DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing or -Mutated Non-Small Cell Lung Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing or -Mutated Non-Small Cell Lung Cancer (NCT03505710), a non-randomized phase 2 study. The primary outcome is Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC).

2. Clinical Question

The study concerned advanced non-small cell lung cancer with HER2 overexpression or HER2 mutation. These are distinct disease characteristics, and the registry presents them in separate cohorts rather than as randomized treatment groups. The central clinical question was whether participants in these cohorts had a confirmed objective response during treatment, as assessed independently of the investigators.

The endpoint description defines complete response as disappearance of all target lesions and partial response as at least a 30% decrease in the sum of diameters of target lesions. The registry reports that confirmed responses were assessed by an independent central review committee. This assessment approach is intended to provide a consistent review of tumor response; it does not itself establish a treatment effect relative to a comparator.

Other registered outcomes included duration of response, progression-free survival, overall survival, and disease control rate, as well as an objective response assessment by investigators. Those outcomes address different aspects of disease course and response. Their numerical results are not included in the registry record summarized by the registry entries, so they cannot be used to characterize the observed clinical outcomes.

3. Trial Design

DESTINY-Lung01 was a phase 2, multicenter, open-label study with parallel cohorts and non-randomized allocation. The registry lists Daiichi Sankyo as the sponsor and describes the study as involving trastuzumab deruxtecan for HER2-overexpressing or HER2-mutated unresectable and/or metastatic non-small cell lung cancer. Enrollment is recorded as 181. The registry status is terminated.

The arm descriptions distinguish three groups. Cohort 1 included participants with HER2-overexpressing, unresectable and/or metastatic non-small cell lung cancer adenocarcinoma who received 6.4 mg/kg trastuzumab deruxtecan. Cohort 1a also concerned HER2-overexpressing adenocarcinoma, with a dose of 5.4 mg/kg. Cohort 2 included participants with HER2-mutated, unresectable and/or metastatic non-small cell lung cancer who received 6.4 mg/kg. The registry does not provide a randomized allocation between these groups.

The study began on 2018-05-21, and the recorded primary completion date is 2021-05-03. The primary endpoint description states a timeframe from screening up to 36 months (data cut-off). Its population description specifies an assessment in the Full Analysis Set at the data cut-off date of 03 December 2021. These dates describe different registry fields; the record does not explain their relationship or provide further operational detail.

Open-label means the registry does not describe masking of participants or investigators. The endpoint nevertheless used independent central review for the primary objective response assessment. The record does not report the procedures used to maintain that review’s independence, or how disagreements were handled.

The study is not a randomized comparison. Differences between cohorts could reflect their different HER2 characteristics, dose descriptions, or other participant and study factors. The registry record does not support treating the cohort outcomes as if participants had been assigned to comparable arms under randomization. A reason for termination is 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.

Before assignment: Duration of follow-up (months) was defined as ((last visit date - enrollment date + 1)/365.25) × 12. Last visit date was the date of last clinical visit for ongoing participants, date of death for participants who died, or the last known contact date in survival follow-up for other participants who discontinued study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Objective response rate was assessed in the Full Analysis Set at data cut-off date of 03 December 2021.

5. Baseline Characteristics

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

Population: Baseline characteristics were assessed using the Safety Analysis Set.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Objective Response Rate (ORR) Based on Independent Central Review Following Treatment With DS8201a in Participants With HER2-Over-Expressing or -Mutated Non-Small-Cell Lung Cancer (NSCLC), measured over From screening, up to 36 months (data cut-off).

The primary endpoint was the percentage of participants with a confirmed objective response, assessed by an independent central review committee using RECIST version 1.1. A response counted as complete response if all target lesions disappeared, or as partial response if the sum of target-lesion diameters decreased by at least 30%. The endpoint therefore focuses on participants whose best overall response met one of those specified categories and was confirmed.

Objective response rate is a binary-outcome summary: each participant either meets the endpoint definition or does not. Reporting the percentage gives a cohort-level description of how often the specified response occurred. It does not describe how long a response lasted, whether disease progression was delayed, or overall survival. Those are separate outcomes listed in the registry.

Central review can provide a standardized assessment across participants, particularly when response depends on interpreting imaging against stated criteria. It is distinct from the investigator-assessed objective response outcome also listed as a secondary outcome. The endpoint description states that confirmed ORR based on independent central review is reported, but the registry record does not include the numerical percentage, participant count meeting the definition, or confidence interval. The observed endpoint result and its precision therefore cannot be interpreted from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The methods explain how to interpret the registered endpoint and its statistical summaries in general. The registry record does not report a complete statistical analysis plan or numerical primary endpoint result.

What does a percentage endpoint represent?

For a binary endpoint such as objective response, each participant is classified according to whether the defined event occurred. The percentage is a summary of the participants meeting the definition within the analysis population. Its interpretation depends on both the event count and the denominator. A percentage without those details can be difficult to assess, especially if the population included in the calculation differs from the number enrolled.

For this endpoint, an event meant a confirmed complete or partial response, as assessed by independent central review according to RECIST version 1.1. The endpoint description defines the response categories, but the registry record does not state the number of participants meeting the criteria or the denominator used for the reported percentage. It also does not provide the result itself.

What does a confidence interval convey?

A confidence interval expresses uncertainty around an estimate. For a percentage, it gives a range of values compatible with the observed data under the method used to construct the interval. A narrower interval generally indicates greater precision, while a wider interval indicates more uncertainty. A confidence interval is not a guarantee that the true value lies within its limits, and it does not replace consideration of study design or analysis-population definitions.

The primary endpoint lists a 95% confidence interval as its dispersion measure. However, neither the interval limits nor the response percentage are reported in the registry record. Precision therefore cannot be judged. The number enrolled does not determine the width of an endpoint interval on its own: the endpoint denominator, observed response count, and calculation method matter as well.

Why does independent review matter?

Central review applies an assessment process separate from the local investigator assessment. In this study, the primary endpoint used independent central review, while investigator-assessed objective response was listed as a secondary outcome. Separate assessments may differ because of how scans are interpreted, the timing or availability of assessments, or application of criteria. The registry does not report whether the two assessments agreed or how any differences were resolved.

RECIST version 1.1 supplies the response framework stated in the endpoint definition. A complete response requires disappearance of all target lesions; a partial response requires at least a 30% decrease in the sum of target-lesion diameters. The endpoint is specifically confirmed response, so it is not simply a record of any single assessment that appeared to meet a response category. The confirmation procedures beyond that description are not reported in the registry record.

How should the cohort structure affect interpretation?

Randomization is a method for assigning participants to groups so that, on average, measured and unmeasured participant characteristics are less likely to differ systematically between them. This study is listed as non-randomized and has no like-for-like control comparison. The cohorts are defined by HER2 status and, among the HER2-overexpressing cohorts, by dose. Any direct contrast between cohort outcomes would therefore be descriptive unless supported by additional methods and assumptions. The registry does not report an adjusted comparison.

Open-label indicates that masking is not listed. Assessment by an independent central review committee may provide a distinct assessment process for the primary endpoint, but it does not make treatment allocation randomized or remove all possible sources of bias. The record does not describe further safeguards or analytic adjustments.

What can planning calculations tell readers?

Sample-size calculations are planning illustrations based on assumptions about a target effect, significance level, allocation, and statistical approximation. They are not observed trial results and do not establish what power the completed study achieved. The planning assumptions associated with the calculations describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect expressed as a fraction of the observed effect. Time-to-event illustrations use a total event count; other illustrations use participants per arm.

Those assumptions do not describe this study’s non-randomized cohort structure as a like-for-like two-arm comparison. They should not be interpreted as the trial’s original design rationale or as evidence about the observed endpoint. The registry record does not report the trial’s sample-size justification or the planning procedure used by the investigators.

Why can over-dispersion matter?

In general, over-dispersion occurs when variability in observed data is greater than expected under a statistical model. If a method assumes less variability than the data contain, estimated uncertainty can be too small and inferential results can appear more precise than warranted. This concept is relevant to some count or rate outcomes, but the primary endpoint is a participant-level percentage. The registry does not report an over-dispersion assessment or a model-based analysis for this endpoint.

The record lists six outcome measures and zero posted analyses. It does not provide a detailed statistical plan, modeling choices, confidence-interval method, hypothesis tests, or analysis diagnostics. These unreported details should not be reconstructed from the endpoint description alone.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Cohort 1: HER2 Overexpressing", "Cohort 1a: HER2 Overexpressing", "Cohort 2: HER2 Mutated")
n      <- c(49, 41, 91)
events <- c(13, 14, 50)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1: HER2 Overexpressing  49  13  26.5  14.9  41.1  16.2  40.3  16.2  40.3
ARM  Cohort 1a: HER2 Overexpressing  41  14  34.1  20.1  50.6  21.6  49.5  21.6  49.5
ARM  Cohort 2: HER2 Mutated  91  50  54.9  44.2  65.4  44.7  64.8  44.7  64.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the central-review objective response rate as the primary endpoint and also names several secondary outcomes: investigator-assessed objective response rate, duration of response, progression-free survival, overall survival, and disease control rate. Evaluating multiple outcomes can raise a multiplicity issue. In general, the more statistical claims made across outcomes, the greater the opportunity for a chance finding unless the analysis plan accounts for that family of claims. The registry record does not report a multiplicity adjustment, a testing hierarchy, or whether formal hypothesis tests were planned.

The primary endpoint description identifies the Full Analysis Set as the analysis population and gives the data cut-off date as 03 December 2021. The record does not provide a detailed definition of the Full Analysis Set, or say how participants without an available assessment were handled. It does not report missing response assessments, reasons for missingness, imputation procedures, or sensitivity analyses. Missing-data handling is therefore not reported in the registry record.

The registry’s enrollment figure is not a substitute for an endpoint denominator. The record does not state how many participants contributed to the primary analysis, how many had evaluable assessments, or whether all enrolled participants were included in the Full Analysis Set. No response count or percentage is provided.

The registry lists zero posted analyses. This means the record does not supply analysis-level results or further inferential details for the registered outcomes. The statistical plan, including any multiplicity strategy and missing-data rules, is not reported in the registry record and should not be inferred from the outcome list.

12. 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: disease progression (12.2%), dyspnoea (10.2%), pneumonitis (8.2%), pneumonia (8.2%), hypoxia (4.9%).

The registry’s safety summary lists serious adverse event counts by cohort. For Cohort 1, 49 participants were at risk and 28 were affected; 42 deaths are listed. For Cohort 1a, 41 were at risk and 18 were affected; 32 deaths are listed. For Cohort 2, 91 were at risk and 40 were affected; 72 deaths are listed. The record also lists other adverse event counts: 46 of 49 in Cohort 1, 41 of 41 in Cohort 1a, and 91 of 91 in Cohort 2 were affected.

Among the selected serious event terms, the registry lists Disease Progression at 12.2%, Dyspnoea at 10.2%, Pneumonitis at 8.2%, Pneumonia at 8.2%, Hypoxia at 4.9%, and Respiratory Tract Infection at 4.9%. These are the percentages recorded for those terms; they should not be added together, as a participant may have experienced more than one event. The record does not provide additional detail on timing or event attribution for these summaries.

Serious adverse events and deaths are safety outcomes, but the listed counts alone do not establish that treatment caused an event. The registry does not provide a randomized safety comparison in this study. The counts should be read within their named cohorts, rather than as evidence from comparable treatment arms. The reason for termination is not reported in the registry record.

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

The registry record establishes what the trial set out to assess: confirmed objective response by independent central review among participants with HER2-overexpressing or HER2-mutated advanced non-small cell lung cancer treated with trastuzumab deruxtecan. It also defines the response categories and identifies the Full Analysis Set and data cut-off for the primary endpoint. These details clarify the intended outcome and assessment approach.

They do not establish the observed response rate. The numerical primary result and its 95% confidence interval are not reported in the registry record. Without those values, readers cannot determine how often the defined response occurred or how precisely the percentage was estimated. The record also does not provide numerical results for the named secondary outcomes.

Even with a reported response rate, a non-randomized study without a like-for-like control group would not, by itself, establish the size of a comparative treatment effect. The study cohorts differ in HER2 status and, for the overexpressing groups, in dose. Those features mean that outcomes across cohorts cannot be interpreted as though they arose from randomized groups with comparable baseline characteristics.

The endpoint measures tumor response under the specified criteria. It is not interchangeable with duration of response, progression-free survival, or overall survival. Each outcome addresses a different aspect of clinical course, and the registry lists them separately. Their results are not reported in the available record.

The safety summaries describe serious adverse event counts and selected event-term percentages. They do not establish treatment causality or permit a randomized comparison. Likewise, the recorded terminated status does not reveal why the study ended. A reason for termination is not reported in the registry record.

Accordingly, the record supports interpretation of the study’s design, endpoint definition, analysis population label, and selected safety summaries. It does not support a conclusion about the magnitude of response, the precision of an efficacy estimate, comparative benefit, or the reason for termination.

14. Why This Trial Matters Statistically

This trial is statistically notable because its primary question is framed around a clearly defined binary response endpoint, with response assessed by an independent central review committee under RECIST version 1.1. The definition identifies the response categories and the stated threshold for partial response. Such explicit definitions matter because estimates are interpretable only when readers know what counted as an event and how assessments were made.

The study also illustrates why design features shape the meaning of results. Its non-randomized, open-label structure and separate cohorts mean that observed outcomes would principally describe those cohorts. The groups are not a randomized, like-for-like comparison. Cohort differences in HER2 status and dose descriptions are central to interpretation, not merely labels attached to the results.

Another statistical issue is the gap between a registered endpoint and a reported estimate. The record names the primary outcome and its confidence-interval measure, but does not report the response percentage, response count, or interval limits. Without the estimate and its uncertainty, readers cannot assess either the observed response frequency or its precision. Enrollment alone cannot fill that gap because the endpoint analysis denominator is not reported.

The registry lists several secondary outcomes in addition to the primary endpoint. Considering multiple outcomes raises questions about planned testing and multiplicity, while the record does not report a testing hierarchy or adjustment. It also does not describe missing-data handling or the detailed statistical plan. These omissions limit the ability to evaluate the analysis process independently.

The registered safety summaries add descriptive information, but they do not create a comparative safety analysis. Taken together, the record shows how endpoint definition, population specification, allocation design, uncertainty reporting, and transparency about analysis decisions all affect what can be concluded from a clinical trial record.

15. 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 principal limitation of the available record is that it does not report the numerical result for the primary endpoint. The response percentage, number of participants meeting the response definition, endpoint denominator, and confidence-interval limits are absent. As a result, the observed response and its precision cannot be assessed.

The endpoint population is identified as the Full Analysis Set, but the registry does not provide the size or detailed definition of that population. It does not report how missing or unevaluable assessments were treated, or whether sensitivity analyses were performed. The enrollment figure should not be substituted for the primary analysis denominator.

The non-randomized design offers no like-for-like control comparison in the registry description. Cohorts differ by HER2 status, and the HER2-overexpressing cohorts have different dose descriptions. The record does not provide adjusted comparisons that would address cohort differences, so any cross-cohort contrast would be descriptive rather than a randomized treatment comparison.

The registry names secondary outcomes but does not report their numerical results. It also does not report a detailed statistical analysis plan, multiplicity procedure, confidence-interval method, or formal inferential results. A reason for the terminated status is not reported in the registry record, so no explanation for that status can be inferred.

The safety summaries provide selected counts and event-term percentages, but the record does not report enough context to establish causality or support a randomized comparison. These limitations apply to interpretation of the available registry information and should not be taken as claims about unreported study documents.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Expressing or -Mutated Non-Small Cell Lung Cancer — NCT03505710.
• Registry record last updated 2025-05-30; status last verified 2025-05.
• Results first posted 2022-05-17.
• 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.

19. Record Summary

DESTINY-Lung01 was a phase 2, multicenter, open-label, non-randomized study of trastuzumab deruxtecan in HER2-overexpressing or HER2-mutated unresectable and/or metastatic non-small cell lung cancer. The registry lists enrollment of 181, sponsor Daiichi Sankyo, and status terminated.

The primary endpoint was confirmed objective response rate by independent central review using RECIST version 1.1, assessed in the Full Analysis Set at the data cut-off date of 03 December 2021. The numerical primary result and confidence interval are not reported in the registry record. Secondary outcomes included investigator-assessed response, duration of response, progression-free survival, overall survival, and disease control rate; numerical results for these outcomes are also not reported in the available record.

The registry describes three cohorts with different HER2 characteristics and dose descriptions. It does not describe a like-for-like randomized control group. Selected serious adverse event counts and event-term percentages are recorded, but the reason for termination and detailed statistical methods are not reported in the registry record.