Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. (NCT01336634), a non-randomized phase 2 study. The primary outcome is Overall Response Rate (ORR).

2. Clinical Question

3. Trial Design

This was a Phase II, multicenter, non-randomized, open-label study. The registry lists a total enrollment of 177 and identifies the study status as completed. Participants were assigned to cohorts rather than randomized between treatments. There was no masking, and the study model is recorded as single group. Those features matter when interpreting the cohorts: their outcomes are descriptive and are not a randomized head-to-head test.

The three main cohorts involved dabrafenib alone or dabrafenib with trametinib. Cohort A received dabrafenib 150mg BID and continued treatment until disease progression, death, or an unacceptable adverse event. The description says that participants tolerating dabrafenib and continuing to meet eligibility criteria had the option to switch, but the description of that option is incomplete in the registry record. Cohort B received dabrafenib 150 mg BID with trametinib 2 mg once daily. Cohort C received the same combination regimen. The record also lists a crossover combination group.

The stated study purpose was to assess efficacy, safety, and tolerability in subjects with BRAF mutant advanced non-small cell lung cancer. Central testing for BRAF V600E was performed, with the stated intention of having at least 125 centrally confirmed subjects among the three cohorts. The number centrally confirmed in each cohort and whether the intention was met are not reported in the registry record.

Other listed outcomes include local-investigator assessments of progression-free survival and duration of response, overall survival, treatment-emergent adverse events, and pharmacokinetic measures for dabrafenib and trametinib. The registry identifies 10 outcome measures but reports no analyses. Randomization procedures, allocation concealment, detailed cohort assignment rules, and a statistical analysis plan are not reported in the registry record. The treatment duration rules in the cohort descriptions do not substitute for those missing design details.

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: All Treated Population (ATP).

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 Overall Response Rate (ORR), measured over From study treatment start date until first documented complete response or partial response, assessed up to approximately 50 months.

The primary endpoint, Overall Response Rate, is the percentage of participants in the All Treated Population with a confirmed complete response or partial response, as assessed by investigators using RECIST v1 .1 criteria. In general, response rate compresses a participant-level tumor-response classification into a proportion for a defined group. It can describe how often a specified response was recorded during the assessment period, but it does not by itself describe how long a response lasted or how long participants lived.

The registry defines the response as confirmed and specifies the assessment method and analysis population. Confirmation is relevant because a response classification is not counted under the endpoint definition unless it meets the stated confirmation requirement. The timeframe runs from study treatment start until the first documented complete or partial response, with assessment up to approximately 50 months. This describes the period over which response was assessed; it is not a reported follow-up duration for every participant.

Response rate is used as an efficacy endpoint because it gives a direct summary of the frequency of documented tumor responses in the specified population. Interpretation still depends on how responses were assessed, which participants were included, how missing or unevaluable assessments were handled, and the precision of the estimate. Those analysis details and the numerical response result are not reported in the registry record. The endpoint definition alone therefore cannot show how many participants responded or how precisely the study estimated that proportion.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins with the design and the estimand: what outcome is being summarized, for whom, and over what period. The primary endpoint is a participant-level response classification converted to a percentage for the All Treated Population. Its definition specifies confirmed complete or partial response, investigator assessment, and RECIST v1 .1 criteria. The registry does not report the observed percentage or a corresponding uncertainty estimate, so the endpoint’s numerical result and precision remain unknown.

What does a response proportion summarize?

In general, a proportion is a count of participants meeting a definition relative to a stated analysis population. The numerator and denominator must refer to compatible participants and rules. A response proportion does not convey response duration, progression-free survival, or overall survival. Those are distinct outcomes, and this record lists them separately. For a response endpoint, assessment schedules, confirmation rules, and handling of participants without an assessable response can affect the result. The endpoint definition identifies confirmation, but the registry does not report the detailed assessment schedule or missing-assessment rules.

Why does non-randomization matter?

Random allocation is a design method that, in general, helps make treatment groups comparable with respect to both measured and unmeasured characteristics. This study was non-randomized and open-label. Cohort membership may therefore be associated with participant characteristics or clinical circumstances. If outcomes differ between cohorts, those differences may arise from treatment, cohort composition, or both. Statistical adjustment can address measured differences only under appropriate assumptions; it cannot guarantee control of unmeasured differences. The registry does not report an adjusted treatment comparison or an adjustment plan.

Open-label assessment means participants and investigators were not masked to treatment assignment. The primary endpoint was assessed by investigators. In general, knowledge of treatment can influence assessment or reporting, although use of defined response criteria provides an assessment framework. The registry does not report independent central review of the primary response endpoint, so such a review should not be assumed.

What do the safety counts represent?

Safety summaries typically distinguish participants at risk from participants with one or more events, but the interpretation depends on the event definitions and counting rules. A participant can experience more than one event, and a participant-level count is not necessarily the same as a count of all event episodes. The registry lists at-risk and affected figures for serious and other adverse events in each group, as well as deaths. It does not provide the exposure-time details or all counting rules needed to compare event frequency across groups. The selected serious-event terms and percentages provide a descriptive list, not a controlled estimate of excess risk.

In general, exposure duration matters for adverse-event interpretation: a group observed for longer may have more opportunity to experience an event. Rates based on person-time can address exposure duration in some settings, but no such comparative rate is reported in the registry record. Nor does the record establish that participants in different groups had equivalent follow-up or treatment exposure. The listed counts should therefore be read as descriptive group summaries, not as adjusted comparisons.

How should uncertainty and planning be read?

A confidence interval is a statistical summary of uncertainty around an estimate under a specified model and assumptions. A narrow interval indicates greater precision than a wide interval, while neither interval width nor a point estimate alone establishes clinical importance. No confidence interval or primary-effect estimate is reported for this endpoint. P-values and the prespecified testing plan are also not reported.

General sample-size calculations can illustrate the number of participants needed to detect a chosen effect under stated assumptions. The registry’s planning illustration is described as based on the observed effect, with a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. Such planning figures are not observed power and do not demonstrate that the study had a particular probability of detecting an effect. The registry record does not report the trial’s own sample-size justification, and the planning description does not establish that these assumptions governed the original design.

For a non-randomized study, equal allocation in a generic planning calculation is a calculation assumption, not evidence that the treatment cohorts were balanced. Likewise, an effect fraction used in a planning illustration is a hypothetical target, not an observed treatment effect. The registry reports no analysis results from which to judge the estimate, its uncertainty, or whether any planning target was met.

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 A (Dabrafenib Monotherapy)", "Cohort B - Double Combination (Dabrafenib+Trametin", "Cohort C - Double Combination (Dabrafenib+Trametin", "Crossover - Double Combination (Dabrafenib+Trameti")
n      <- c(78, 57, 36, 20)
events <- c(27, 39, 23, 4)
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 A (Dabrafenib Monotherapy)  78  27  34.6  24.2  46.2  25.0  45.7  25.0  45.7
ARM  Cohort B - Double Combination (Dabrafenib+Trametin  57  39  68.4  54.8  80.1  55.5  79.0  55.5  79.0
ARM  Cohort C - Double Combination (Dabrafenib+Trametin  36  23  63.9  46.2  79.2  47.6  77.5  47.5  77.5
ARM  Crossover - Double Combination (Dabrafenib+Trameti  20  4  20.0  5.7  43.7  8.1  41.6  8.2  41.9

11. Multiplicity, Missing Data and Analysis Populations

The study lists multiple outcomes, including response rate, progression-free survival, duration of response, overall survival, adverse events, and pharmacokinetic measures. When a study examines multiple outcomes or makes multiple statistical comparisons, the chance of at least one apparently notable result can increase. In general, a prespecified testing hierarchy or an adjustment method can help define how such results should be interpreted. The registry record does not report a multiplicity strategy, a testing hierarchy, or a statistical analysis plan. It is therefore not possible to determine which outcomes were intended to support formal claims or how multiple testing was handled.

The registry identifies the All Treated Population for the primary endpoint. It does not report detailed inclusion rules for that population, the number analyzed, or how participants with missing or unevaluable response assessments were handled. General approaches to missing outcomes include explicit assumptions and sensitivity analyses, but no missing-data method or sensitivity analysis is reported in the registry record. Without those details, the effect of missing assessments on the endpoint cannot be evaluated.

The record also does not describe analysis populations for the secondary outcomes, how crossover participants were handled in efficacy analyses, or whether any participants were excluded after enrollment. A named outcome or analysis population is not enough to establish the actual denominator used. The number of analyses reported is zero, so the registry offers no statistical estimates or testing results to assess. Missing analysis details should not be replaced with assumptions about standard practice.

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: pyrexia (17.5%), alanine aminotransferase increased (13.9%), aspartate aminotransferase increased (8.3%), ejection fraction decreased (8.3%), squamous cell carcinoma of skin (8.3%).

The registry lists serious and other adverse-event summaries for Cohort A, Cohort B, Cohort C, and the crossover combination group. For serious events, the entries include numbers at risk and affected; the record also gives deaths by group. These are descriptive safety figures. They should not be treated as a randomized comparison because cohort allocation was non-randomized, and they do not by themselves account for differences in follow-up or treatment exposure.

Selected serious-event terms are listed with percentages: pyrexia, 17.5%; alanine aminotransferase increased, 13.9%; aspartate aminotransferase increased, 8.3%; ejection fraction decreased, 8.3%; squamous cell carcinoma of skin, 8.3%; and vomiting, 5.6%. The registry record does not state the denominator or detailed calculation rules for these percentages in the information reported. They should not be assumed to represent a comparison between treatment groups or a rate adjusted for exposure.

In general, an affected-participant count and an event count answer different questions: one participant may have multiple events, while a participant-level summary counts that participant once under its rules. The registry’s summary does not give enough detail to resolve every counting convention. The figures describe what the record reports; they do not establish that a regimen caused an event or that groups had equivalent opportunities for events to be recorded.

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

The registry record documents a Phase II investigation of dabrafenib monotherapy and dabrafenib plus trametinib in BRAF V600E mutation-positive metastatic non-small cell lung cancer. It specifies a primary response endpoint, identifies the treated population, describes the main regimens, and includes descriptive safety summaries. Those details clarify what the study set out to examine and how the primary outcome was defined.

The record does not report the primary response result, confidence interval, or statistical test. It therefore cannot establish the response frequency or how precisely that frequency was estimated. It also does not report statistical analyses for the listed secondary outcomes. The absence of posted analyses is not evidence that an outcome occurred or did not occur; it means the registry record does not supply a result that can be interpreted.

The non-randomized design means that cohort outcomes cannot be treated as a randomized estimate of the difference between treatments. Even if cohort estimates are available elsewhere, differences may reflect cohort composition or other factors as well as treatment. The registry does not report an adjusted comparison that would address those concerns. The open-label design and investigator assessment are additional features relevant to outcome interpretation.

The adverse-event figures provide descriptive information about affected participants and selected serious-event terms. They do not establish comparative safety, adjust for exposure, or identify causation. The record’s listed deaths also cannot be interpreted as treatment-attributable without further definitions and analysis.

In general, a trial result is most informative when the endpoint definition, analysis population, estimate, uncertainty, missing-data handling, and prespecified analysis plan can be considered together. Several of those elements are absent from this registry record. The careful conclusion is therefore limited: the record describes the study and its intended endpoint, but does not report the statistical findings needed to quantify the primary result or support a treatment comparison.

14. Why This Trial Matters Statistically

This study is statistically notable for the distinction between a defined clinical question and an interpretable treatment comparison. The registry specifies a response endpoint and treatment cohorts, but the design is non-randomized. Cohort descriptions can organize the evidence, yet they do not create the exchangeability that random allocation is intended to support. This distinction is essential when readers encounter apparent differences between treatments.

The study also illustrates why endpoint definitions and endpoint results must be read separately. The primary endpoint is clearly described as confirmed complete or partial response by investigator assessment under RECIST v1 .1, in the All Treated Population. That definition establishes what would count as a response, but it does not reveal the observed proportion or its precision. A well-specified outcome is not itself a reported finding.

Safety summaries raise a related issue. Counts of affected participants and selected event percentages can describe what was recorded, but exposure time, group composition, event-counting rules, and comparative methods shape what can be concluded. In a non-randomized study, descriptive safety figures are not a direct causal contrast. This is especially important when a record includes multiple cohorts and a crossover group.

Finally, the registry lists several efficacy, safety, and pharmacokinetic outcomes but reports no analyses. This makes transparent reporting of estimates, uncertainty, populations, missing-data methods, and multiplicity procedures particularly important for interpretation. The record demonstrates that study design, outcome specification, and analysis reporting are separate parts of statistical evidence. A reader should not infer results from the stated aims or endpoint definitions.

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 interpretation is that the registry record reports no analyses and no numerical result for the primary endpoint. It therefore does not provide a response estimate, a measure of precision, or a statistical test. Although the record lists secondary outcomes, their results are not reported there either.

The non-randomized allocation limits causal interpretation of comparisons across cohorts. The registry does not explain in detail how participants entered each cohort, whether groups differed at baseline, or whether statistical adjustment was used. The study was also open-label, and the primary outcome was assessed by investigators; independent central review is not reported in the registry record.

The intended number of centrally confirmed participants is described, but the number actually centrally confirmed and its distribution across cohorts are not reported in the registry record. The Cohort A description is incomplete after noting an option to switch for participants meeting specified conditions. The details needed to understand that transition and its analysis are therefore unavailable in the record.

The registry does not report detailed response-assessment schedules, missing-data rules, analysis denominators, or the statistical analysis plan. It also does not report how multiplicity across outcomes was handled. For safety, exposure duration, full event definitions, and all counting rules are not described in the information reported. These omissions limit assessment of precision, bias, and comparability. They do not imply that a particular result or bias occurred; they identify what cannot be established from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of Selective BRAF Kinase Inhibitor Dabrafenib Monotherapy Twice Daily and in Combination With Dabrafenib Twice Daily and Trametinib Once Daily in Combination Therapy in Subjects With BRAF V600E Mutation Positive Metastatic (Stage IV) Non-small Cell Lung Cancer. — NCT01336634.
• Registry record last updated 2022-04-04; status last verified 2022-03.
• Results first posted 2017-12-07.
• 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

The registry describes a completed, multicenter, open-label, non-randomized Phase II study with total enrollment of 177. It examined dabrafenib monotherapy and dabrafenib with trametinib in BRAF V600E mutation-positive metastatic non-small cell lung cancer. The primary endpoint was Overall Response Rate, defined using confirmed investigator-assessed complete or partial response under RECIST v1 .1 in the All Treated Population.

The record lists additional survival, adverse-event, and pharmacokinetic outcomes and gives descriptive safety figures for three main cohorts and a crossover group. It reports zero analyses. The primary endpoint result, its precision, detailed missing-data procedures, and the statistical analysis plan are not reported in the registry record. Because allocation was non-randomized, cohort results do not constitute a like-for-like randomized treatment comparison.