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 ClinicalTrials.gov record.
1. Trial at a Glance
COMBI-v was a randomized, open-label, parallel phase 3 trial evaluating dabrafenib plus trametinib versus vemurafenib in patients with unresectable or metastatic BRAF V600E/K cutaneous melanoma. The registered primary endpoint was overall survival, a time-to-event endpoint analyzed in the intention-to-treat population.
| Feature | COMBI-v |
|---|---|
| Trial name | COMBI-v |
| Phase | Phase 3 |
| Condition | Melanoma |
| Population | Unresectable or metastatic BRAF V600E/K cutaneous melanoma |
| Design | Randomized, parallel-group, unmasked |
| Primary purpose | Treatment |
| Enrollment | 704 |
| Primary endpoint | Overall Survival (OS) |
| Primary endpoint type | Time-to-event |
| Primary hypothesis | Superiority |
| Lead sponsor | Novartis Pharmaceuticals |
| ClinicalTrials.gov | NCT01597908 |
2. Clinical Question
The primary statistical question was whether dabrafenib plus trametinib produced a different overall-survival experience from vemurafenib in patients with unresectable or metastatic BRAF V600E/K cutaneous melanoma, under a prespecified superiority framework.
Population
Patients with unresectable or metastatic BRAF V600E/K cutaneous melanoma.
Intervention
Dabrafenib plus trametinib.
Comparator
Vemurafenib alone.
Primary question
Does dabrafenib plus trametinib improve overall survival relative to vemurafenib?
3. Trial Design
Participants were allocated to the two treatment groups.
The registry identifies the study as a parallel-group trial.
The registry identifies the trial as unmasked.
The study was designed to evaluate treatment effects.
Dabrafenib Plus Trametinib
- Dabrafenib
- Trametinib
- Combination treatment
Vemurafenib
- Vemurafenib
- Single-drug comparator
The ClinicalTrials.gov record does not provide arm-specific randomized sample sizes, allocation ratios, stratification factors, crossover rules, non-inferiority margins, or details of interim-analysis boundaries. Those design features are therefore not inferred here.
4. Trial Timeline
Study start
The registered study start date was 2012-06-04.
Primary completion
The registered primary completion date was 2014-04-17.
Registry status
The trial is listed as COMPLETED, with results posted on ClinicalTrials.gov.
5. Endpoints
| Endpoint | Registry definition / time frame | Role |
|---|---|---|
| Overall Survival (OS) | From the date of randomization until date of death due to any cause (up to approximately 6 years). For patients who did not die, OS was censored at the date of last contact. | Primary |
| Progression-Free Survival (PFS), as Assessed by the Investigator | From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years). | Secondary |
| Duration of Response (DOR), as Assessed by the Investigator | From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years). | Secondary |
The registry classifies the primary endpoint as a time-to-event outcome. The same general time-to-event framework is used for the posted secondary PFS and DOR analyses.
6. Analysis Populations
| Population | Role in the registry-reported analysis |
|---|---|
| Intent-to-Treat (ITT) | The analysis population specified for the posted OS, PFS, and DOR statistical analyses. |
| Confirmed responders | For the DOR analysis, only participants with confirmed response by RECIST version 1.1 were included. |
The ITT designation is particularly important for the primary OS comparison. Participants are analyzed according to their randomized treatment assignment rather than being reassigned according to subsequent treatment exposure. This preserves the comparison created by randomization.
7. Primary Result: Overall Survival
The registered primary endpoint was overall survival, defined as the interval between randomization and death due to any cause, with censoring at last contact for participants who did not die. The registry-reported statistical analysis compares dabrafenib plus trametinib with vemurafenib in the ITT population.
Hazard ratio for overall survival
95% CI: 0.58–0.83 · Two-sided 95% CI
Superiority analysis; p-value not reported in the ClinicalTrials.gov record.
| Endpoint | Comparison | Effect measure | Estimate | 95% CI | Hypothesis |
|---|---|---|---|---|---|
| Overall Survival | Dabrafenib + Trametinib vs Vemurafenib | Hazard Ratio | 0.70 | 0.58–0.83 | Superiority |
What the estimate means: An HR of 0.70 means that, under the time-to-event model represented by the reported hazard ratio, the estimated instantaneous hazard of death in the dabrafenib-plus-trametinib group was 70% of that in the vemurafenib group. Expressed as a simple relative-hazard interpretation, this corresponds to an estimated 30% lower hazard.
What it does not mean: It does not mean that 30% of patients were saved, that every patient experienced a 30% reduction in risk, or that the probability of death was exactly 30% lower at every point in time.
What the confidence interval says: The two-sided 95% confidence interval of 0.58–0.83 describes uncertainty around the estimated hazard ratio under the analysis framework. It does not describe the range of individual patient outcomes.
Why the p-value is different: The ClinicalTrials.gov record does not report a p-value for this comparison. In general, a p-value addresses compatibility with a null hypothesis; it does not measure the size or clinical importance of an observed effect.
Important time-to-event caution: A hazard ratio is a relative measure of event rates over follow-up. Its interpretation relies on the underlying survival-analysis framework, and a single HR can be less descriptive if the relative hazards vary materially over time. The registry analysis does not report a separate assessment of the proportional-hazards assumption.
Analysis method reported by the registry
The registry states that hazard ratios were estimated using a Pike estimator. The ClinicalTrials.gov record does not report a more detailed normalized statistical-method description.
8. Secondary Result: Progression-Free Survival
Investigator-assessed progression-free survival was a secondary time-to-event endpoint. The registry definition measures time from randomization until the earliest date of disease progression or death due to any cause, with a time frame of up to approximately 6 years.
Hazard ratio for progression or death
95% CI: 0.52–0.73 · Two-sided 95% CI
Superiority analysis; p-value not reported in the ClinicalTrials.gov record.
| Endpoint | Comparison | Effect measure | Estimate | 95% CI | Hypothesis |
|---|---|---|---|---|---|
| Progression-Free Survival | Dabrafenib + Trametinib vs Vemurafenib | Hazard Ratio | 0.62 | 0.52–0.73 | Superiority |
What the estimate means: An HR of 0.62 corresponds to an estimated instantaneous hazard of progression or death that is 62% of the comparator hazard under the reported time-to-event analysis. In simple relative terms, this corresponds to an estimated 38% lower hazard.
What it does not mean: It is not a 38% absolute reduction in the probability of progression, and it does not mean that each participant experienced the same proportional reduction in risk.
Precision: The 95% CI of 0.52–0.73 quantifies uncertainty around the estimated hazard ratio. The interval is entirely below 1, but the ClinicalTrials.gov record does not provide a formal p-value.
Interpretation: PFS combines two possible events—disease progression and death. Consequently, an HR for PFS is not an estimate of the hazard of death alone.
Censoring: Time-to-event methods can incorporate participants whose event has not occurred by their last evaluable follow-up. The registry text does not provide enough detail to reconstruct the censoring rules beyond the endpoint definition.
9. Secondary Result: Duration of Response
Duration of response was assessed by the investigator and defined from the first documented response, complete response or partial response, until disease progression, with a time frame of up to approximately 6 years. The analysis population was the ITT population with the additional requirement that participants have a confirmed response by RECIST version 1.1.
Hazard ratio for duration of response
95% CI: 0.51–0.81 · Two-sided 95% CI
Superiority analysis; p-value not reported in the ClinicalTrials.gov record.
| Endpoint | Comparison | Effect measure | Estimate | 95% CI | Hypothesis |
|---|---|---|---|---|---|
| Duration of Response | Dabrafenib + Trametinib vs Vemurafenib | Hazard Ratio | 0.64 | 0.51–0.81 | Superiority |
What the estimate means: An HR of 0.64 corresponds to an estimated instantaneous hazard of disease progression of 64% of the comparator hazard within the analyzed responder population. In simple relative terms, this corresponds to an estimated 36% lower hazard.
Why this endpoint differs from PFS: PFS begins at randomization and includes progression or death. DOR begins later, at the first documented response, and therefore addresses durability among participants who achieved a confirmed response.
Population matters: Because only participants with confirmed response by RECIST version 1.1 were included, the DOR analysis should not be interpreted as an estimate of the probability that an unselected randomized participant will respond or remain progression-free.
Precision and p-value: The two-sided 95% CI is 0.51–0.81. The registry statistical-analysis record does not report a p-value for this comparison.
10. Results Overview
| Endpoint | Role | Analysis population | HR | 95% CI | Method note |
|---|---|---|---|---|---|
| Overall Survival | Primary | ITT | 0.70 | 0.58–0.83 | Pike estimator |
| Progression-Free Survival | Secondary | ITT | 0.62 | 0.52–0.73 | Pike estimator |
| Duration of Response | Secondary | ITT; confirmed responders by RECIST version 1.1 | 0.64 | 0.51–0.81 | Hazard ratio reported; formal method not normalized in registry record |
11. Statistical Methodology
Intention-to-treat analysis
The statistical analyses posted on ClinicalTrials.gov use the Intent-to-Treat (ITT) Population. In an ITT analysis, participants are analyzed according to their randomized treatment assignment. This is important because randomization is the mechanism that creates the basis for a causal comparison between treatment groups.
For an overall-survival endpoint, maintaining the randomized assignment means that later treatment changes or differences in treatment exposure do not automatically redefine the original comparison. That makes the ITT analysis particularly useful for preserving the interpretation of the randomized trial.
Time-to-event analysis
OS, PFS, and DOR are time-to-event endpoints. Unlike a simple binary outcome measured at one fixed date, these analyses use both whether an event occurred and information about when the event occurred. Participants who have not experienced the specified event during available follow-up may contribute censored observations.
Here, S(t) represents the probability that the event time T exceeds time t. The ClinicalTrials.gov record does not state that a particular survival estimator such as Kaplan-Meier was used, so the page does not attribute that specific estimator to COMBI-v.
Hazard ratio
The principal reported effect measure for all three posted statistical analyses was the hazard ratio. A hazard ratio compares event hazards between two groups within a time-to-event framework.
For COMBI-v, the first-named group is dabrafenib plus trametinib and the comparator is vemurafenib. An HR below 1 therefore corresponds to a lower estimated event hazard for the combination under the reported analysis.
Pike estimator
The registry analysis notes that hazard ratios are estimated using a Pike estimator. The Pike estimator is a method used to estimate a relative risk or hazard ratio from survival-event information. The registry does not provide the additional computational details needed to reconstruct the estimator from individual-level data.
Confidence intervals
Each posted effect estimate is accompanied by a two-sided 95% confidence interval. The interval provides a measure of statistical uncertainty around the point estimate under the relevant sampling and analysis framework.
A confidence interval should not be interpreted as the probability that the true hazard ratio lies inside the particular interval after the data have been observed. It is better understood as a procedure that, under repeated sampling and the model assumptions, produces intervals with the stated coverage property.
12. Statistical Methods Explained
Why was an intention-to-treat population used?
The ITT principle keeps participants associated with their randomized treatment assignment. This protects the comparison generated by randomization and avoids redefining treatment groups according to events that occurred after randomization. For COMBI-v, the registry specifically identifies the ITT population for OS, PFS, and DOR analyses.
What does an OS hazard ratio of 0.70 mean?
An OS HR of 0.70 indicates that the estimated instantaneous hazard of death for dabrafenib plus trametinib was 70% of the estimated hazard for vemurafenib under the reported analysis. The complementary interpretation is a 30% lower estimated hazard. It is not a 30-percentage-point difference in survival probability.
Why is a confidence interval needed in addition to the hazard ratio?
The hazard ratio is a point estimate, so it provides only one value summarizing the treatment comparison. The 95% confidence interval shows how much statistical uncertainty surrounds that estimate. For OS, the estimate is 0.70 and the corresponding interval is 0.58–0.83.
Why does PFS use a different event definition from OS?
OS counts death from any cause. PFS counts the earliest of disease progression or death. A participant can therefore experience a PFS event without having died. This means that an HR for PFS and an HR for OS are estimates for different event processes.
Why is DOR analyzed in a responder population?
DOR begins at the first documented response. A participant cannot have a response duration without first experiencing a confirmed response. The registry-reported analysis therefore includes only participants with confirmed response by RECIST version 1.1. This makes DOR a conditional measure of durability rather than an endpoint defined from randomization for every participant.
What does the Pike estimator contribute?
The registry states that the hazard ratios were estimated using a Pike estimator. Its role is to produce a relative treatment-effect estimate from time-to-event information. The ClinicalTrials.gov record does not provide enough detail to reconstruct the underlying event table or calculation, so the reported hazard ratios should be treated as registry results rather than independently recomputed estimates.
Why does a p-value not measure effect size?
A p-value addresses evidence against a specified null hypothesis under a statistical model. It depends on both the magnitude of an observed effect and the amount of information available. A hazard ratio and its confidence interval are therefore more directly informative about the estimated size and precision of a time-to-event effect. For the three registry-reported statistical analyses, the ClinicalTrials.gov record does not report p-values.
13. Primary Endpoint and Statistical Inference
Superiority framework
The primary OS analysis is explicitly classified as a superiority analysis. This differs fundamentally from a non-inferiority analysis, where the question is whether an effect remains within a prespecified acceptable margin.
Two-sided confidence interval
The registry-reported OS analysis reports a two-sided 95% confidence interval of 0.58–0.83 around the hazard ratio of 0.70.
Effect measure
The registry reports the hazard ratio as the effect measure for the primary OS comparison.
Formal p-value
No p-value is included in the ClinicalTrials.gov record, so no p-value is attributed to the COMBI-v result on this page.
14. Safety Results
The ClinicalTrials.gov record reports serious adverse events by arm using affected participants over participants at risk. These counts are distinct from the efficacy analyses and should not be interpreted as estimates of treatment effect on overall survival or progression-free survival.
| Safety group | Serious adverse events | Affected / at risk |
|---|---|---|
| Dabrafenib Plus Trametinib | Serious adverse events | 172/350 |
| Vemurafenib | Serious adverse events | 139/349 |
| Crossover Dabrafenib Plus Trametinib | Serious adverse events | 15/34 |
| All Patients | Serious adverse events | 319/699 |
15. What the Hazard Ratios Do — and Do Not — Mean
An OS HR of 0.70 means that the estimated instantaneous hazard of death was 70% as high in the dabrafenib-plus-trametinib group as in the vemurafenib group under the reported time-to-event analysis. This corresponds to an estimated 30% lower hazard.
It does not mean that 30% of participants survived, that 30% of deaths were prevented, or that each individual experienced exactly a 30% reduction in their probability of death.
An HR of 0.62 means that the estimated instantaneous hazard of progression or death was 62% as high in the dabrafenib-plus-trametinib group as in the vemurafenib group. This corresponds to an estimated 38% lower hazard.
Because PFS includes both progression and death, it is not equivalent to an estimate of mortality alone.
An HR of 0.64 means that the estimated instantaneous hazard of disease progression during the response-duration analysis was 64% as high in the combination group as in the comparator group within the analyzed confirmed-responder population.
This does not establish how many randomized participants responded in the first place; that is a separate question from how long a confirmed response lasted.
16. Confidence Intervals Across Endpoints
The visual above is a conceptual comparison of the reported point estimates, not a forest plot. The page does not fabricate interval graphics from insufficient underlying data. The exact reported intervals are shown in the table below.
| Endpoint | HR | 95% CI | Interpretive question |
|---|---|---|---|
| Overall Survival | 0.70 | 0.58–0.83 | Relative hazard of death after randomization |
| Progression-Free Survival | 0.62 | 0.52–0.73 | Relative hazard of progression or death after randomization |
| Duration of Response | 0.64 | 0.51–0.81 | Relative hazard of progression after confirmed response |
17. Statistical Design Topics Not Reported in the Supplied Data
Several design topics are important in clinical-trial statistics but are not described sufficiently in the registry-reported COMBI-v registry data. Rather than infer them from general knowledge or external publications, this page identifies the limits of the available record.
| Topic | What the ClinicalTrials.gov record supports |
|---|---|
| Non-inferiority margin | Not applicable to the registry-reported primary hypothesis description; the primary OS analysis is classified as superiority. |
| Crossover | A crossover dabrafenib-plus-trametinib safety subgroup of 15/34 is reported, but crossover rules and timing are not reported. |
| Factorial design | No factorial design is reported; the registry identifies a parallel design. |
| Multiplicity | The ClinicalTrials.gov record identifies one primary endpoint and three posted statistical analyses, but do not provide a multiplicity-adjustment procedure. |
| Interim analysis | No interim-analysis boundary, alpha-spending procedure, or information fraction is reported. |
| Missing data / imputation | No missing-data or imputation procedure is reported. |
| Stratification | No stratification factors are reported in the ClinicalTrials.gov record. |
| Bayesian methods | No Bayesian method is reported in the statistical analyses posted on ClinicalTrials.gov. |
18. Limitations
- Registry-level detail: The ClinicalTrials.gov record does not provide a complete statistical analysis plan, so several implementation details cannot be reconstructed.
- Unreported p-values: The statistical analyses posted on ClinicalTrials.gov provide hazard ratios and 95% confidence intervals but do not provide p-values.
- No event counts: The registry-reported efficacy analyses do not report the number of OS, PFS, or DOR events by treatment group.
- No median event times: Median OS, PFS, and DOR values are not included in the ClinicalTrials.gov record and therefore are not reported here.
- No subgroup estimates: The statistical analyses posted on ClinicalTrials.gov do not include subgroup hazard ratios or interaction tests.
- No baseline table: Baseline demographic and clinical characteristics are not reported in the ClinicalTrials.gov record.
- Hazard-ratio assumptions: A single hazard ratio summarizes a relative event-rate comparison but does not by itself demonstrate that the proportional-hazards assumption holds throughout follow-up.
- DOR conditioning: Duration of response is evaluated among confirmed responders, so it answers a different question from an endpoint defined for all randomized participants.
- Safety denominators: Serious-adverse-event counts use the registry-reported at-risk denominators, including an all-patient denominator of 699 despite total enrollment of 704. No reconciliation is attempted without additional registry information.
19. Why This Trial Matters Statistically
COMBI-v is a useful teaching case because the ClinicalTrials.gov record illustrates how a randomized oncology trial can be represented through several related but distinct time-to-event estimands.
| Concept | How it appears in COMBI-v |
|---|---|
| Randomization | The study is registered as randomized with a parallel design. |
| ITT analysis | OS, PFS, and DOR analyses are reported in the ITT population, with the DOR analysis additionally restricted to confirmed responders. |
| Time-to-event endpoints | OS, investigator-assessed PFS, and investigator-assessed DOR are all time-to-event outcomes. |
| Hazard ratio | HR is the reported effect measure for all three statistical analyses. |
| Confidence intervals | Each reported HR is accompanied by a two-sided 95% CI. |
| Superiority | The primary OS analysis is classified as a superiority hypothesis. |
| Pike estimator | The registry states that hazard ratios are estimated using a Pike estimator. |
| Endpoint conditioning | DOR starts at first documented response, unlike OS and PFS, which begin at randomization. |
| Safety analysis | Serious adverse events are reported separately using affected/at-risk counts. |
20. Statistical Concepts in This Trial
Learn more about the methods used in this trial:
21. Related Statistical Calculators
22. Sources
- ClinicalTrials.gov: COMBI-v, NCT01597908.
- PubMed: PMID 34225229.
- PubMed: PMID 31166680.
- PubMed: PMID 27864013.
- PubMed: PMID 26433819.
- PubMed: PMID 25399551.
Continue with the statistical methods behind clinical trials
Explore tutorials on survival analysis, hazard ratios, confidence intervals, randomization, and intention-to-treat analysis, then apply the concepts with statistical calculators.
23. Record Summary
COMBI-v provides a clear example of a randomized phase 3 oncology trial centered on a time-to-event primary endpoint. The registry analysis reports an OS hazard ratio of 0.70 with a two-sided 95% CI of 0.58–0.83 for dabrafenib plus trametinib versus vemurafenib in the ITT population. Secondary analyses report HRs of 0.62 for investigator-assessed PFS and 0.64 for investigator-assessed DOR, with corresponding 95% CIs of 0.52–0.73 and 0.51–0.81.
The most important statistical distinction is that these three estimates describe different event processes and populations. OS begins at randomization and measures death from any cause. PFS begins at randomization and measures progression or death. DOR begins only after a confirmed response and measures progression thereafter. The hazard ratios quantify relative event hazards, while the confidence intervals describe uncertainty around those estimates.