Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Previously Treated Patients With Metastatic, Radio-active Iodine Refractory BRAF V600E Mutation Positive Differentiated Thyroid Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Previously Treated Patients With Metastatic, Radio-active Iodine Refractory BRAF V600E Mutation Positive Differentiated Thyroid Cancer (NCT04940052), a randomized phase 3 study. The primary outcome is Progression Free Survival (PFS).

2. Clinical Question

3. Trial Design

This is a randomized, double-blind, placebo-controlled phase III study with quadruple masking. The registry identifies its model as crossover. The planned comparison described in the primary outcome is between dabrafenib plus trametinib and matching placebo. The registry also lists a crossover dabrafenib-plus-trametinib group in the safety results, but the operational details of crossover, including when or under what criteria it occurred, are not reported in the registry record.

The study concerns previously treated adults with locally advanced or metastatic, radioactive iodine refractory DTC carrying the BRAFV600E mutation. Eligibility in the brief summary includes disease progression after one or two prior VEGFR-targeted treatments. The active regimen is dabrafenib 150 mg twice a day with trametinib 2 mg once a day; the comparator is matching placebo for both drugs. The stated treatment period continues until a specified discontinuation condition, including progression assessed using RECIST 1.1 and confirmed by blinded independent review committee, unacceptable toxicity, pregnancy, or investigator-determined loss of clinical benefit. The complete stopping description is not reported in the registry record.

Enrollment is reported as 153. The primary results list 101 participants in the combination group and 52 in the placebo group. The registry gives the start date as 2021-11-15 and primary completion as 2025-01-22. Its status is active, not recruiting. The primary analysis description says it was conducted after all patients had completed a minimum of 16 weeks of treatment or discontinued earlier, and after approximately 95 PFS events; the data cut-off date was 22 January 2025.

Several design details cannot be established from this record. The randomization procedure, allocation ratio as implemented, site structure, detailed eligibility criteria, crossover rules, and original sample-size justification are not reported in the registry record. The enrollment and posted analysis group sizes describe the record, not an explanation of how the study was planned or conducted in every operational detail.

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: Participants were randomized in a 2:1 ratio to either Dabrafenib plus Trametinib or placebo. Randomization was stratified by the number of prior VEGFR targeted therapies (1 vs. 2) and prior lenvatinib treatment (yes vs. no).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS).

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 Progression Free Survival (PFS), measured over From randomization to first documented progression or deaths, whichever comes first, assessed up to approximately 3 years.

Progression-free survival (PFS) is the time from randomization until the first documented progression or death from any cause, whichever occurs first. In this trial, progression was defined using RECIST 1.1 and assessed by a blinded independent review committee. The primary endpoint is reported as a median in months, with a 95% confidence interval. The analysis population is the Full Analysis Set.

PFS is a time-to-event endpoint: it uses both the timing of an event and whether an event has been observed during follow-up. Participants without a recorded event by the analysis cut-off can contribute information up to the last relevant observation rather than being treated as though an event had occurred. The detailed censoring rules are not reported in the registry record.

Using progression or death as the endpoint captures disease worsening and death within a single measure. It also means that the reported result is not a direct estimate of overall survival, symptom change, or quality of life. Overall survival is listed as a secondary outcome, but its numerical results are not reported in the registry record. PFS is therefore the primary measure for the trial’s stated efficacy question, while its interpretation should remain specific to the endpoint definition, assessment method, analysis population, and follow-up represented in the posted results.

7. Results Posted in the Registry

• Dabrafenib Plus Trametinib vs Dabrafenib Placebo Plus Trametinib Placebo: hazard ratio 0.38 (95% CI 0.25–0.57), reported p < 0.001 (as reported in the registry).

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Overall Response Rate (ORR)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Dabrafenib Plus Trametinib: 57.4% (58/101) versus 3.8% (2/52) on control; risk difference 53.6 percentage points (95% CI 42.6 to 64.5), risk ratio 14.93 (3.80–58.72); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Dabrafenib Plus Trametinib than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The listed secondary outcomes cover response, survival, duration of response, and safety. ORR is the secondary efficacy result with numerical estimates and a reported comparison in the registry record. Overall survival and duration of response are listed, but their numerical results are not reported in the registry record. Safety outcomes are reported separately and should be interpreted according to their own definitions and exposure periods rather than as efficacy measures.

The ORR result is directionally consistent with the primary PFS comparison in that both posted efficacy comparisons favor the combination group on their respective scales. They address different questions: ORR concerns whether a response was recorded, while PFS concerns time to progression or death. Neither endpoint can stand in for the other, and ORR does not establish the duration of response or overall survival.

Secondary analyses generally carry less weight than the prespecified primary question when many outcomes are examined. If multiple comparisons are tested without adjustment, the chance of at least one apparently notable result can increase. Whether the study adjusted for multiplicity, how the secondary outcomes were ordered, and whether any were confirmatory are not reported in the registry record. Therefore, the secondary findings should be treated as supportive or exploratory unless the full analysis plan establishes otherwise.

The registry lists six outcome measures and reports five secondary outcomes by name, while the numerical secondary results available in the record are limited. The absence of numerical results for a listed outcome is not evidence that the outcome had no effect; it means that a result cannot be interpreted from this record. Likewise, an ORR finding does not fill in missing results for overall survival, duration of response, or other outcomes. The evidence across endpoints is therefore incomplete in the registry record, and the primary PFS result remains the central posted efficacy comparison.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Overall Response Rate (ORR)
• Overall Survival (OS)
• Duration of Response (DOR)
• Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
• Number of Participants With Trametinib Associated Serous Retinopathy Ocular Events

9. Statistical Interpretation

10. Statistical Methods Explained

The methods below explain the statistical quantities in general terms and then relate them to the analyses reported in the registry. The detailed statistical analysis plan is not reported in the registry record, so the explanations distinguish the posted methods from analysis choices that cannot be verified.

What does a median PFS describe?

A median is the point in the estimated time-to-event distribution at which half of the distribution is on either side. For PFS, the event is the first documented progression or death from any cause. The posted medians are 12.8 months for dabrafenib plus trametinib and 3.7 months for placebo. These are estimates from the analysis, not statements that every participant had an event at those times. Follow-up and censoring affect the estimation, and the registry record does not report the detailed censoring rules or the numbers at risk over time.

The median gives a readily interpretable summary of a time-to-event outcome, but it does not describe the complete shape of the event-time distribution. Two groups can have different patterns at different points in follow-up even when their medians alone do not reveal those patterns. The registry reports a hazard ratio as the main comparative estimate, which uses the event-time comparison beyond a single median point.

What does the hazard ratio express?

The sponsor-reported hazard ratio is 0.38, with a 95% confidence interval from 0.25 to 0.57. In general, a hazard ratio compares the event hazards between groups over the analyzed follow-up. A hazard is an instantaneous event rate among participants who have not yet experienced the event and remain under observation. A hazard ratio is not a probability, a difference in months, or a direct comparison of the reported medians.

The registry identifies the method for the reported comparison as log rank. The log-rank test evaluates evidence of a difference between time-to-event distributions, while the hazard ratio describes the relative contrast reported for the groups. The p-value is reported as p < 0.001. The registry does not report the full model specification, checks of assumptions, or detailed handling of the crossover in the primary analysis. In general, a single hazard ratio is easiest to interpret when the relative hazards are reasonably stable over follow-up; whether that assumption was evaluated is not reported in the registry record.

Why is the confidence interval important?

A confidence interval conveys uncertainty around an estimated quantity. In repeated use of a method under its assumptions, confidence intervals are designed to cover the underlying parameter at the stated confidence level at the stated frequency. For this study, the PFS medians and hazard ratio are accompanied by 95% confidence intervals. The interval is not a range containing a fixed proportion of individual participant outcomes, nor does it express the probability that the true value lies inside this particular interval. Its width indicates how precisely the estimate is supported by the analysis, while its location indicates which values remain compatible with the data under the method.

For a hazard ratio, the value 1 represents no relative difference in hazard. The reported interval from 0.25 to 0.57 does not include 1. This is consistent with the reported p-value below 0.001, although the interval and p-value are different summaries of uncertainty and depend on the analysis method.

How should ORR be distinguished from PFS?

ORR is a binary outcome: a participant is classified as having an overall response or not under the response definition used by the study. The registry reports 57.4% in the combination group and 3.8% in the placebo group. A percentage summarizes the proportion meeting the outcome definition; unlike PFS, it does not by itself describe when a response occurred or how long it lasted. Duration of response is separately listed as a secondary outcome, but its numerical result is not reported in the registry record.

The sponsor’s reported ORR comparison is an odds ratio from a Cochran-Mantel-Haenszel analysis. Odds compare the chance of the outcome with the chance of not having it; an odds ratio compares those odds across groups. It is not interchangeable with a risk difference or a ratio of response percentages. The sponsor reports an odds ratio of 29.90 with a 95% confidence interval from 7.02 to 127.39 and p < 0.001. The wide interval indicates substantial uncertainty about the magnitude of the odds ratio, even though the interval is above 1.

What does over-dispersion mean in general?

Over-dispersion is a general issue in statistical models for count data: observed variability can be greater than a model’s assumptions allow. When that happens, a model that ignores the extra variability can understate uncertainty. It is not reported whether over-dispersion is relevant to an analysis in this trial, and it should not be inferred from the posted PFS or ORR results. PFS is presented as a time-to-event endpoint and ORR as a binary percentage, so an explanation of over-dispersion does not change the interpretation of those reported measures.

More broadly, the registry does not report the complete statistical analysis plan, including detailed model assumptions, missing-data procedures, or multiplicity control. Those omissions limit how much can be concluded about analysis choices beyond the methods explicitly named for the reported endpoints.

11. Confidence Intervals and Precision

The PFS medians are reported with 95% confidence intervals: 12.8 months (10.2 to 21.2) for dabrafenib plus trametinib and 3.7 months (2.3 to 7.5) for placebo. The sponsor-reported hazard ratio is 0.38, with an interval from 0.25 to 0.57. The intervals express uncertainty in the estimated medians and relative hazard; they are not measures of variation in individual outcomes.

The hazard-ratio interval lies below 1. This indicates that values compatible with the reported analysis are on the side of a lower event hazard in the combination group relative to placebo. The interval still spans a range of possible effect magnitudes, so the estimate should not be treated as an exact or universal quantity. Its lower and upper limits reflect the precision of this analysis under its methods and assumptions.

For ORR, the combination-group estimate is 57.4% with a 95% confidence interval from 47.2 to 67.2, while the placebo estimate is 3.8% with a 95% confidence interval from 0.5 to 13.2. The sponsor’s odds-ratio interval is 7.02 to 127.39 around an estimate of 29.90. The broad range for the odds ratio shows that the magnitude is imprecisely estimated even though the interval is above 1. Confidence intervals for the two groups and the interval for a comparative measure answer different questions; comparing their overlap alone is not a replacement for the reported group comparison.

Precision depends on the number and timing of observed events, follow-up, and the analysis method. The registry says the primary analysis followed approximately 95 PFS events, but it does not provide full event-time data, numbers at risk at each time, or the detailed missing-data and censoring procedures. The confidence intervals therefore provide the most direct posted indication of precision, while the unreported details constrain independent assessment of how that precision was obtained.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations based on fractions of the observed effect, not the trial’s original design calculations. For the PFS planning rows, the figures are total events, not participants per arm. At 100% of the observed effect, the illustration gives 34 total events for 80% power and 45 for 90% power. At 75% of the observed effect, it gives 60 total events for 80% power and 80 for 90% power. At 50% of the observed effect, it gives 135 total events for 80% power and 180 for 90% power.

The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The time-to-event illustrations use the Schoenfeld method. The original trial’s own design assumptions and sample-size justification are not reported in the registry record.

In plain language, 80% power means that a study planned under the stated assumptions would have an 80% chance of meeting its statistical significance criterion if the effect to detect were the assumed effect. The 90% column uses a higher probability of detecting that assumed effect. The binary-outcome sample-size figures, including ORR, are participants per arm: at 100% of the observed effect, 11 participants per arm for 80% power and 14 for 90% power; at 75%, 17 and 22; and at 50%, 31 and 40. Smaller effects require more information to detect, so the illustrations require more events or participants as the assumed effect becomes smaller. These figures are not observed power; they are planning illustrations under the listed assumptions.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

d is the total number of events needed (Schoenfeld's formula) with 1:1 allocation and proportional hazards.

Worked calculation for this trial

1. Hazard ratio HR = 0.380, so ln(HR) = -0.9676.
2. d = 4 × (1.96 + 0.842)² / [ln(0.380)]² = 33.5, rounded up to 34 events in total for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
hr <- 0.38                              # observed hazard ratio
events_needed <- function(power, frac = 1) ceiling(round(4 * (z_a + qnorm(power))^2 / log(hr^frac)^2, 6))   # Schoenfeld, 1:1 allocation
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: events = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(events_needed(0.80, f), big.mark = ","), format(events_needed(0.90, f), big.mark = ",")))

# Simulation: given d total events under proportional hazards, events in the treatment arm are Binomial(d, hr / (1 + hr)).
# The score (log-rank type) statistic is (D1 - d / 2) / sqrt(d / 4).
set.seed(4940052)
d    <- events_needed(0.80)
reps <- 20000
D1 <- rbinom(reps, d, hr / (1 + hr))
z  <- (D1 - d / 2) / sqrt(d / 4)
cat(sprintf("Simulated power with %s events: %.3f (%d replicates)\n", format(d, big.mark = ","), mean(abs(z) > z_a), reps))

Output from running the code

100% of observed effect: events = 34 (80% power), 45 (90% power)
 75% of observed effect: events = 60 (80% power), 80 (90% power)
 50% of observed effect: events = 135 (80% power), 180 (90% power)
Simulated power with 34 events: 0.795 (20000 replicates)

The simulation uses the fact that, with d events in total and proportional hazards, the number of events in the treatment arm is binomial. It is an approximation that conditions on the total number of events, and it should land close to the target power.

14. Group-Sequential Design Analysis

Many time-to-event trials, especially in oncology, stop or report early when interim data are overwhelming, so a single fixed-sample number understates the real design problem. The calculation below is an illustrative group-sequential design built from this trial's posted control median and hazard ratio. The registry record does not state the planned number of looks or the spending function, so the design is a planning illustration, not a reconstruction of the protocol. Assumed: one-sided α = 0.025, 90% power, three equally spaced looks on information, Lan-DeMets O'Brien-Fleming spending, 24 months of accrual, 60 months in total and a 1% monthly dropout hazard.

Under these assumptions the design needs about 50 participants in total, with the boundaries below.

Fixed design versus group-sequential alternatives

Group-sequential designs cost a small increase in maximum sample size and events compared with the fixed design, in exchange for the chance to stop early for overwhelming efficacy. O'Brien-Fleming spending keeps early boundaries very conservative and the final boundary close to the fixed-design value, whereas Pocock spending spends more alpha early.

Sensitivity to a smaller true effect

Planning for exactly the observed effect is optimistic, because observed effects in published trials tend to be somewhat larger than the true effect. The table repeats the main design (three looks, O'Brien-Fleming spending, 90% power) for smaller true hazard ratios.

For context, this trial enrolled 153 participants.

Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993. Agreement between the two packages confirms the boundary calculation.

R code and output

suppressWarnings(suppressMessages({ library(gsDesign); library(rpact) }))
med_control <- 3.7          # control-arm median, months (converted from the posted unit)
hr          <- 0.38          # hazard ratio used for planning
lambdaC     <- log(2) / med_control
eta         <- 0.01               # dropout hazard per month (assumption)
acc_months  <- 24                 # accrual duration (assumption)
study_months<- 60                 # total study duration (assumption)

design <- function(k, sfu, beta, h = hr) gsSurv(k = k, test.type = 1, alpha = 0.025, beta = beta, sfu = sfu,
  lambdaC = lambdaC, hr = h, hr0 = 1, eta = eta, gamma = 1, R = acc_months, T = study_months, minfup = study_months - acc_months)

# Main design: 3 looks, Lan-DeMets O'Brien-Fleming spending, one-sided alpha 0.025, 90% power
x <- design(3, sfLDOF, 0.10)
cat(sprintf("N_TOTAL|%s\n", format(ceiling(sum(x$gamma * x$R)), big.mark = ",")))
for (i in 1:3) cat(sprintf("GS|%d|%.1f|%.0f|%.3f|%.5f|%.5f\n", i, x$T[i], x$n.I[i], x$upper$bound[i], pnorm(-x$upper$bound[i]), cumsum(x$upper$spend)[i]))
cat("\n"); print(gsBoundSummary(x))

# Comparison of designs
cmp <- list(list("Fixed design, one analysis", 1, sfLDOF), list("Two looks, O'Brien-Fleming", 2, sfLDOF),
            list("Three looks, O'Brien-Fleming", 3, sfLDOF), list("Three looks, Pocock", 3, sfLDPocock))
cat("\n")
for (b in c(0.20, 0.10)) for (d in cmp) {
  y <- design(d[[2]], d[[3]], b)
  cat(sprintf("DES|%s|%d|%.0f|%s|%.1f\n", d[[1]], round(100 * (1 - b)), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ","), tail(y$T, 1)))
}

# Sensitivity: what if the true effect is smaller than the observed one? (3 looks, O'Brien-Fleming, 90% power)
cat("\n")
for (fr in c(1, 0.75, 0.5)) {
  y <- design(3, sfLDOF, 0.10, exp(log(hr) * fr))
  cat(sprintf("SENS|%.2f|%.3f|%.0f|%s\n", fr, exp(log(hr) * fr), tail(y$n.I, 1), format(ceiling(sum(y$gamma * y$R)), big.mark = ",")))
}

# Independent cross-check of the boundaries with rpact
r <- getDesignGroupSequential(kMax = 3, alpha = 0.025, beta = 0.10, sided = 1, typeOfDesign = "asOF", informationRates = x$timing)
cat(sprintf("\nCross-check, upper boundaries: gsDesign %s | rpact %s\n", paste(round(x$upper$bound, 3), collapse = ", "), paste(round(r$criticalValues, 3), collapse = ", ")))

Method: LachinFoulkes 
   Analysis               Value Efficacy
  IA 1: 33%                   Z   3.7103
      N: 30         p (1-sided)   0.0001
 Events: 15        ~HR at bound   0.1465
  Month: 14    P(Cross) if HR=1   0.0001
            P(Cross) if HR=0.38   0.0338
  IA 2: 67%                   Z   2.5114
      N: 50         p (1-sided)   0.0060
 Events: 30        ~HR at bound   0.3987
  Month: 23    P(Cross) if HR=1   0.0060
            P(Cross) if HR=0.38   0.5603
      Final                   Z   1.9930
      N: 50         p (1-sided)   0.0231
 Events: 45        ~HR at bound   0.5511
  Month: 60    P(Cross) if HR=1   0.0250
            P(Cross) if HR=0.38   0.9000



Cross-check, upper boundaries: gsDesign 3.71, 2.511, 1.993 | rpact 3.71, 2.511, 1.993

15. Analyses Reported by the Sponsor

For PFS, the registry’s reported analysis is the sponsor’s log-rank comparison, with a hazard ratio of 0.38, a 95% confidence interval from 0.25 to 0.57, and p < 0.001. No recalculated PFS comparison is being substituted for this sponsor-reported time-to-event result. The registry’s description identifies the reported hazard ratio as the basis for the primary interpretation.

For ORR, the sponsor reports a Cochran-Mantel-Haenszel odds ratio of 29.90, with a 95% confidence interval from 7.02 to 127.39 and p < 0.001. A simple unadjusted recalculation from the posted group summaries instead describes the comparison on the risk-difference scale: 0.536, with a 95% confidence interval from 0.426 to 0.645 and an unadjusted p-value < 0.001. These statistics use different measures and methods, so their numerical values are not directly interchangeable. The recalculation is a descriptive check based on posted summaries, not a replacement for the sponsor’s analysis. The registry reports no discrepancy requiring a different precedence.

The reported analysis should take priority for understanding what the trial sponsor concluded under its chosen method. A simple recalculation can offer a useful supplementary view, but it does not reproduce the full analysis unless the underlying model and adjustments match. The registry does not provide enough detail to independently reconstruct every aspect of the sponsor’s analyses.

16. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when statistical tests or confidence intervals are considered across several outcomes, time points, or analysis populations. Without a planned approach to control the overall chance of false-positive findings, a nominal p-value for a secondary outcome may overstate how strong the total evidence is. This is a general statistical concern, not a claim that the trial’s analyses were incorrect.

The primary endpoint is PFS. ORR, overall survival, duration of response, and safety outcomes are also listed. The registry record does not report whether a hierarchical testing sequence, multiplicity adjustment, or other prespecified control was used for secondary outcomes. It also does not provide the complete statistical analysis plan. The ORR p-value should consequently be read as the reported result for that comparison, not assumed to be adjusted for all outcomes unless the record says so.

The primary analysis population is identified as the Full Analysis Set. The record does not define the exact membership rules for that set, nor does it report the handling of missing measurements, loss to follow-up, censoring details, or deviations from assigned treatment. These choices can influence time-to-event and response analyses. For PFS, the registry gives the endpoint definition and says the primary progression assessment was by blinded independent review, but further analytic details are not reported in the registry record.

The trial is identified as a crossover study, and a crossover combination group appears in the safety results. The primary PFS comparison is reported between the randomized combination and placebo groups, but the registry does not explain crossover timing, eligibility, or how crossover participants were handled in the efficacy analysis. It is therefore not possible to assess from this record how crossover affected later treatment exposure or other outcomes.

These missing details do not invalidate the posted estimates, but they limit independent appraisal of robustness, multiplicity, and analysis-population choices. Conclusions should remain tied to the analyses and definitions explicitly stated in the registry record.

17. 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 4.9999% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (7.9%), multiple organ dysfunction syndrome (6.7%), dyspnoea (6.7%), pleural effusion (6.7%), pyrexia (4.0%).

The safety results separate on-treatment groups from post-treatment reporting and include both serious and other adverse events. In the on-treatment dabrafenib-plus-trametinib group, 43 participants are reported with serious adverse events and 96 with other adverse events, with 101 listed at risk for each measure. In the on-treatment placebo group, the corresponding figures are 13 and 44, with 52 listed at risk. The crossover dabrafenib-plus-trametinib group reports 14 serious and 30 other adverse events, with 30 at risk.

These are participant counts, not event counts or comparisons adjusted for duration of exposure. The crossover group is distinct in the registry’s safety listing; the record does not provide the details needed to compare its exposure with the randomized groups. Serious adverse events are not necessarily caused by study treatment, and the counts alone do not establish causation. The record also lists deaths for on-treatment and post-treatment groups, but the circumstances and attribution are not specified in the information.

The registry lists pneumonia at 7.9%, multiple organ dysfunction syndrome at 6.7%, dyspnoea at 6.7%, pleural effusion at 6.7%, pyrexia at 4.0%, and pneumonia bacterial at 3.8% among the top serious adverse-event terms. These percentages describe reported terms; details of their denominators and any attribution assessment are not reported in the registry record. Safety counts should be read alongside the trial’s population, exposure, and reporting definitions, which are not fully available in this record.

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

The posted primary analysis supports a difference in PFS between the randomized groups in this trial’s defined population. The estimated medians are 12.8 months for dabrafenib plus trametinib and 3.7 months for placebo, and the reported hazard ratio is 0.38 with a 95% confidence interval from 0.25 to 0.57. The interval lies below 1, and the reported log-rank p-value is p < 0.001. These statistics describe the observed study comparison under the reported endpoint definition and analysis.

They do not mean that every participant experienced the same course, that an individual outcome can be predicted from a group estimate, or that the hazard ratio is a direct percentage change in survival time. They do not establish an effect on overall survival: OS is listed as a secondary outcome, but its numerical result is not reported in the registry record. Nor do the primary PFS data alone describe quality of life, symptoms, or all aspects of safety.

The ORR comparison is a separate secondary finding and should not be treated as a substitute for PFS or as proof of response duration. Numerical results for duration of response are not reported in the registry record. Safety results report adverse-event counts, but counts alone cannot determine whether events were caused by treatment or whether the balance of benefits and risks is favorable for an individual.

The findings apply most directly to the population described in the registry: adults with locally advanced or metastatic, radioactive iodine refractory DTC with the BRAFV600E mutation, previously treated with one or two VEGFR-targeted treatments, and represented in the FAS. Generalizing beyond that population requires evidence not contained in this record. The crossover model and the presence of crossover safety results also make treatment-sequence details relevant, but those procedures are not described in sufficient detail.

Statistical evidence is not the same as a clinical recommendation. The registry result reports an estimated group difference with uncertainty; it does not determine which option is appropriate for a particular patient. That requires clinical judgment and information beyond the statistical results described in the record.

19. Why This Trial Matters Statistically

This trial addresses a defined time-to-event question in a specific molecular and treatment-history subgroup of differentiated thyroid cancer. The randomized, placebo-controlled design provides a direct group comparison, while double-blind treatment and blinded independent review of progression are intended to reduce bias in treatment delivery and endpoint assessment. The registry identifies quadruple masking, although the exact roles covered by that masking are not reported in the registry record.

Statistically, the result illustrates why the median and hazard ratio should be read together. The medians give an intuitive time-based summary, while the hazard ratio captures a relative comparison of event hazards over follow-up. Their confidence intervals show that the estimates have uncertainty, and the hazard-ratio interval is entirely below 1. The report also names the log-rank method and gives the primary analysis timing in relation to treatment duration and PFS events, which helps locate the result within the study’s analysis process.

The secondary ORR finding provides another efficacy perspective, but its odds ratio and the primary hazard ratio describe different outcomes and different scales. The registry’s safety summaries add context about reported adverse events without establishing attribution. Interpreting the overall evidence therefore requires keeping efficacy, safety, endpoint definitions, and analysis methods distinct rather than collapsing them into a single conclusion.

At the same time, important statistical details remain unavailable in the registry record: multiplicity control, missing-data procedures, full model specifications, and crossover handling. This distinction between a clearly reported estimate and an incompletely reported analysis plan is important for biostatistical interpretation. It allows the posted result to be described accurately while recognizing the limits on independent verification and on claims beyond the stated population and endpoints.

20. 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.

Several limitations specific to this trial are apparent from the registry record. The primary endpoint is PFS, not overall survival, and the record does not report numerical OS results despite listing OS as a secondary outcome. Numerical results for duration of response are also not reported. The posted efficacy picture is therefore incomplete for outcomes that could add different information about survival and the persistence of response.

The study is identified as crossover, and the safety listing includes a crossover dabrafenib-plus-trametinib group. The record does not explain the timing, eligibility, or operational rules for crossover, or how crossover may have been addressed in later efficacy analyses. This limits interpretation of treatment exposure after randomization and makes it difficult to assess whether the primary comparison represents the full treatment experience.

Although the primary endpoint definition and blinded independent review are stated, further details about censoring, missing data, model assumptions, and analysis populations are not reported in the registry record. The FAS is named but not defined. The full statistical analysis plan and the original design assumptions are also not reported, so multiplicity procedures and the rationale for the planned enrollment cannot be assessed from this record.

The safety figures are presented as participant counts, with on-treatment and post-treatment groupings and a crossover group. The registry record does not provide enough information to interpret exposure-adjusted event rates, establish event attribution, or compare risks accounting for time on treatment. The reported serious adverse-event terms and percentages should be interpreted within their reporting definitions, which are not fully described in the posted information.

Finally, the findings concern a selected population with a specific disease setting, mutation, and prior-treatment history. They should not automatically be generalized to patients with different disease characteristics or treatment histories.

21. Related Tutorials

22. Related Statistical Calculators

23. Sources

• ClinicalTrials.gov: Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Previously Treated Patients With Metastatic, Radio-active Iodine Refractory BRAF V600E Mutation Positive Differentiated Thyroid Cancer — NCT04940052.
• Registry record last updated 2026-09-21; status last verified 2026-09.
• Results first posted 2026-05-22.
• 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.

24. Record Summary

The registry record describes NCT04940052, a randomized, double-blind, placebo-controlled phase III study of dabrafenib plus trametinib in previously treated adults with locally advanced or metastatic, radioactive iodine refractory, BRAFV600E mutation-positive DTC. Enrollment is reported as 153, and the study status is active, not recruiting.

The primary endpoint is PFS in the Full Analysis Set, measured from randomization to progression assessed by blinded independent review under RECIST 1.1 or death from any cause. Median PFS is reported as 12.8 months for the combination group and 3.7 months for placebo. The sponsor-reported hazard ratio is 0.38 (95% confidence interval 0.25 to 0.57; p < 0.001).

ORR is the secondary efficacy outcome with numerical results reported in the registry record. Other listed outcomes include overall survival, duration of response, and safety measures, but numerical results for OS and duration of response are not reported in the registry record. The record identifies a crossover model but does not describe its procedures in detail. Multiplicity control, missing-data handling, and the full statistical analysis plan are also not reported.