Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG (NCT03973918), a non-randomized phase 2 study. The primary outcome is Tumor Radiographic Response Per RANO for 3 Treatment Cohorts.

2. Clinical Question

The registry describes a Phase II study intended to estimate efficacy using radiographic response in recurrent high-grade primary brain tumors. Its population spans several tumor types, with separate treatment cohorts described for anaplastic astrocytoma and glioblastoma, anaplastic pleomorphic xanthoastrocytomas, and other tumors. A surgical arm is also described. These groupings reflect the study structure, not randomized comparisons.

The registry lists enrollment of 5 and states that the trial terminated early. It explains that results are given per cohort per patient because the data are considered uninformative otherwise given the small numbers. This makes the central question descriptive: what response categories were recorded for participants? It does not establish how the combination compares with another treatment or with an untreated control group.

3. Trial Design

This was a Phase II, non-randomized, parallel study with no masking. The sponsor was Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. The registry lists a start date of 2019-07-29, primary completion of 2022-04-30, an enrollment of 5, and a status of terminated.

Encorafenib and binimetinib were the study drugs. The treatment cohort descriptions list encorafenib 450mg QD with binimetinib 45mg BID in a 28 day cycle. The named treatment cohorts were Treatment Cohort 1 AA & GBM, Treatment Cohort 2 anaplastic PXAs, and Treatment Cohort 3 Other Tumors. Research bloods are listed for these cohorts. A Surgical Arm is also described, with preoperative treatment, tumor and other sample collection, and treatment after surgery. The exact schedule and sampling details are not reported in the registry record beyond those arm descriptions.

The primary outcome was the number of participants in each treatment cohort with a radiographic response under RANO criteria, with a timeframe of up to 1 year. Secondary outcomes listed include progression-free survival for 3 treatment cohorts, overall survival, duration of complete and partial response, and participants with adverse events under CTCAE v5.0.

Because allocation was non-randomized and the record does not identify a like-for-like control arm, differences between the tumor cohorts cannot be interpreted as treatment effects. The registry describes early termination and very small numbers, and reports results per cohort per patient. A full account of the reasons 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: 1 patient on Treatment Cohort 2 anaplastic PXAs was still on treatment at the time of the mandated stop of treating patients by NCI/CTEP. This patient continues to receive treatment but not on this study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Due to early termination, results are given per cohort per patient, as the data is meaningless otherwise due to small numbers

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: No patient were enrolled on the Surgical arm. this study was terminated early by a mandate from NCI to shut down the ABTC Consortium due to wanting a different strategy for Brain Tumor Research. As such,

6. Primary Endpoint

The registry lists the primary outcome as Tumor Radiographic Response Per RANO for 3 Treatment Cohorts, measured over Up to 1 year.

The primary endpoint counts participants in each treatment cohort according to radiographic tumor response under Response Assessment in Neuro-Oncology (RANO) criteria. Its timeframe is up to 1 year. The registry defines complete response, partial response, stable disease, and progressive disease using imaging findings together with factors such as corticosteroid use and clinical status. Thus, response is not defined by imaging size alone.

RANO criteria are used in neuro-oncology because assessment of brain tumors can involve more than change in an enhancing lesion. The registry’s definitions incorporate T1-gadolinium-enhancing disease, T2/FLAIR signal, new lesions, corticosteroid use, and clinical status. In general, combining imaging and clinical information can make an endpoint more relevant to the disease being studied, while also requiring consistent assessment rules.

The endpoint is a participant count, not a continuous measure of tumor size or a time-to-event measure. A count can describe how many participants fell into response categories, but it does not by itself establish the precision of an estimated response rate. The record says results are presented per cohort per patient because the study terminated early and the numbers were small. Specific response counts and uncertainty estimates are not reported in the registry record.

The endpoint should therefore be read as a descriptive account of radiographic response categories, not as a randomized estimate of comparative benefit. The registry does not report details of independent review, assessor masking, or how missing or unevaluable assessments were handled.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level classification: a participant either meets a specified response category or does not. The registry reports the primary measure as a count of participants, with responses classified using RANO criteria. This is different from a continuous outcome, such as a measured change in tumor size, and different from a time-to-event endpoint, such as progression-free survival.

What does a participant count tell us?

A count records how many participants fall into a defined category. In general, counts are easy to interpret, but their meaning depends on the number of participants assessed and on clear rules for defining the outcome. A count alone does not convey how uncertain an estimated response frequency may be. The registry’s statement that outcomes are listed per cohort per patient reflects the small numbers following early termination. Specific response counts and confidence intervals are not reported in the registry record.

How should RANO categories be read?

The registry defines response using multiple components. Complete response includes requirements related to T1-gadolinium-enhancing disease, T2/FLAIR signal, new lesions, corticosteroid use, and clinical status. Partial response uses a change in enhancing disease together with requirements for the other listed features. Stable disease and progressive disease are also defined using tumor imaging, new lesions, or clinical status. In general, using a prespecified classification system can improve consistency, but interpretation still depends on how assessments are performed and how ambiguous or missing assessments are handled. Those operational details are not reported in the registry record.

What does non-randomized allocation imply?

In a randomized trial, allocation is designed to make comparison groups similar on average, subject to chance. Here, the registry identifies the study as non-randomized and does not describe a like-for-like control group. The cohorts are organized around tumor categories, while the surgical arm has its own treatment and sampling description. In general, observed differences between non-randomized groups can arise from baseline differences, clinical selection, or other factors as well as from treatment. The record does not report adjustment methods that would address such differences.

What can the analysis record establish?

The registry lists 0 analyses. This indicates that analysis entries are not present in the record; it does not establish that no statistical work took place elsewhere. Details of the statistical analysis plan, including any models, hypothesis tests, confidence intervals, interim analyses, or adjustment for covariates, are not reported in the registry record. In general, a confidence interval describes a range of values compatible with data and an analysis model. Its width conveys precision, but no such interval for the primary response result is reported in the record.

How should planning illustrations be interpreted?

Planning illustrations based on an observed effect are not the same as the study’s prospective sample-size justification and are not observed power. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. In general, such calculations show how a hypothetical future study might be sized under chosen assumptions. They do not recover a randomized treatment effect from a non-randomized study, and they do not show that the current study had adequate power. The protocol’s own sample-size justification is not reported in the registry record.

The study also lists progression-free survival, overall survival, duration of response, and adverse events as secondary outcomes. In general, time-to-event outcomes require information about follow-up and event timing, while adverse-event counts require clear definitions and exposure context. The registry record does not report enough detail to assess censoring, event adjudication, or the handling of participants with incomplete follow-up for these outcomes.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary radiographic-response outcome and secondary outcomes covering progression-free survival, overall survival, duration of response, and adverse events. When a study evaluates multiple outcomes or makes multiple comparisons, the chance of a false-positive finding can increase unless the analysis plan accounts for multiplicity. This is a general statistical concern; the registry record does not report a multiplicity strategy, a hierarchy of tests, or which outcomes were intended to support formal claims.

The primary endpoint is described for 3 treatment cohorts, and the record says results are provided per cohort per patient after early termination. The analysis entries count is 0. Statistical tests, model specifications, confidence intervals, and adjustment for multiple comparisons are not reported in the registry record. Without those details, it is not possible to determine how any inferential results were obtained or whether reported comparisons were prespecified.

Missing-data handling is also not reported in the registry record. The record does not specify how participants without an evaluable scan, with incomplete follow-up, or with an assessment outside the stated timeframe were classified or excluded. In general, missing outcomes can affect both the number of participants analyzed and the interpretation of a response estimate; the direction and size of any effect depend on why data are missing and how they are handled.

The analysis populations are not described in detail in the registry record. It does not state whether the primary analysis used all enrolled participants, only participants who received treatment, or another defined group. The safety summary reports participants at risk, but this does not define the population used for each efficacy outcome. These gaps limit reproducibility and make it difficult to judge whether the reported participant-level outcomes reflect a consistent analysis population.

11. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cpk increase (20.0%), eye disorder other (20.0%).

The registry’s adverse-event summary covers patients treated with encorafenib or binimetinib in all cohorts. It lists 5 participants at risk, 2 participants with serious adverse events, 5 with other adverse events, and 5 deaths. These entries are counts in the safety record, not evidence that a particular drug caused an event or death. They also do not provide information about timing, duration, severity beyond the serious-event classification, or each participant’s clinical circumstances.

The top serious adverse-event terms are CPK Increase and eye disorder other, each listed as 20.0%. These are registry-reported terms and percentages. The record does not provide further detail in the registry record for this analysis about event onset, recurrence, management, or attribution. The terms should not be interpreted as a complete account of all safety concerns or as a comparison between treatment arms.

In general, adverse-event counts depend on how events are defined, collected, and attributed, as well as on the time participants are observed. The registry record does not report exposure-adjusted event rates or a comparative safety analysis. The listed deaths should therefore be reported as part of the registry summary without inferring that treatment caused them.

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

The record documents a Phase II study of encorafenib combined with binimetinib in adults with recurrent BRAF V600-mutated high-grade astrocytoma or other primary brain tumors. It describes a radiographic response endpoint based on RANO criteria and provides a registry safety summary. It also documents that the study was non-randomized, terminated early, and enrolled 5 participants.

These registry entries do not establish whether the treatment combination is effective or ineffective. Specific response counts are not reported in the registry record, and the small numbers and early termination limit what can be learned from cohort-level descriptions. The study has no randomized control group, so the record cannot estimate a causal treatment effect by comparing treated participants with a comparable untreated or alternative-treatment group.

The safety entries are descriptive. They do not show that the drugs caused the listed serious adverse events, other adverse events, or deaths. Nor do the registry entries establish how risks compare with another treatment. Such conclusions would require suitable comparative data and details about event assessment and follow-up that are not reported in the registry record.

The record can still be useful for understanding how the study was organized, which outcomes it intended to assess, and what safety counts were registered. It also illustrates why small studies that stop early may leave outcome estimates imprecise and difficult to interpret. In general, a study’s intended endpoint, the number of observations available, the allocation design, and the completeness of reporting all shape the strength of conclusions that can be drawn.

Any planning illustration based on the observed effect should be read as a hypothetical sample-size exercise, not as observed power or proof that a future trial would reproduce an effect. The registry does not report the protocol’s own sample-size justification or a detailed statistical plan. The appropriate conclusion is therefore limited: the record describes the study and its reported safety counts, while efficacy and comparative conclusions remain unsupported by the registry entries.

13. Why This Trial Matters Statistically

This trial matters statistically because it brings together several features that sharply constrain interpretation: non-randomized allocation, tumor-specific cohorts, early termination, and very small numbers. Those features are not merely technical details. They determine whether observed participant outcomes can support precise estimates or fair comparisons.

The endpoint also shows how outcome definitions shape what a study measures. RANO response categories incorporate imaging and clinical criteria, rather than relying only on a single measurement. Such a composite clinical classification can be informative, but it requires consistent assessment and transparent reporting of how each participant was evaluated. The relevant assessment procedures and missing-data rules are not reported in the registry record.

The trial’s structure makes the distinction between description and comparison especially important. Separate cohorts may be useful for reporting outcomes in different tumor groups, but they are not substitutes for randomized controls. Any apparent difference between cohorts may reflect their different clinical populations. With an early-terminated study and results described per cohort per patient, the record is better suited to documenting what was attempted than to establishing a stable treatment effect.

Finally, the registry’s limited analysis detail underscores why statistical plans and complete results matter. Reporting the analysis population, uncertainty, handling of missing assessments, and rationale for sample size would help readers judge the robustness of findings. Those details are not reported in the registry record. The trial is therefore a useful example of how design and reporting boundaries govern the conclusions that can responsibly be drawn from clinical data.

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 is the small enrollment and early termination. The registry lists enrollment of 5 and says that results are reported per cohort per patient because larger-scale summaries would be meaningless given the small numbers. This limits precision and makes subgroup patterns especially difficult to interpret. Specific primary response counts are not reported in the registry record.

The study was non-randomized, with no like-for-like control comparison and no masking. Cohorts were organized around different tumor types, and a surgical arm had a distinct treatment and sample-collection description. The record does not report baseline characteristics or an adjusted analysis that would allow differences between groups to be accounted for. A comparative treatment effect therefore cannot be isolated from the registry entries.

The registry does not report the statistical analysis plan, sample-size justification, confidence intervals for the primary outcome, interim analyses, or a multiplicity approach. It also does not describe analysis populations or how missing and unevaluable outcome assessments were handled. These omissions reduce reproducibility and prevent a full assessment of the validity and precision of efficacy estimates.

Safety findings are also limited by the level of detail reported. The summary provides counts and selected serious-event terms, but not event timing, duration, exposure-adjusted rates, or detailed attribution. The deaths in the safety summary cannot be assumed to have been caused by study treatment. These limitations are specific to the information reported in the registry record and do not imply that additional information is unavailable elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Binimetinib With Encorafenib in Adults With Recurrent BRAF V600-Mutated HGG — NCT03973918.
• Registry record last updated 2024-10-31; status last verified 2024-10.
• Results first posted 2024-03-06.
• 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

The registry describes NCT03973918, a Phase II study of binimetinib with encorafenib in adults with recurrent BRAF V600-mutated high-grade astrocytoma or another primary brain tumor. It was non-randomized, unmasked, and parallel, with a listed enrollment of 5. The status is terminated.

The primary outcome was the number of participants in each treatment cohort with a radiographic response under RANO criteria, assessed up to 1 year. Secondary outcomes included progression-free survival, overall survival, duration of response, and adverse events. The registry says results are presented per cohort per patient because of early termination and small numbers. Specific response counts and detailed statistical analyses are not reported in the registry record.

The safety summary lists 5 participants at risk, 2 with serious adverse events, 5 with other adverse events, and 5 deaths. CPK Increase and eye disorder other are the top serious adverse-event terms, each listed as 20.0%. These are descriptive registry entries and do not establish causation.