This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain (NCT01266967), a non-randomized phase 2 study. The primary outcome is Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01266967 |
| Phase | Phase 2 |
| Condition | Melanoma and Brain Metastases |
| Allocation | Non-Randomized |
| Design model | Single Group |
| Masking | None (open label) |
| Enrollment | 172 |
| Arms in the primary outcome | n/a |
| Lead sponsor | GlaxoSmithKline |
| Results posted | Yes |
2. Clinical Question
Population
Participants had BRAF mutation-positive metastatic melanoma involving the brain. The primary endpoint population was participants with BRAF V600E mutation-positive melanoma who received at least one dose of study treatment. The study also included participants with V600K mutations, but the stated primary endpoint concerns the V600E population.
Intervention
The study assessed GSK2118436 as a single agent. The registry summary describes an oral dose of 150 mg taken twice daily, with treatment continuing until disease progression, death, or an unacceptable adverse event.
Comparator
There was no randomized control group. Participants were enrolled in one of two cohorts according to whether they had received prior local therapy for brain metastases: Cohort A had no prior local brain therapy, and Cohort B had prior local therapy. These cohorts are not like-for-like randomized treatment groups.
Primary question
The primary question was how many participants in the V600E population had an investigator-assessed overall intracranial response: a confirmed complete or partial response under modified RECIST, version 1.1. The registry record defines the endpoint but does not report the number of responders or the response estimate.
This is therefore a single-group treatment study with cohorts distinguished by treatment history, not a trial designed to estimate a randomized treatment contrast. The registry describes assessment of response during treatment, from baseline until disease progression or the end of study treatment; the stated average timeframe was 18.3 weeks. The endpoint focuses on response within the brain rather than response at all disease sites. The record also lists outcomes for V600E and V600K populations, including overall response, response duration, and progression-free survival. Those additional outcomes do not change the population specified for the primary endpoint.
3. Trial Design
This was a phase 2, open-label, multicentre study of GSK2118436 as a single agent in participants with BRAF mutation-positive metastatic melanoma to the brain. The registry describes a non-randomized, single-group design, with two cohorts based on prior local therapy for brain metastases. Cohort A had not received local brain therapy; Cohort B had received prior local therapy. The study enrolled 172 participants. The registry record does not state how many participants were assigned to each cohort or how many received at least one dose.
The intervention was an oral dose of 150 mg twice daily. Treatment was to continue until disease progression, death, or an unacceptable adverse event. The study is listed as completed. Its recorded start was 2011-02, and primary completion was 2011-11. The sponsor was GlaxoSmithKline.
Open-label means that masking was not used. Because allocation was non-randomized and there was no separate control group, comparisons between cohorts cannot be interpreted as randomized comparisons of prior local therapy or of GSK2118436 against another treatment. The cohorts differed by treatment history, which may also relate to participant characteristics or clinical circumstances; the registry record does not provide information to resolve such differences. A numerical comparison between cohorts would therefore be descriptive, not a controlled estimate of a treatment effect.
The primary outcome was a participant count for investigator-assessed overall intracranial response in the V600E population. The registry also lists secondary outcomes concerning V600E and V600K response, response duration, and progression-free survival. The record lists 22 outcome measures and two analyses, but does not describe a complete statistical analysis plan, including the specific methods used for those analyses.
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
| Stage | GSK2118436 150 mg: No Prior Local Therapy | GSK2118436 150 mg: Prior Local Therapy |
|---|---|---|
| STARTED | 89 | 83 |
| COMPLETED | 0 | 0 |
| NOT COMPLETED | 89 | 83 |
Reasons for not completing this period:
| Reason | GSK2118436 150 mg: No Prior Local Therapy | GSK2118436 150 mg: Prior Local Therapy |
|---|---|---|
| Death | 69 | 61 |
| Study Closed/Terminated | 15 | 17 |
| Lost to Follow-up | 2 | 1 |
| Physician Decision | 0 | 1 |
| Withdrawal by Subject | 3 | 3 |
Analysis population for the primary outcome, as defined in the registry: V600E Population: all participants with BRAF V600E mutation-positive melanoma who received at least one dose of study treatment
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.
| Characteristic | Unit | GSK2118436 150 mg: No Prior Local Therapy | GSK2118436 150 mg: Prior Local Therapy | Total |
|---|---|---|---|---|
| Participants analysed | 89 | 83 | 172 | |
| Age, Continuous | Years | 52.3 (SD 13.35) | 52.7 (SD 13.83) | 52.5 (SD 13.55) |
| Sex: Female, Male: Female | Participants | 24 | 28 | 52 |
| Sex: Female, Male: Male | Participants | 65 | 55 | 120 |
| Race/Ethnicity, Customized: White | participants | 89 | 82 | 171 |
| Race/Ethnicity, Customized: Not reported | participants | 0 | 1 | 1 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator, measured over From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks).
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint counts participants with BRAF V600E mutation-positive melanoma whose intracranial response was a confirmed complete response or partial response, as assessed by investigators using modified Response Evaluation Criteria in Solid Tumors, version 1.1. A complete response was defined as disappearance of all lesions. A partial response required at least a 30% decrease in the sum of target-lesion diameters relative to the baseline sum.
Confirmation was to occur no less than 4 weeks after response criteria were initially met and could be assessed at the next scheduled protocol assessment. The endpoint therefore requires more than an initial change that meets response criteria: the response must also be confirmed. The registry states that participants with a missing or non-evaluable intracranial response were treated as non-responders for the primary analysis.
Counting participants with a defined response gives a clinically interpretable summary of observed intracranial tumor response in the specified population. It does not, by itself, describe how long a response lasted, whether disease progressed elsewhere, or how outcomes compare with an alternative treatment. The registry record does not report the primary response count or an estimate of its precision, so the magnitude and uncertainty of the observed endpoint cannot be described from the posted record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies the primary endpoint and its assessment rules, but does not report the primary outcome result. In particular, it does not state how many participants in the V600E population had a confirmed overall intracranial response. No response proportion, confidence interval, or test result for this endpoint is reported in the registry record. The result therefore cannot be characterized as more or less frequent, or as precise or imprecise, on the basis of this record.
The enrollment was 172, but this is not the same as the analysis population for the primary endpoint. That population was defined as participants with V600E mutation-positive melanoma who received at least one dose. The registry record does not report the number meeting that definition. It also does not report the count of participants who had evaluable response assessments. The primary analysis rule classifies missing and non-evaluable responses as non-responders, but the record does not say how many participants fell into those categories.
The two cohorts reflect prior local brain therapy status. They are not randomized comparison groups, and the study had no stated control arm. Any outcome differences between them would not establish that prior therapy or the study drug caused the difference. Prior treatment history and other participant characteristics could differ across cohorts; details needed to assess these possibilities are not reported in the registry record.
The endpoint is a count of confirmed intracranial responses, not a measure of response duration or overall disease control. The registry lists response duration and progression-free survival among other outcomes, but their results are not reported in the registry record in this record. The stated endpoint timeframe extends from baseline to disease progression or the end of study treatment, with an average of 18.3 weeks. This describes the timeframe attached to the endpoint, not a response result or a follow-up duration for every participant.
The study is described as phase 2 and open-label. Investigator assessment and the absence of masking are relevant context when interpreting a response endpoint. The modified RECIST criteria and confirmation requirement define how a response was to be classified, but do not remove all possible assessment variation. Since the record does not provide the response count, uncertainty estimate, or detailed analysis method, it supports description of the planned endpoint and study structure, not a statistical conclusion about the size or reliability of the observed response.
9. Statistical Methods Explained
What does the endpoint count?
The primary outcome is a number of participants, not a continuous measurement. Each participant in the stated V600E population is classified according to whether an investigator assessed a confirmed complete or partial intracranial response. Complete response means disappearance of all lesions. Partial response requires at least a 30% decrease in the sum of target-lesion diameters relative to baseline. The confirmation rule requires the response criteria to be met again at an assessment no less than 4 weeks after the initial criteria were met, or at the next scheduled assessment.
For a binary response outcome, a count can be accompanied by a proportion and an interval describing statistical uncertainty. In general, a confidence interval gives a range of values compatible with the observed data under the method's assumptions. It does not guarantee that the true value lies in the interval, and it is not a measure of the range of individual participant outcomes. The registry record does not report the response count or a confidence interval for the primary endpoint, so no endpoint estimate or precision range can be interpreted.
Why does the analysis population matter?
The registry defines the primary population as V600E mutation-positive participants who received at least one dose. This is narrower than all enrolled participants: enrollment alone does not establish mutation status or receipt of treatment for every participant. The record does not state the size of the primary analysis population. It says that missing or non-evaluable response assessments were counted as non-responses. This rule makes those participants part of the non-responder count for the primary analysis rather than removing them from the response classification.
That rule is important because missing outcomes can affect an estimated response rate. Treating missing outcomes as non-responses is a specified classification choice, but the record does not report how many responses were missing or non-evaluable, or whether other sensitivity analyses were conducted. It also does not describe handling of other possible analysis issues, such as participants with incomplete follow-up.
What can cohort comparisons establish?
The study has one treatment group with two cohorts defined by prior local brain therapy. The cohorts were not randomized, and no control group is stated. General statistical interpretation distinguishes descriptive comparisons from causal treatment comparisons: a difference between non-randomized groups can reflect differences in their characteristics, treatment histories, or other factors, as well as differences in outcomes. Randomization is one way to balance such factors on average; it was not used in this study.
Accordingly, the cohorts should not be treated as if they were equivalent groups differing only in treatment. The registry record does not report an adjusted comparison or describe methods intended to account for differences between them. Its non-randomized design is especially relevant to interpreting any cohort-level response or safety figures.
How should statistical tests and intervals be read?
In general, a statistical test evaluates how compatible observed data are with a specified null hypothesis, under assumptions about the data and analysis. A p-value does not measure the probability that a treatment works, and it does not describe the size or clinical importance of an effect. An interval estimate gives information about uncertainty in an estimate, while the estimate itself describes the observed magnitude. Both are needed for a fuller interpretation than a test result alone.
The registry record lists two analyses, but does not identify the tests, interval methods, hypotheses, or adjustment procedures. It does not report a p-value or confidence interval for the primary endpoint. No statistical significance conclusion can therefore be drawn from the endpoint information in the record. General concepts about tests and intervals do not substitute for those missing results.
What does the endpoint timing mean?
The primary endpoint timeframe is described as baseline through disease progression or the end of study treatment, with an average of 18.3 weeks. In general, a defined assessment window specifies the period over which an outcome is considered; it is not necessarily the same as a fixed visit schedule for every participant. The primary analysis was to be conducted when all participants in both treatment arms had two post-baseline disease assessments, as stated in the registry. The record does not explain the relationship between this wording and its description of a single group with two cohorts, or provide further detail on assessment schedules.
The registry also lists response duration and progression-free survival as secondary outcomes. These are different from the binary primary response count. Duration outcomes concern time until a specified event after response, while progression-free survival concerns time to progression or another defined event. The specific analysis methods and results for those outcomes are not reported in the registry record.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists 22 outcome measures, including a primary endpoint and secondary outcomes for V600E and V600K populations. Listed outcomes include investigator-assessed overall response, overall intracranial response, response duration, and progression-free survival. When multiple outcomes or analyses are examined, the chance of at least one apparently notable result can increase. General statistical approaches may address this through prespecified outcome hierarchies or adjustments, but the registry record does not report whether any multiplicity strategy was planned or used.
The record lists two analyses but does not describe their hypotheses, statistical tests, confidence interval methods, or any adjustment for multiple analyses. It does not identify which analyses correspond to the outcomes or explain whether they were prespecified. The absence of these details means that the interpretation of any inferential findings cannot be assessed from the registry record; in any case, the primary response result itself is not reported.
The primary analysis definition includes participants with V600E mutation-positive melanoma who received at least one dose. Participants with missing or non-evaluable intracranial response were treated as non-responders. This explicit rule helps clarify how those response classifications were intended to enter the primary endpoint. However, the registry does not state how many participants had missing or non-evaluable assessments, how many were excluded from the analysis population, or whether other missing-data approaches were used for secondary outcomes.
The record does not report further analysis-population definitions, such as a separate per-protocol population, nor does it explain whether all enrolled participants were analyzed for any outcome. Details about protocol deviations, withdrawal, or sensitivity analyses are also not reported in the registry record. These omissions limit assessment of how robust the planned analyses were to missing observations and population choices.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| GSK2118436 150 mg: No Prior Local Therapy | 26 | 89 | 29.2% |
| GSK2118436 150 mg: Prior Local Therapy | 31 | 83 | 37.3% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| GSK2118436 150 mg: No Prior Local Therapy | 79 of 89 |
| GSK2118436 150 mg: Prior Local Therapy | 74 of 83 |
Most frequent serious adverse event terms
| Event term | Organ system | GSK2118436 150 mg: No Prior Local Therapy | GSK2118436 150 mg: Prior Local Therapy |
|---|---|---|---|
| Pyrexia | Gastrointestinal disorders | 4 of 89 | 9 of 83 |
| Squamous cell carcinoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 6 of 89 | 7 of 83 |
| Haemorrhage intracranial | Nervous system disorders | 2 of 89 | 3 of 83 |
| Headache | Nervous system disorders | 2 of 89 | 2 of 83 |
| Chills | General disorders | 1 of 89 | 2 of 83 |
| Hypotension | Vascular disorders | 0 of 89 | 3 of 83 |
| Ejection fraction decreased | Investigations | 3 of 89 | 0 of 83 |
| Cerebral haemorrhage | Nervous system disorders | 2 of 89 | 1 of 83 |
| Atrial fibrillation | Cardiac disorders | 2 of 89 | 0 of 83 |
| Fatigue | General disorders | 0 of 89 | 2 of 83 |
Most frequent non-serious adverse event terms
| Event term | Organ system | GSK2118436 150 mg: No Prior Local Therapy | GSK2118436 150 mg: Prior Local Therapy |
|---|---|---|---|
| Headache | Nervous system disorders | 24 of 89 | 20 of 83 |
| Hyperkeratosis | Skin and subcutaneous tissue disorders | 24 of 89 | 20 of 83 |
| Fatigue | General disorders | 18 of 89 | 25 of 83 |
| Nausea | Gastrointestinal disorders | 16 of 89 | 26 of 83 |
| Pyrexia | General disorders | 23 of 89 | 15 of 83 |
| Vomiting | Gastrointestinal disorders | 18 of 89 | 15 of 83 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 17 of 89 | 13 of 83 |
| Rash | Skin and subcutaneous tissue disorders | 16 of 89 | 14 of 83 |
| Alopecia | Skin and subcutaneous tissue disorders | 15 of 89 | 10 of 83 |
| Myalgia | Musculoskeletal and connective tissue disorders | 12 of 89 | 13 of 83 |
Serious events with the highest arm-level rate: pyrexia (10.8%), squamous cell carcinoma (8.4%), haemorrhage intracranial (3.6%), hypotension (3.6%), ejection fraction decreased (3.4%).
The registry reports serious adverse event counts for the two cohorts and lists selected serious adverse event terms with percentages. In the no-prior-local-therapy cohort, 89 participants were at risk for serious adverse events and 26 were reported as affected. In the prior-local-therapy cohort, 83 were at risk and 31 were affected. These are cohort-specific counts, not randomized comparisons. The record also reports other adverse event counts: 79 of 89 participants in the no-prior-local-therapy cohort and 74 of 83 in the prior-local-therapy cohort were affected.
The listed serious adverse event terms include pyrexia at 10.8%, squamous cell carcinoma at 8.4%, haemorrhage intracranial at 3.6%, hypotension at 3.6%, ejection fraction decreased at 3.4%, and headache at 2.4%. These percentages describe the terms as listed in the registry; they should not be added together, since a participant may have experienced more than one event. The record does not provide the detailed event definitions or a full account of the safety analysis methods.
The death counts are not reported in the registry record. Safety figures describe events recorded during the study and do not, on their own, establish whether an event was caused by treatment. Because the cohorts were not randomized, their event counts should not be interpreted as evidence that one cohort had greater or lesser risk due to treatment history.
12. What the Result Does, and Does Not, Mean
The registry record describes a study designed to assess GSK2118436 in participants with BRAF mutation-positive metastatic melanoma involving the brain. It defines an investigator-assessed primary endpoint based on confirmed complete or partial intracranial response in participants with V600E mutations who received at least one dose. The response criteria, confirmation requirement, and treatment-history cohorts are specified in the record.
However, the record does not report the primary response count or an estimate of uncertainty. It therefore does not establish how many participants met the endpoint, how precisely an outcome was estimated, or how the observed result compares with any alternative. No randomized control group is described, so the study design does not support a randomized comparison of GSK2118436 with another treatment.
The record's sample size of 172 is enrollment, not the number known to have contributed to the primary analysis. The registry defines that population by V600E mutation status and receipt of at least one dose, but does not report its size. It also does not provide response results for the listed secondary outcomes, including response duration and progression-free survival. Safety counts and listed serious adverse event terms provide descriptive event information, but do not establish that treatment caused those events or permit a controlled risk comparison.
In general, a defined endpoint and assessment rule make a study outcome interpretable when results are reported. They do not replace the results themselves. Here, the available registry information supports understanding of the question, design, and response classification, while leaving the magnitude, precision, and inferential significance of the primary outcome unreported. No conclusion about treatment benefit or lack of benefit follows from the absence of a result in this record.
13. Why This Trial Matters Statistically
This study illustrates how a clear endpoint definition and a limited design description can coexist with substantial uncertainty about the result. The primary endpoint specifies the disease location, mutation group, response criteria, assessment method, and confirmation rule. These details help identify what the study intended to count and which participants were meant to contribute to the primary analysis.
At the same time, the primary outcome count and its statistical uncertainty are not reported in the registry record. Without those values, readers cannot judge the observed response frequency or how precisely it was estimated. The distinction between enrollment and the analysis population also matters: 172 participants were enrolled, but the primary analysis was defined for treated V600E participants, whose number is not reported.
The non-randomized structure is another key statistical feature. The two cohorts were formed according to prior local brain therapy rather than random assignment. Their outcomes may be described separately, but differences between them cannot be interpreted as an unbiased treatment contrast. This is a useful reminder that cohort labels do not create a control group and that a numerical difference between cohorts would not by itself establish a causal explanation.
The registry also lists 22 outcome measures and two analyses without describing the full statistical plan or any approach to multiplicity. This limits evaluation of how outcome selection and multiple analyses were handled. Together, these features show why interpretation depends not only on an endpoint's clinical definition, but also on the reported analysis population, outcome estimates, uncertainty, and design constraints.
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 direct limitation of the registry record is that it does not report the primary endpoint result. There is no responder count or uncertainty estimate in the record, and the size of the primary analysis population is not stated. Although the enrollment was 172, that total cannot be substituted for the defined V600E treated population.
The study was non-randomized, open-label, and single-group, with cohorts distinguished by prior local brain therapy. There was no stated randomized control group. As a result, outcomes cannot be interpreted as a controlled comparison with another treatment, and comparisons between cohorts may reflect differences in participant characteristics or prior treatment history. The registry does not report an adjusted cohort comparison.
The record describes the primary response rules and says missing or non-evaluable responses were treated as non-responders, but does not give counts for missing assessments or describe sensitivity analyses. It does not report the detailed statistical methods, the approach to multiple outcomes, or how the two listed analyses were conducted. Results for the listed secondary outcomes are also not reported in this record.
Safety information is limited to specified counts and selected serious adverse event terms. Death counts are not reported, and the record does not provide enough detail to establish causality for events. The stated endpoint timeframe has an average of 18.3 weeks, but participant-level follow-up details are not reported. These limitations restrict both assessment of the response estimate and broader interpretation of efficacy and safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain — NCT01266967.
- Registry record last updated 2014-05-08; status last verified 2014-03.
- Results first posted 2014-03-05.
- 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.
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18. Record Summary
The registry describes a completed, open-label, phase 2, non-randomized, single-group study of GSK2118436 in BRAF mutation-positive metastatic melanoma to the brain. It enrolled 172 participants and separated them into two cohorts according to prior local brain therapy. The intervention was an oral dose of 150 mg twice daily.
The primary endpoint counted confirmed investigator-assessed intracranial complete or partial responses in treated participants with V600E mutation-positive melanoma. Missing or non-evaluable responses were classified as non-responses. The registry record does not report the primary response count, its precision, or the size of the primary analysis population. It lists additional response, duration, and progression-free survival outcomes, but their results are not reported in the record. Safety counts are reported by cohort, with selected serious adverse event terms; death counts are not reported.