LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma (NCT01820364), a na phase 2 study. The primary outcome is Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II).

2. Clinical Question

3. Trial Design

This was a phase II, multicenter, open-label study with a single-group design. The registry lists allocation as not applicable and masking as none. Enrollment was 15, and the status is terminated. The reason for termination is not reported in the registry record.

The official title describes a sequence in which adults with locally advanced or metastatic BRAF V600 melanoma received single-agent LGX818, followed by a rational combination with other agents after progression on LGX818. The listed intervention is LGX818, and the arm description is for LGX818 single-agent treatment. The registry record does not give enough information to establish which participants received a subsequent combination, or which combination they may have received.

The single-agent arm required written documentation of a BRAF V600 mutation, preferably from a fresh tumor biopsy, or otherwise from the most recent available archival tumor sample. The primary outcome timeframe is baseline through study completion, described as approximately 2 years. Enrollment is not the same as the number analyzed for every outcome: the primary analysis population is defined as patients who received at least one dose, but the size of that population is not separately reported.

The study includes outcomes concerning dose-limiting toxicities, pharmacokinetic measures, tumor response, and molecular markers. The record lists no analyses. It does not report a statistical analysis plan, a sample-size justification, details of interim analyses, or the reason the study was terminated. The single-group design permits description of outcomes among enrolled participants, but does not provide a randomized comparison with another treatment.

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: After careful evaluation of slow enrollment and the BRAF-mutant melanoma treatment landscape, recruitment was permanently halted on 26-Jul-2014. This recruitment halt was not a consequence of any safety concern and patients who were ongoing in the study continued to be treated as per protocol.

Part I: LGX818

Reasons for not completing this period:

Part II: LGX818 + MEK162

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: This analysis is comprised of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.

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: The analysis population for Baseline Demographics is composed of the Full Analysis Set, which consists of all patients who received at least one dose of LGX818.

6. Primary Endpoint

The registry lists the primary outcome as Tumor Response (Overall Response Rate) Per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Part I & Part II), measured over Baseline through study completion (approximately 2 years).

The primary endpoint is the number of participants with an overall tumor response according to RECIST v1.1, based on investigator assessment, across Part I and Part II. The registry defines complete response as disappearance of all target lesions and partial response as at least a 30% decrease in the sum of target-lesion diameters. It defines progressive disease as at least a 20% increase in that sum; stable disease is neither enough shrinkage for partial response nor enough increase for progressive disease.

Overall response rate is used in oncology trials to describe the proportion of an analysis population whose tumors meet the specified response categories. It provides a structured way to summarize tumor change under defined assessment rules. In a single-group study, this endpoint describes responses observed among participants receiving the study treatment; it does not by itself estimate a treatment effect relative to a concurrent control group.

The registry specifies that the primary analysis population consists of patients who received at least one dose of LGX818. It does not report the number of complete or partial responses, the total included in the analysis, an overall response estimate, or its precision. Consequently, the endpoint definition is available, but its result is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation begins with the distinction between the question a study asks and the evidence it reports. This study's primary question concerns the number of participants with an overall response under RECIST v1.1. The registry describes the response categories and the analysis population, but does not report response counts or an estimate. Without those results, there is no observed response estimate to interpret or compare with a target.

What does overall response measure?

Overall response rate is a binary outcome at the participant level: a participant either meets the response definition or does not. For this endpoint, the response categories are complete response and partial response. The registry specifies disappearance of all target lesions for complete response and at least a 30% decrease in the sum of target-lesion diameters for partial response. Stable disease and progressive disease are distinct categories under the stated RECIST definitions. Those classification rules make the endpoint interpretable, but the registry does not report how participants were classified.

A count and a rate answer related but different questions. The count is the number of participants meeting the response definition. The rate relates that count to a defined analysis population. Both depend on knowing who was assessed and how participants without an evaluable assessment were handled. The registry defines the full analysis set as participants who received at least one dose of LGX818, but does not report its size or the response denominator. No rate can be reconstructed from the enrollment figure alone.

What can a single-group design establish?

A single-group study can describe outcomes observed in its participants. It does not include a concurrent randomized control group, so it cannot directly estimate the difference between LGX818 and another treatment under the same trial conditions. This limitation is not repaired by comparing the observed response with an outside value unless the basis and assumptions for such a comparison are specified. No such comparison is reported in the registry record.

Open-label means the study is not described as masked. General statistical context: when outcome assessment involves judgment, knowledge of treatment can be relevant to how results are assessed. The registry identifies investigator assessment for the RECIST outcome, but does not report procedures intended to reduce assessment bias. This observation concerns design and does not establish that assessments were inaccurate.

How should uncertainty be understood?

General statistical context: a confidence interval describes a range of estimates compatible with the observed data under the method's assumptions. It communicates precision, not certainty that a particular value is true, and it does not remove limitations in study design or measurement. No confidence interval for the primary endpoint is reported in the registry record. Since the response estimate itself is also absent, neither its magnitude nor its precision can be assessed.

The registry's sample-size assumptions describe planning illustrations, not the study's own design or an observed-power calculation. The stated illustration uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is specified as a fraction of the observed effect. For time-to-event outcomes, the illustration refers to the total number of events; for other outcomes, it refers to participants per arm. These are hypothetical planning assumptions. They should not be read as evidence that this single-group study randomized participants equally between arms or was designed with those assumptions.

General statistical context: power is a design property calculated under specified assumptions about the effect, variability, analysis, and sample size. It is not a measure of whether a study's observed result is reliable. A planning calculation based on an observed effect is not observed power and cannot substitute for the missing endpoint results or their uncertainty.

Why can over-dispersion matter?

General statistical context: over-dispersion occurs when observed variability in count data is greater than a model assumes. If a method assumes less variation than the data contain, uncertainty may be understated and inferential conclusions can be too confident. This issue is relevant in some count-data analyses, but the primary endpoint is defined as participants with a response, and no model or analysis result is reported. The registry record does not indicate that an over-dispersion adjustment was used; whether one was relevant to any analysis is not reported.

More broadly, the registry does not report the statistical methods used to estimate response, handle missing assessments, or analyze secondary outcomes. It also lists no analyses. The available methodological information therefore supports explanation of the endpoint and design, but not reconstruction of the investigators' analysis.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary response outcome spanning Part I and Part II, as well as several secondary outcomes. These include dose-limiting toxicities in Part II, plasma concentrations and derived pharmacokinetic parameters, overall response in each part, and molecular status of markers relevant to the RAP/MEK/ERK and PI3K/AKT pathways. It also reports six outcome measures in total. The record does not describe how inferential testing across endpoints or study parts was handled.

Multiplicity arises when several outcomes, comparisons, or repeated opportunities to test results are considered. General statistical context: without an adjustment or a prespecified hierarchy, the chance of at least one apparently notable result can increase as more tests are considered. The registry does not report a multiplicity strategy, endpoint hierarchy beyond identifying the primary outcome, or any analysis results. It is therefore not possible to judge how multiplicity was addressed.

Missing-data methods are not reported in the registry record. The primary analysis population is defined as all patients who received at least one dose of LGX818, but the number meeting that definition is not stated. The record also does not explain how participants with missing tumor assessments, incomplete follow-up, or other unavailable measurements were handled. This matters because the denominator and classification of participants affect interpretation of a response outcome.

The registry lists no analyses. A statistical analysis plan, interim analyses, and sample-size justification are not reported. No assumptions about these procedures should be inferred from the endpoint definitions or study title. The listed planning illustrations are not a record of the trial's own analysis plan or evidence of observed power.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hypotension (6.7%), metastases to central nervous system (6.7%), metastatic pain (6.7%), atrial fibrillation (6.7%), dyspnoea (6.7%).

For Part I, the LGX818 single-agent group lists 15 participants at risk for serious adverse events and 3 participants affected. It lists 15 participants at risk for other adverse events and 15 affected. These are participant counts in the registry record, not estimates of comparative risk. The record does not provide a concurrent control group for interpreting these counts.

The listed serious adverse event terms are hypotension, metastases to central nervous system, metastatic pain, atrial fibrillation, dyspnoea, and coagulopathy. Each is reported at 6.7%. These entries describe the registry's serious-event terms and their reported percentages; they do not state that each term occurred in a distinct participant or establish that the drug caused any event. Details such as event timing, duration, recurrence, and attribution are not reported in the registry record.

Serious adverse events and other adverse events are separate reporting categories in the record. The count of participants with an event does not describe how many total events occurred, and the listed serious terms do not provide a complete account of event severity or clinical course. Deaths are not reported in the registry record. These data support a limited description of recorded safety counts, not a causal comparison or an overall safety judgment.

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

The registry establishes that a phase II, open-label, single-group study of LGX818 in melanoma enrolled 15 participants and was terminated. It specifies an investigator-assessed RECIST v1.1 overall response endpoint across Part I and Part II, defines the response categories, and describes the full analysis set as participants who received at least one dose. It also provides selected adverse-event counts for the Part I single-agent group.

These details do not show how many participants achieved complete or partial response. No primary response count, response rate, or confidence interval is reported. The registry therefore does not establish the size or precision of any observed response, and it cannot support a conclusion about whether the primary endpoint was met. The enrollment count is not a substitute for the analysis denominator.

The design also does not support a randomized comparison with another treatment. A single-group record can describe outcomes among participants, but it does not isolate a comparative treatment effect. The study's open-label status and investigator-assessed endpoint are relevant features for interpretation; the record does not give enough information to determine whether they affected assessment.

The safety figures document participants with serious and other adverse events and list selected serious-event terms. They do not establish that LGX818 caused those events, and the record does not give the contextual detail needed to interpret their timing or course. Likewise, termination status alone does not explain why the study ended. The reason for termination is not reported in the registry record.

In short, the available record is useful for identifying the study question, its design, the intended response measure, and selected safety observations. It does not provide the primary efficacy results, a comparative estimate, or a complete account of analysis methods. Those absences limit what can be concluded from the registry record.

13. Why This Trial Matters Statistically

This study illustrates why endpoint definitions and endpoint results must be read separately. RECIST v1.1 gives explicit criteria for classifying tumor changes, which helps make response assessment more structured. But a detailed definition does not tell readers how many participants responded. When the outcome count and analysis denominator are absent, even a well-defined endpoint cannot answer the clinical question.

The trial also makes the role of design clear. A single-group study can describe what was observed among participants, but does not provide the concurrent randomized comparison needed to estimate a treatment contrast within the trial. The open-label design and investigator assessment are additional features readers should recognize when considering how outcomes were ascertained, without assuming that they caused bias.

The registry's separation of serious adverse events from other adverse events is another useful statistical distinction. Participant counts and event-term percentages convey limited descriptive information; they do not by themselves establish causation or comparative safety. Interpreting them requires attention to denominators and to information that is not available in the record, including event timing and attribution.

Finally, the record demonstrates the limits of registry-level interpretation when analysis results and statistical methods are absent. The primary response results, the analysis denominator, missing-data procedures, and multiplicity methods are not reported. Recognizing those gaps prevents a study's title, enrollment, or status from being mistaken for evidence about efficacy or the reason for termination.

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 main limitation for interpretation is that the primary outcome results are not reported in the registry record. The response count, response rate, analysis denominator, and uncertainty estimate are absent. Although the full analysis set is defined as participants who received at least one dose, its size is not stated. The enrollment figure cannot fill that gap.

The design is single-group and open-label, with no concurrent comparator described. Outcomes can therefore be described for participants but not interpreted as a randomized treatment contrast. The primary endpoint is based on investigator assessment, and the record does not report masking or other assessment procedures beyond indicating that the study was unmasked.

The official title describes combination treatment after progression on LGX818, while the listed intervention and arm description identify LGX818 single-agent treatment. The registry record does not explain which participants proceeded to a combination, which agents they received, or how outcomes were analyzed across treatment stages. This limits interpretation of the combined Part I and Part II endpoint.

The record does not report how missing outcome assessments were handled, the statistical analysis plan, interim analyses, or a sample-size justification. It lists no analyses. The reason for termination is not reported, and deaths are not reported. Safety information is limited to selected participant counts and serious-event terms; event timing, attribution, and clinical course are absent. These limits preclude stronger conclusions about efficacy, safety, or the circumstances of study termination.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: LGX818 in Combination With Agents (MEK162; BKM120; LEE011; BGJ398; INC280) in Advanced BRAF Melanoma — NCT01820364.
• Registry record last updated 2017-01-09; status last verified 2016-11.
• Results first posted 2017-01-09.
• 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

This registry record describes a phase II, multicenter, open-label, single-group study of LGX818 in adults with locally advanced or metastatic BRAF V600 melanoma. Enrollment was 15, and the study status is terminated. The official title describes single-agent treatment followed by a rational combination after progression, while the listed intervention is LGX818.

The primary endpoint is the number of participants with an investigator-assessed overall response by RECIST v1.1 across Part I and Part II. The response definitions and full analysis set criteria are stated, but response results and the analysis denominator are not reported. The record lists 3 of 15 participants with serious adverse events and 15 of 15 with other adverse events in the Part I single-agent group. The reason for termination, analysis methods, and missing-data procedures are not reported in the registry record.