This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. View NCT04209855 on ClinicalTrials.gov.
1. Trial at a Glance
MIRASOL was a randomized, open-label, parallel phase 3 trial evaluating mirvetuximab soravtansine against investigator's choice chemotherapy in patients with platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high FRα expression. The registered primary endpoint was progression-free survival (PFS) assessed by RECIST Version 1.1.
| Feature | MIRASOL |
|---|---|
| Phase | Phase 3 |
| Population | Platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high FRα expression |
| Design | Randomized, parallel, open-label |
| Allocation | Randomized |
| Primary endpoint | Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 |
| Primary endpoint type | Time-to-event |
| Primary hypothesis | Superiority |
| Primary analysis | Log-rank test |
| Effect measure | Hazard ratio from a Cox proportional-hazards analysis |
| Enrollment | 453 |
| Lead sponsor | AbbVie |
| Sponsor type | Industry |
| Trial start | December 31, 2019 |
| Primary completion | March 6, 2023 |
| ClinicalTrials.gov | NCT04209855 |
2. Clinical Question
The central statistical question was whether mirvetuximab soravtansine would produce longer progression-free survival than investigator's choice chemotherapy in the specified platinum-resistant cancer population with high FRα expression.
Population
Patients with platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal, or fallopian tube cancers with high FRα expression.
Intervention
Mirvetuximab soravtansine.
Comparator
Investigator's Choice (IC) chemotherapy.
Primary question
Does mirvetuximab soravtansine improve progression-free survival relative to investigator's choice chemotherapy?
3. Trial Design
Mirvetuximab Soravtansine
- Mirvetuximab soravtansine
- Randomized treatment arm
Investigator's Choice Chemotherapy
- Investigator's Choice chemotherapy
- Permitted chemotherapy interventions included paclitaxel, topotecan, and pegylated liposomal doxorubicin
The design is statistically important because randomization establishes the treatment groups as the principal basis for causal comparison. The absence of masking does not invalidate a randomized time-to-event comparison, but it is relevant when considering endpoints or clinical decisions that can be influenced by knowledge of treatment assignment. For the primary PFS analysis, the registry identifies an objective radiologic progression definition under RECIST Version 1.1 together with death as an event.
4. Endpoints
| Endpoint | Registry definition / time frame | Statistical role |
|---|---|---|
| Progression-free Survival (PFS) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | From randomization until PD or death, whichever occurred first (up to approximately 36 months) | Primary endpoint; time-to-event; superiority hypothesis |
Registered PFS definition
PFS was defined as the time from randomization until progressive disease (PD) or death whichever occurred first. PD: At least a 20% increase in the sum of the longest diameters (SoD) of target lesion, taken as reference the smallest (nadir) SoD since and including baseline. In addition to the relative increase of 20%, the SoD must also demonstrate an absolute increase of at least 5 millimeters (mm). Unequivocal progression of non-target lesions and appearance of new lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase.
5. Primary Results: Progression-Free Survival
The registry reports one formal statistical analysis for the primary endpoint. The analysis population was the intention-to-treat population, defined as all participants randomized to the study regardless of whether or not they received study treatment.
Hazard ratio for progression or death
95% CI: 0.513–0.785 · P < 0.0001 · Two-sided
Analysis: log-rank test; effect measure: Cox proportional hazard.
| Primary endpoint | Analysis population | Method | Effect estimate | 95% CI | P-value |
|---|---|---|---|---|---|
| Progression-free Survival (PFS) | ITT | Log-rank | Hazard ratio 0.63 | 0.513–0.785 | <0.0001 |
A hazard ratio of 0.63 means that, under the Cox proportional-hazards interpretation, the estimated instantaneous rate of progression or death in the mirvetuximab soravtansine group was approximately 63% of that in the investigator's choice chemotherapy group. Expressed as a relative complement, this corresponds to a 37% lower estimated hazard of progression or death.
The hazard ratio does not mean that 37% of patients avoided progression, that every patient experienced exactly a 37% reduction in risk, or that median PFS differed by a particular number of months. Those would require different statistics.
The 95% confidence interval of 0.513–0.785 describes statistical uncertainty around the estimated hazard ratio. It does not describe the range of effects experienced by individual patients. Because the entire interval is below 1, every value in this reported interval corresponds to a lower estimated hazard in the mirvetuximab soravtansine group relative to the comparator.
The P-value < 0.0001 addresses evidence against the null hypothesis used for the statistical comparison. It does not measure the size or clinical importance of the treatment effect. The effect size is described by the hazard ratio and its confidence interval; the p-value answers a different question about statistical evidence under the null framework.
Because the effect is expressed through a Cox proportional-hazards model, the usual interpretation assumes that a single hazard ratio is an appropriate summary of the relative hazards over the analyzed period. The ClinicalTrials.gov record does not provide sufficient information to independently assess the proportional-hazards assumption.
6. How to Read the Primary Result
The most informative way to read the MIRASOL primary result is to keep three statistical quantities separate: the hazard ratio, its confidence interval, and its p-value.
Hazard ratio: magnitude
The estimate of 0.63 is the principal relative-effect measure reported for PFS. Values below 1 favor the first-listed treatment in this comparison with respect to the event of progression or death.
Confidence interval: precision
The interval 0.513–0.785 shows the range of hazard-ratio values compatible with the reported statistical uncertainty under the analysis framework.
P-value: evidence
The value <0.0001 quantifies statistical evidence against the null hypothesis. It is not a measure of how large or clinically important the treatment effect is.
ITT population: analysis principle
All randomized participants were included in the primary efficacy population regardless of whether they received study treatment, preserving treatment assignment as the basis of comparison.
The corresponding relative complement is 1 − 0.63 = 0.37, or a 37% lower estimated hazard. This is a direct interpretation of the reported hazard ratio; it is not an estimate of absolute risk reduction.
7. Statistical Methodology
Intention-to-treat analysis
The primary analysis used the ITT population. The registry defines this population as all participants randomized to the study, regardless of whether or not participants received study treatment. This is an important design principle because the comparison remains tied to the original randomization.
ITT analysis is particularly relevant in superiority trials because excluding randomized participants after allocation can introduce selection into the treatment comparison. Retaining randomized participants according to their assigned group helps preserve the comparability created by randomization.
Log-rank test
The reported primary statistical method was the log-rank test. The log-rank test is designed for comparing survival or time-to-event distributions between randomized groups while accounting for different follow-up times and right censoring.
The log-rank procedure compares the observed pattern of events with the pattern expected under the null hypothesis across event times. It is therefore fundamentally different from a simple comparison of proportions at one fixed time point.
Cox proportional-hazards model
The registry reports the effect measure as a Cox proportional hazard and the effect measure as a hazard ratio. The Cox model is commonly used to estimate a relative hazard while retaining censored observations in the time-to-event analysis.
For a two-group treatment comparison, exponentiating the treatment coefficient produces the hazard ratio. The registry's reported estimate of 0.63 therefore summarizes the relative hazard under the fitted Cox model.
Right censoring
Time-to-event analyses allow some participants to reach their last known assessment without having experienced the event by that time. Such participants are censored rather than treated as if the event had occurred. This lets their available follow-up contribute information without assigning an unobserved event date.
For PFS, the event definition is especially important because either progressive disease or death can end event-free follow-up. The registered time frame begins at randomization and continues until PD or death, whichever occurs first.
8. Statistical Methods Explained
Why was a log-rank test used?
PFS is a time-to-event endpoint, not merely a binary outcome. Participants can have different follow-up times, and some may be censored before experiencing progression or death. The log-rank test is designed for this setting because it compares event-time distributions while incorporating the available follow-up information.
What does a hazard ratio of 0.63 mean?
A hazard ratio of 0.63 indicates an estimated instantaneous event rate approximately 37% lower in the mirvetuximab soravtansine group relative to investigator's choice chemotherapy, under the Cox model. It is a relative time-to-event measure, not an absolute percentage of patients who avoid progression.
Why is the confidence interval important?
The point estimate alone gives only one estimate of the treatment effect. The 95% confidence interval of 0.513–0.785 shows the statistical uncertainty around that estimate. A narrower interval would indicate greater precision, whereas a wider interval would indicate less precision.
Why does the p-value not measure effect size?
The p-value and the hazard ratio answer different questions. The hazard ratio describes the estimated relative treatment effect. The p-value describes the degree of statistical evidence against the null hypothesis used by the test. A very small p-value can occur with a relatively modest effect when the data are highly informative, while a larger effect estimate can be imprecisely estimated in a smaller or more variable dataset.
Why does the ITT population matter?
Analyzing all randomized participants according to their randomized assignment preserves the principal comparison created by randomization. In MIRASOL, the registry explicitly defines the ITT population as all randomized participants regardless of whether they received study treatment.
What does censoring mean for PFS?
Censoring occurs when a participant's event-free follow-up ends without observing progression or death during the available observation period. The participant contributes information up to the censoring time. Censoring is therefore not the same thing as a PFS event.
Why is the proportional-hazards assumption relevant?
The Cox hazard ratio is most naturally interpreted as a common relative hazard over time. If the relative hazard changes substantially over time, a single hazard ratio can compress a more complicated time-dependent treatment effect into one summary number. The ClinicalTrials.gov record does not report an assessment of this assumption.
9. What the Confidence Interval Tells Us
The reported hazard ratio is 0.63, with a two-sided 95% CI of 0.513–0.785. The interval is entirely below 1, so the full reported interval represents hazard-ratio values below the no-difference value of 1.
The lower endpoint, 0.513, corresponds to a stronger estimated relative reduction in hazard than the point estimate, while the upper endpoint, 0.785, corresponds to a smaller relative reduction. Thus the confidence interval communicates both the direction and the statistical precision of the estimated treatment effect.
| Quantity | Reported value | How to interpret it |
|---|---|---|
| Hazard ratio | 0.63 | Estimated relative hazard of progression or death under the Cox model |
| 95% CI lower | 0.513 | Lower endpoint of the reported uncertainty interval |
| 95% CI upper | 0.785 | Upper endpoint of the reported uncertainty interval |
| P-value | <0.0001 | Statistical evidence from the reported comparison |
A confidence interval should not be interpreted as saying that there is a 95% probability that the true hazard ratio lies between 0.513 and 0.785. In the frequentist framework, the interval is a property of the statistical procedure and the observed data. Its practical role here is to show the uncertainty associated with the reported point estimate.
10. Primary Endpoint Analysis Population
This definition has an important statistical consequence. The primary comparison does not redefine the groups based on treatment exposure after randomization. Instead, the treatment groups remain the randomized groups. This protects the principal advantage of randomization: treatment assignment is determined independently of subsequent treatment receipt and other post-randomization events.
For a superiority analysis, this distinction is central. A comparison restricted only to participants who completed treatment could differ systematically from the randomized comparison because treatment completion can itself be related to prognosis, tolerability, disease progression, or other post-randomization factors.
11. Safety Results
The ClinicalTrials.gov record reports serious adverse events by randomized arm. The reported counts are the number affected divided by the number at risk for each arm.
| Safety measure | Mirvetuximab Soravtansine | Investigator's Choice (IC) Chemotherapy |
|---|---|---|
| Serious adverse events | 62 / 227 | 73 / 226 |
The safety information should be kept conceptually separate from the PFS analysis. The primary efficacy endpoint is a time-to-event comparison analyzed in the ITT population, whereas the ClinicalTrials.gov record is presented as affected participants over those at risk in each arm. The ClinicalTrials.gov record does not provide a formal statistical comparison of serious adverse-event rates, so no comparative p-value or effect estimate is presented for this safety outcome.
12. What Is and Is Not Reported in the Supplied Registry Data
The ClinicalTrials.gov record contains a formal statistical analysis for the primary PFS endpoint. They do not provide additional formal statistical analyses that can be reproduced here for other outcome measures.
| Analysis element | Supplied data | Interpretation |
|---|---|---|
| Primary PFS analysis | Reported | Log-rank test with Cox proportional-hazard effect estimate |
| Hazard-ratio estimate | 0.63 | Reported for PFS |
| 95% CI | 0.513–0.785 | Reported for PFS |
| P-value | <0.0001 | Reported for PFS |
| Secondary endpoint formal analyses | Not reported | No additional comparative result is presented |
| Subgroup analyses | Not reported | No subgroup effect estimates are presented |
| Median PFS | Not reported | No median is reported here |
| Kaplan-Meier estimates | Not reported | No time-specific survival probabilities are reported here |
| Interim-analysis details | Not reported | No interim alpha-spending or stopping rule is described here |
| Multiplicity procedure | Not reported | No multiplicity adjustment is described here |
| Missing-data or imputation procedure | Not reported | No imputation method is reported here |
| Stratification factors | Not reported | No stratified analysis factors are identified here |
| Bayesian analysis | Not reported | No Bayesian method is reported |
This distinction is important for an educational statistical record. A time-to-event trial may use several additional analytical components in its full protocol or statistical analysis plan, but they should not be attributed to MIRASOL unless they are documented in the ClinicalTrials.gov record.
13. A Closer Look at the Primary PFS Result
The primary result combines a very small p-value with a hazard ratio substantially below 1 and a confidence interval entirely below 1. Those three pieces of information are complementary rather than interchangeable.
Direction
The hazard ratio of 0.63 is below 1, indicating a lower estimated hazard of progression or death in the mirvetuximab soravtansine group relative to investigator's choice chemotherapy.
Magnitude
The point estimate corresponds to a 37% lower estimated hazard, calculated directly as the complement of the reported hazard ratio.
Precision
The 95% CI extends from 0.513 to 0.785, providing a range of plausible effect estimates under the reported statistical framework.
Evidence
The two-sided p-value is <0.0001, indicating strong statistical evidence against the null comparison used by the primary test.
It is also important not to confuse the hazard ratio with an absolute treatment effect. Without reported median PFS, fixed-time PFS probabilities, or the underlying event and censoring data, the ClinicalTrials.gov record does not support a calculation of an absolute difference in PFS duration or a number-needed-to-treat measure.
14. Why the Time Origin Matters
The registry defines PFS from randomization until PD or death. This time origin is statistically consequential. Randomization occurs before subsequent treatment exposure and before the future course of disease is known, making it a clean anchor for the randomized comparison.
If time were instead measured only among participants who began or completed treatment, the analysis population and time origin could become conditional on post-randomization events. Such conditioning can compromise the interpretation of the randomized comparison.
If neither event is observed during available follow-up, the participant contributes follow-up information up to the applicable censoring point under the analysis framework.
15. The Role of RECIST in the Endpoint
The primary endpoint was not simply "time until treatment failure." It was specifically PFS as assessed by RECIST Version 1.1. The registry definition identifies progressive disease using a relative increase in the sum of the longest diameters of target lesions, together with an absolute increase requirement.
This makes endpoint definition part of the statistical design. A time-to-event analysis can only be interpreted correctly when the event itself is defined consistently. Here, the event is either RECIST-defined PD or death, whichever occurs first.
16. Superiority Hypothesis
The registered hypothesis type was superiority. This means the statistical question was whether the treatment groups differed in the prespecified direction of interest rather than whether the new treatment stayed within a predefined non-inferiority margin.
| Hypothesis feature | MIRASOL |
|---|---|
| Hypothesis type | Superiority |
| Primary endpoint | Progression-free survival |
| Event | PD or death, whichever occurred first |
| Primary test | Log-rank |
| Effect measure | Hazard ratio |
| Reported hazard ratio | 0.63 |
| Reported two-sided 95% CI | 0.513–0.785 |
| Reported p-value | <0.0001 |
Because this is a superiority analysis, the central null reference for the hazard ratio is 1. A hazard ratio of 1 would correspond to equal hazards under the model. The reported estimate is below 1, and the entire reported confidence interval remains below 1.
17. Limitations
- Limited statistical detail in the ClinicalTrials.gov record: the ClinicalTrials.gov record identifies the primary test and effect measure but do not provide a complete statistical analysis plan.
- No median PFS reported: the ClinicalTrials.gov record does not include median PFS or its confidence interval, so no median treatment difference is reported.
- No time-specific PFS estimates reported: no Kaplan-Meier probabilities at particular time points are provided in the ClinicalTrials.gov record.
- No subgroup estimates reported: the available data do not support a subgroup-by-subgroup assessment of treatment-effect consistency.
- No multiplicity procedure reported: the ClinicalTrials.gov record does not describe adjustment for multiple endpoints or repeated analyses.
- No interim-analysis procedure reported: the ClinicalTrials.gov record does not identify interim looks, alpha spending, or stopping boundaries.
- No missing-data or imputation strategy reported: the ClinicalTrials.gov record does not specify how missing assessments were handled.
- Open-label design: masking was listed as none. This is a design characteristic that should be considered when interpreting endpoints potentially influenced by knowledge of treatment assignment.
- Cox-model interpretation: a single hazard ratio is most straightforward when the proportional-hazards interpretation is reasonable; the ClinicalTrials.gov record does not report an assumption check.
- Safety comparison: serious adverse-event counts are reported descriptively, but no formal comparative safety analysis is reported in the statistical analyses posted on ClinicalTrials.gov.
18. Why This Trial Matters Statistically
MIRASOL is a useful teaching example because it connects a randomized phase 3 treatment comparison directly to the core machinery of time-to-event analysis. The primary endpoint is defined from randomization, the event combines progression and death, the analysis uses a log-rank test, and the treatment effect is summarized using a Cox proportional-hazards hazard ratio.
| Statistical concept | How it appears in MIRASOL |
|---|---|
| Randomization | Participants were randomized between two parallel treatment arms. |
| Intention-to-treat analysis | The primary analysis included all randomized participants regardless of whether study treatment was received. |
| Time-to-event endpoint | PFS was measured from randomization until PD or death. |
| RECIST endpoint definition | Progression was defined using the registered RECIST Version 1.1 criteria. |
| Log-rank test | Used as the reported primary statistical comparison. |
| Hazard ratio | Reported Cox proportional-hazard estimate of 0.63. |
| Confidence interval | Two-sided 95% CI of 0.513–0.785. |
| P-value | Two-sided p-value <0.0001. |
| Censoring | Relevant because PFS is a time-to-event endpoint with follow-up potentially ending before an event. |
| Superiority testing | The registered hypothesis type was superiority. |
| Open-label design | Masking was listed as none. |
| Safety analysis | Serious adverse events are reported descriptively by arm. |
19. Statistical Concepts in This Trial
Learn more about the methods used in this trial:
20. Related Statistical Calculators
21. Sources
- ClinicalTrials.gov: MIRASOL, NCT04209855.
- PubMed: PMID 40179908.
- PubMed: PMID 38055253.
Continue with the statistical methods behind MIRASOL
Explore the underlying survival-analysis concepts, then apply them with Clinical Biostats statistical calculators.
22. Record Summary
MIRASOL is a randomized phase 3 superiority trial with a primary time-to-event endpoint: progression-free survival from randomization until RECIST Version 1.1-defined progressive disease or death, whichever occurred first. The primary analysis used the ITT population and a log-rank test, with a Cox proportional-hazard effect measure.
The reported hazard ratio of 0.63 corresponds to a 37% lower estimated hazard of progression or death in the mirvetuximab soravtansine group relative to investigator's choice chemotherapy. The two-sided 95% confidence interval of 0.513–0.785 describes the statistical uncertainty around that estimate, while the reported p-value <0.0001 describes the statistical evidence against the null hypothesis. These quantities should be interpreted together rather than treating the p-value as a measure of treatment magnitude.
The ClinicalTrials.gov record also report serious adverse events of 62/227 in the mirvetuximab soravtansine arm and 73/226 in the investigator's choice chemotherapy arm. No formal comparative safety analysis is reported here. Likewise, the ClinicalTrials.gov record does not provide median PFS, time-specific Kaplan-Meier estimates, subgroup effects, multiplicity procedures, interim-analysis details, or missing-data methods, so those elements are not inferred.