analysis to participants who completed treatment or complied with treatment assignment.
How should the PFS-rate and OS-rate analyses be distinguished from hazard ratios?
The rate analyses report differences at specified time points and use a Wald / z-test. The primary PFS and OS analyses instead use time-to-event methods and report hazard ratios. A time-point difference answers a question about separation at a particular time, whereas a hazard ratio summarizes relative event rates across the follow-up period used in the analysis.
10. Interpretation of the Primary Hazard Ratios
The reported PFS hazard ratio of 0.77 corresponds to a 23% lower estimated hazard for the first-listed group relative to the second-listed group. The 95% CI of 0.62–0.96 describes uncertainty around that estimate, while the P-value of 0.0170 addresses the statistical test rather than the magnitude of the effect.
The reported OS hazard ratio of 0.70 corresponds to a 30% lower estimated hazard for the first-listed group relative to the second-listed group. The 95% CI of 0.54–0.91 provides the corresponding uncertainty measure, and the P-value of 0.0069 describes evidence against the relevant null hypothesis under the reported framework.
Neither hazard ratio directly states the proportion of participants who were progression-free or alive at a particular time. The secondary PFS-rate and OS-rate analyses illustrate why time-specific absolute measures can answer a different question from a hazard ratio.
11. Analysis Populations and Statistical Interpretation
| Analysis | Population | Statistical role |
|---|---|---|
| Primary PFS | ITT | Primary superiority time-to-event comparison |
| Primary OS | ITT | Primary superiority time-to-event comparison |
| ORR | ITT | Secondary binary endpoint |
| DOR | ITT | Secondary time-to-event endpoint |
| PFS rates | ITT | Secondary time-point binary analyses |
| OS rate | ITT | Secondary time-point binary analysis |
| TTD | ITT | Secondary time-to-event analyses |
The consistency of the registry-reported efficacy analyses around the ITT definition is important. The registry does not describe a separate per-protocol efficacy population in the ClinicalTrials.gov record, so no additional efficacy interpretation should be inferred from a population that is not reported.
12. Stratification
The ClinicalTrials.gov record identifies explicit stratification for the reported time-to-deterioration analyses: sex, male versus female, and ECOG, 0 versus 1. The TTD analyses are described as stratified analyses using these factors.
| Stratification factor | Levels reported |
|---|---|
| Sex | Male vs female |
| ECOG | 0 vs 1 |
The primary PFS and OS analyses are described in the ClinicalTrials.gov record as using a stratified hazard ratio, but the provided primary-analysis records do not identify the stratification factors. Accordingly, this page does not add additional primary-endpoint stratification factors.
13. Safety Results
The ClinicalTrials.gov record reports serious adverse events by arm for the global population and for a China subgroup. These are presented as affected participants divided by participants at risk.
| Population | Placebo + Carboplatin + Etoposide | Atezolizumab + Carboplatin + Etoposide |
|---|---|---|
| Global | 69/196 | 81/198 |
| China | 14/52 | 22/57 |
The global serious-adverse-event counts are therefore reported as 69 affected participants among 196 at risk in the placebo combination group and 81 among 198 at risk in the atezolizumab combination group. In the China population, the corresponding reported counts are 14/52 and 22/57.
14. Trial Timeline
Trial start
The registry records the trial start date as 2016-06-07.
Primary completion
The registry records the primary completion date as 2018-04-24.
Registry status
the ClinicalTrials.gov record lists the study status as completed and results as posted.
15. Multiplicity, Interim Analysis, and Other Design Topics
| Design topic | What the ClinicalTrials.gov record supports |
|---|---|
| Superiority | Both primary endpoints are identified as superiority hypotheses. |
| Multiplicity | The ClinicalTrials.gov record identifies two primary endpoints but do not provide an alpha-allocation or multiplicity-adjustment procedure. |
| Interim analysis | The ClinicalTrials.gov record does not report an interim-analysis schedule or interim alpha-spending method. |
| Missing data / imputation | The ClinicalTrials.gov record does not report an imputation strategy. |
| Non-inferiority margin | No non-inferiority margin is reported because the primary hypothesis type is superiority. |
| Crossover | The ClinicalTrials.gov record does not report a crossover procedure. |
| Factorial design | The design model is parallel; no factorial structure is reported. |
| Bayesian methods | No Bayesian method is reported in the analyses posted on ClinicalTrials.gov. |
This distinction is important when interpreting a registry record. A method not contained in the ClinicalTrials.gov record should not be reconstructed from assumptions about how a phase 3 oncology trial might commonly be designed.
16. Limitations
- Registry-level detail: the ClinicalTrials.gov record provides the primary estimates, confidence intervals, P-values, populations, and several analysis methods, but does not provide every element of a full statistical analysis plan.
- Direction of the hazard ratio: the reported comparisons are explicitly ordered as placebo plus carboplatin and etoposide versus atezolizumab plus carboplatin and etoposide. Reversing that ordering would invert the hazard ratio and would not reproduce the reported estimate.
- No primary endpoint medians are reported: the ClinicalTrials.gov record contain hazard ratios, confidence intervals, and P-values for PFS and OS but do not contain median PFS or median OS estimates.
- Limited information about multiplicity: two primary endpoints are reported, but the ClinicalTrials.gov record does not specify an alpha-allocation or multiplicity-control procedure.
- Limited information about interim monitoring: no interim-analysis schedule, stopping boundary, or alpha-spending method is included in the ClinicalTrials.gov record.
- ORR method not reported: the registry provides an odds ratio and confidence interval for objective response rate but identifies the formal statistical method as not reported.
- Safety comparisons: serious-adverse-event counts are provided by arm, but no formal statistical comparison is reported in the ClinicalTrials.gov record.
- Time-to-event assumptions: hazard ratios are model-based relative summaries. The ClinicalTrials.gov record does not provide a separate assessment of the proportional-hazards assumption.
- Secondary endpoints: the registry contains multiple secondary analyses, so individual P-values should be interpreted in the context of their secondary-endpoint role rather than automatically treated as independent confirmatory findings.
17. Why This Trial Matters Statistically
IMpower133 is a useful statistical teaching case because the registry record contains a coherent set of randomized time-to-event analyses alongside binary response and time-point rate analyses. It therefore illustrates how different effect measures answer different questions even when they arise from the same randomized comparison.
| Concept | How it appears in IMpower133 |
|---|---|
| Randomization | The trial is randomized with two parallel treatment arms. |
| Blinding | The trial is double-blind. |
| ITT analysis | The reported efficacy analyses define the ITT population as all randomized participants. |
| Time-to-event endpoints | PFS and OS are the two registered primary endpoints. |
| Log-rank test | Used for the primary PFS and OS analyses and for several secondary time-to-event analyses. |
| Hazard ratio | Reported as the primary effect measure for PFS and OS and for DOR and TTD analyses. |
| Confidence intervals | Two-sided 95% confidence intervals are reported for the primary and secondary estimates. |
| Odds ratio | Used as the reported effect measure for the secondary binary ORR endpoint. |
| Wald / z-test | Used for the reported PFS-rate and OS-rate analyses. |
| Superiority testing | Both primary endpoint analyses are identified as superiority hypotheses. |
| Stratified analysis | TTD analyses are explicitly identified as stratified by sex and ECOG. |
18. Clinical Interpretation vs Statistical Interpretation
Statistical interpretation
The registry reports stratified hazard ratios of 0.77 for PFS and 0.70 for OS for the stated placebo-versus-atezolizumab comparison, with two-sided 95% confidence intervals and P-values of 0.0170 and 0.0069, respectively.
What the numbers do not establish
Those hazard ratios do not directly state an absolute difference in survival probability, the proportion of participants who benefited, or the outcome for an individual participant.
Binary outcomes
The ORR analysis reports an odds ratio of 0.87 with a 95% CI of 0.55–1.37. The registry does not report the formal method used to calculate this effect estimate.
Time-point outcomes
PFS and OS rates are also represented by differences at specified time points, illustrating a complementary way of describing treatment-group separation.
19. What the Registry Results Show
Both primary analyses are reported as superiority analyses in the ITT population using the log-rank test.
These secondary estimates should be interpreted according to their distinct endpoint definitions and statistical effect measures.
20. Related Tutorials
Learn more about the methods used in this trial:
21. Related Calculators
22. Sources
- ClinicalTrials.gov: NCT02763579 — IMpower133.
- Linked publication: PubMed record — PMID 38280181.
- Linked publication: PubMed record — PMID 37931445.
- Linked publication: PubMed record — PMID 33439693.
- Linked publication: PubMed record — PMID 31959349.
- Linked publication: PubMed record — PMID 31466854.
Continue with the underlying statistical methods
Explore the statistical concepts that appear in randomized time-to-event and binary-outcome clinical trial analyses.
23. Record Summary
IMpower133 provides a compact example of several central clinical-trial statistical concepts: randomized parallel-group comparison, double blinding, ITT analysis, two primary time-to-event endpoints, log-rank testing, stratified hazard ratios, binary response analysis using an odds ratio, time-point event-rate comparisons using Wald / z-tests, and stratified time-to-deterioration analyses. The most important interpretive distinction is between the different effect measures: a hazard ratio summarizes relative event rates over time, an odds ratio compares odds for a binary outcome, and a difference in event-free rate describes separation at a specified time point.
The ClinicalTrials.gov record reports formal analyses for both primary endpoints. They also provide several secondary estimates, confidence intervals, and P-values, while leaving some methodological details—such as the formal ORR method, interim-analysis procedures, multiplicity allocation, and missing-data strategy—unspecified in the provided record. A statistically careful interpretation therefore uses the reported estimates directly while avoiding assumptions about methods that are not documented in the ClinicalTrials.gov record.