ECHELON-2: A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell Lymphomas: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for ECHELON-2: A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell Lymphomas (NCT01777152), a randomized phase 3 study. The primary outcome is Progression-free Survival Per Independent Review Facility (IRF).

2. Clinical Question

The central question in ECHELON-2 was whether progression-free survival differed between two chemotherapy regimens used in the frontline treatment of patients with CD30-positive mature T-cell lymphomas. The trial compared A+CHP, consisting of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone, with CHOP, consisting of cyclophosphamide, doxorubicin, vincristine, and prednisone.

Progression-free survival was defined from randomization until the first documentation of progressive disease, death from any cause, or subsequent anticancer chemotherapy for residual or progressive disease, whichever came first. The primary endpoint therefore combines disease progression and specified subsequent events into a time-to-event outcome. The registry record reports medians for both groups, but does not report a hazard ratio or a statistical test comparing them.

3. Trial Design

ECHELON-2 was a randomized, double-blind, parallel-group, phase 3 study. The registry record describes it as multicenter and placebo-controlled. Enrollment was 452, with 226 participants assigned to A+CHP and 226 to CHOP. The trial status is completed. Its start date was 2013-01-31, and its primary completion date was 2018-08-15.

The assigned groups differed in one listed drug: A+CHP included brentuximab vedotin and did not include vincristine, while CHOP included vincristine and did not include brentuximab vedotin. Both regimens included cyclophosphamide, doxorubicin, and prednisone. The record identifies double masking but does not describe which individuals were masked or how masking was maintained.

The primary outcome was progression-free survival assessed by an independent review facility. Its analysis population was the intent-to-treat set, including all randomized participants in the group assigned at randomization regardless of the treatment actually received. The stated endpoint timeframe was up to 60 months.

The registry record also lists secondary outcomes covering progression-free survival in systemic anaplastic large cell lymphoma, complete remission, overall survival, objective response, adverse events, and laboratory abnormalities. Numeric comparisons are available for complete remission and objective response in the posted results. No reported secondary analyses are listed. Details such as site-level allocation procedures, stratification factors, the planned sample-size justification, and the implementation of masking are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Intent-to-Treat (ITT) Analysis Set includes all randomized patients. Patients are included in the treatment group assigned at randomization regardless of the actual treatment received.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Progression-free Survival Per Independent Review Facility (IRF), measured over Up to 60 months.

The primary endpoint was progression-free survival per independent review facility. It measures the time from randomization to the earliest of documented progressive disease, death from any cause, or receipt of subsequent anticancer chemotherapy to treat residual or progressive disease. The registry record specifies that the first of these events determines the endpoint time.

In general, a time-to-event endpoint incorporates both when an event occurs and whether it occurs during observed follow-up. A median is the point in the estimated time distribution at which half the observations are on either side; it is a summary of the distribution, not a comparison of every participant’s outcome. The record reports median progression-free survival of 48.2 months for A+CHP and 20.8 months for CHOP. It lists lower bounds of 8.87 months and 4.7 months, respectively, but does not list upper bounds.

In general, progression-free survival is used to summarize the interval before progression or another defined event, rather than to measure response at a single assessment. Its interpretation depends on the event definition, how follow-up and incomplete observations are handled, and how the groups are compared. The endpoint definition is stated in the registry record, but censoring rules and the statistical method used to estimate the medians are not reported in the registry record. The posted medians alone do not provide a hazard ratio or a formal test of the difference between groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record reports a time-to-event primary endpoint and participant counts for two secondary response outcomes. These results call for different statistical interpretations. The record gives the primary medians and lower bounds, but does not report the primary comparison method or a hazard ratio. The secondary comparisons include risk differences, intervals, and unadjusted p-values.

What does a median time-to-event result describe?

In general, time-to-event data record the time until a defined event, while allowing that some participants may not have an event during the period they are observed. The median is a summary of the event-time distribution. It does not tell the reader how event rates compare at every point in follow-up, nor does it show the shape of the entire distribution. The primary endpoint includes progressive disease, death from any cause, or subsequent anticancer chemotherapy for residual or progressive disease, whichever occurs first.

The posted medians are 48.2 months for A+CHP and 20.8 months for CHOP. The lower bounds listed are 8.87 months and 4.7 months; upper bounds are not listed. The record does not state the method used to estimate the medians or explain the reported bounds. It also does not report a hazard ratio or a primary p-value. A hazard ratio, when reported, summarizes a relative event rate under a particular model; it is not interchangeable with a ratio of medians. No such relative estimate is available in this registry record.

Why does the endpoint definition matter?

The event definition determines what counts as progression-free survival ending. Here, an event could be progression, death from any cause, or specified subsequent anticancer chemotherapy. These components need not have the same clinical meaning, but they are combined under the stated endpoint. In general, a composite endpoint can summarize several events in one outcome, while making it important to understand which events contribute and how frequently they occur. The registry record does not provide component-specific primary results.

In general, incomplete follow-up is handled using censoring, which records that a participant was observed without an event until a particular point. The assumptions and rules for censoring can affect a time-to-event analysis. Censoring rules, follow-up completeness, and the method used to estimate the endpoint are not reported in the registry record. No specific method, such as a particular survival estimator or regression model, should be inferred from the posted medians alone.

How should the secondary risk differences be read?

The complete-remission and objective-response comparisons use A+CHP as the reference and express the risk difference as CHOP relative to A+CHP. The posted estimates are negative: -0.119 for complete remission and -0.111 for objective response. For a risk difference, zero represents equal proportions; a negative value in this stated direction means the observed proportion was lower in CHOP than in A+CHP. The reported intervals are -0.208 to -0.030 for complete remission and -0.187 to -0.035 for objective response. The registry record does not state the confidence level of these intervals.

The unadjusted p-values are 0.009 and 0.005, respectively. A p-value measures how compatible the observed data are with a specified null model under the assumptions of the test; it is not the probability that the null hypothesis is true, nor a measure of clinical importance. “Unadjusted” means these values are presented without a reported correction for multiple testing. The registry record does not describe the tests used for these comparisons.

What do the planning illustrations mean?

The planning illustrations use the observed secondary effect as a reference and show hypothetical participants per arm under assumptions stated in the registry record: two-sided significance level 0.05, equal allocation, and a normal approximation. For complete remission, planning for 100% of the observed effect gives 259 participants per arm for 80% power and 346 for 90% power; planning for 75% gives 454 and 607; planning for 50% gives 1,004 and 1,343. For objective response, the corresponding values are 222 and 296 for 100%, 377 and 504 for 75%, and 807 and 1,080 for 50%.

These calculations are illustrations based on observed effects, not a reconstruction of the trial’s design and not observed power. In general, smaller effects require more participants to reach a chosen power under otherwise fixed assumptions. The registry record does not report its own sample-size justification or the assumptions used when the trial was planned.

10. Multiplicity, Missing Data and Analysis Populations

The primary analysis population is described as the intent-to-treat set: all randomized patients, analyzed in their assigned group regardless of treatment received. That definition supports an assignment-based comparison and preserves the randomized grouping in the stated analysis population. The registry record does not provide a separate per-protocol population or other analysis-population definitions.

The registry record lists multiple secondary outcomes, including response, overall survival, safety, and laboratory abnormalities. It does not report a multiplicity adjustment, a testing hierarchy, or a family of hypotheses used to control the interpretation of these outcomes. The complete-remission and objective-response p-values are explicitly unadjusted. Without a reported multiplicity plan, those values should be interpreted as individual secondary comparisons, not as results protected against the overall number of outcomes examined.

Missing-data procedures are not reported in the registry record. The record does not describe how missing response assessments, incomplete follow-up, or withdrawals were handled. For the time-to-event endpoint, censoring rules and assumptions are also not reported. These omissions limit assessment of how the analysis treated participants without complete outcome information.

The registry record does not report interim analyses, stopping boundaries, the primary statistical model, the primary comparison test, or the sample-size justification. It also does not give a hazard ratio for progression-free survival. These details should not be inferred from the phase, enrollment, or posted medians. The posted results support description of the reported outcomes, but leave important aspects of the analysis plan and missing-data handling unspecified.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: febrile neutropenia (14.3%), pneumonia (4.9%), anaplastic large cell lymphoma t- and null-cell types (4.9%), pyrexia (4.0%), neutropenia (3.6%).

The adverse-event figures use different at-risk group sizes for the serious-event counts: 223 for A+CHP and 226 for CHOP. Serious events affected 89 participants in A+CHP and 90 in CHOP. The record also lists deaths of 67 and 89, respectively. It does not establish in this summary that these deaths were caused by treatment or were adverse-event-related; they should not be interpreted as such.

The most frequently listed serious terms include febrile neutropenia at 14.3%, pneumonia and anaplastic large cell lymphoma T- and null-cell types at 4.9% each, pyrexia at 4.0%, neutropenia at 3.6%, and pulmonary embolism at 2.7%. These entries describe reported event terms, not a comparative statistical analysis between groups. The record does not provide uncertainty estimates or adjusted comparisons for these figures.

In general, safety counts depend on the population assessed, event definitions, and observation time. The registry record does not give enough detail in these figures alone to establish comparative risk or causation. A+CHP subgroup row has zero participants at risk and one death listed, so it does not provide a usable subgroup event rate.

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

The posted results show that median progression-free survival was 48.2 months for A+CHP and 20.8 months for CHOP in the randomized intent-to-treat population. The registry record also reports secondary response counts and unadjusted comparisons. These results describe outcomes in this trial; they do not, on their own, establish a complete account of the comparative treatment effect.

The primary outcome is a median time-to-event summary, not a hazard ratio. The record does not report a hazard ratio, primary p-value, or primary comparison interval. The listed lower bounds have no corresponding upper bounds in the record. Thus, the precision and statistical evidence for the primary comparison cannot be fully assessed from the posted primary results alone. The secondary response comparisons have intervals and unadjusted p-values, but the registry record does not report a multiplicity strategy.

In general, a trial result does not guarantee that an individual participant will experience the group median, and a group-level estimate does not describe every participant’s course. Nor does a secondary response outcome substitute for longer-term time-to-event results. The safety counts likewise describe reported events; without further context and comparative analyses, they do not establish that a particular event was caused by a regimen.

The record identifies the population as patients with CD30-positive mature T-cell lymphomas and includes systemic anaplastic large cell lymphoma among its condition and outcome descriptions. It does not provide enough subgroup results in the posted information to support conclusions about each lymphoma subtype. Results should therefore be read within the stated trial population and reported analyses, without extrapolating to populations or outcomes not described in the registry record.

13. Why This Trial Matters Statistically

ECHELON-2 illustrates why the form of an endpoint matters for statistical interpretation. The primary outcome is time-to-event, but the registry record posts medians without a hazard ratio or a formal comparison result. Those medians convey an important descriptive feature of the observed distributions, while leaving the relative event rate and its precision unreported.

The trial also shows why endpoint families should not be treated as interchangeable. Response counts at end of treatment and progression-free survival capture different aspects of outcome. Their descriptive directions may align, but unadjusted secondary findings do not replace the primary analysis or resolve gaps in its reporting. A clear multiplicity plan is important when several secondary questions are examined, and no such plan is reported in the registry record.

Finally, the planning illustrations demonstrate how sample-size requirements depend on the effect assumed for planning. They are based on observed secondary effects and stated illustrative assumptions, not on the trial’s original design or observed power. Distinguishing these planning calculations from a trial’s actual design protects against reading retrospective illustrations as evidence about the study’s planned operating characteristics.

These points are broadly relevant to clinical-trial reporting: define the event precisely, identify the population analyzed, report comparative estimates with uncertainty, and explain how multiple outcomes and incomplete observations are handled. ECHELON-2’s posted information supplies some of these elements and leaves others unreported.

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 most consequential limitation for interpreting the primary result is that the registry record gives median progression-free survival but no hazard ratio, primary p-value, or formal comparison estimate. It lists lower bounds but no upper bounds, and does not identify the interval type or confidence level. Censoring rules, follow-up completeness, and the method used to estimate the medians are not reported, limiting assessment of precision and analytic assumptions.

The record also does not report a statistical analysis plan, sample-size justification, interim analyses, or a multiplicity strategy. The secondary response comparisons are unadjusted, and other listed secondary outcomes do not have comparative numerical results in the record. Absence of posted results for an outcome does not show that the outcome had no effect.

Safety data are presented as counts and selected event-term percentages, without comparative uncertainty estimates or sufficient detail to interpret causality. The at-risk counts differ between the two main groups, and the subgroup row with one death has no participants at risk listed. The registry summary does not explain that row or provide a basis for subgroup rate estimation.

Although the total enrollment and arm sizes are reported, further details about allocation procedures, stratification, and the exact masking implementation are not reported in the registry record. These reporting limitations restrict reconstruction of the trial’s statistical conduct and the scope of conclusions that can be drawn from the posted results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: ECHELON-2: A Comparison of Brentuximab Vedotin and CHP With Standard-of-care CHOP in the Treatment of Patients With CD30-positive Mature T-cell Lymphomas — NCT01777152.
• Registry record last updated 2021-11-30; status last verified 2021-11.
• Results first posted 2019-07-30.
• 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.

18. Record Summary

ECHELON-2 (NCT01777152) was a randomized, double-blind, parallel-group phase 3 trial comparing A+CHP with CHOP in patients with CD30-positive mature T-cell lymphomas. Enrollment was 452, with 226 participants in each arm. The primary endpoint was progression-free survival per independent review facility in the intent-to-treat population, over a stated timeframe of up to 60 months.

Median progression-free survival was 48.2 months for A+CHP and 20.8 months for CHOP. The registry record does not report a hazard ratio or primary statistical comparison. Secondary complete-remission and objective-response results include unadjusted comparisons. The record is completed; its start date was 2013-01-31 and primary completion date was 2018-08-15. Several analysis-plan, multiplicity, and missing-data details are not reported in the registry record.