Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva...: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva... (NCT01229150), a randomized phase 2 study. The primary outcome is Progression Free Survival.

2. Clinical Question

The scientific question was whether adding erlotinib to AZD6244 was associated with a different time until disease progression, considered separately according to tumor KRAS status. This is not one comparison across all participants: each KRAS group has its own randomized treatment comparison. Keeping those comparisons distinct matters because the trial was organized around tumor mutation status, and the posted results do not establish that the treatment effect is the same across the two groups.

The registry record also identifies disease control or stabilization as a secondary outcome, alongside survival, adverse events, and biological measures. Those outcomes provide additional descriptions of response and safety, but they do not replace the primary progression-free survival question. The record does not report a formal test of whether the treatment comparison differs by KRAS status.

3. Trial Design

The registry record describes a completed, randomized phase II study with a parallel-group model and no masking. Enrollment is listed as 89. The study start date is 2010-10-26 and the primary completion date is 2013-09-30. The sponsor is the National Cancer Institute.

Participants were assigned to treatment arms within tumor KRAS groups. In the mutant group, KRAS Mut 1 received AZD6244 monotherapy and KRAS Mut 2 received AZD6244 plus erlotinib. In the wild-type group, WT KRAS 1 received monotherapy and WT KRAS 2 received the combination. The primary endpoint results are therefore presented as two within-status comparisons, rather than as a single comparison that pools the mutation groups.

The registry record identifies four arms and reports arm-specific participant counts for the primary outcome. The counts differ between arms in the mutant comparison, while the wild-type comparison has equal reported counts. The record does not report the allocation procedure or the method used to generate the randomization sequence, so further details about how assignments were implemented are not reported in the registry record.

Eligibility concerned advanced non-small cell lung cancer that had not responded to standard therapy. Screening was described as including medical history, physical examination, blood tests, imaging, and potentially tumor biopsy to determine KRAS status. The registry record lists AZD6244, erlotinib, and their combination as interventions. It does not report enough detail to characterize treatment schedules, treatment adherence, or subsequent therapies in the posted results.

This design can estimate treatment comparisons within the two KRAS-defined groups. It does not, on its own, establish whether KRAS status modifies the relative effect of the combination; that requires a directly reported interaction analysis, which 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: 89 participants were enrolled and 79 participants started. 10 patients should be classified as screen failures. Of the 10, one died during the screening process, and one patient withdrew during the screening process.

Overall Study

Reasons for not completing this period:

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, measured over 2.1 to 4 months.

The primary endpoint was progression-free survival, measured in months. It was defined as the time from the first day of treatment to disease progression. Progression included a specified increase in the sum of target-lesion diameters relative to the smallest sum observed on study, with an absolute increase requirement; the appearance of one or more new lesions also counted as progression. The record gives the primary outcome timeframe as 2.1 to 4 months.

Progression-free survival is a time-to-event outcome: the event is disease progression, and the analysis concerns how long participants remain free of that event. A median summarizes the time point by which half of the relevant observed survival distribution has experienced the event, subject to the way censoring is handled. It is different from an average duration and does not describe every participant’s experience.

Time-to-event outcomes are useful when follow-up duration can vary or when some participants have not experienced the event by the end of their observation. Such participants can contribute information up to their last known follow-up rather than being treated as if progression occurred at that time. General statistical interpretation depends on the censoring and analysis methods, however, and those implementation details are not reported in the registry record.

The posted median estimates are accompanied by 95% confidence intervals. These intervals communicate uncertainty in the estimated median; they are not ranges that contain a fixed share of individual participants’ progression times. Progression-free survival is the primary measure in this record, while disease control or stabilization is listed as a secondary outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Progression-free survival is analyzed as a time-to-event outcome. A participant’s observed time is measured from the defined starting point until progression, or until the last follow-up at which progression has not been documented. In general, censoring allows information from participants without a recorded event to contribute up to their last observation. The registry record defines progression and the starting point, but does not report censoring rules, follow-up procedures, or all details of the time-to-event analysis.

What does a median convey?

A median time-to-event estimate describes the midpoint of the estimated event-time distribution. It is not the time at which every participant progresses, nor is it an arithmetic average. A median can be estimated even when follow-up differs between participants, provided the relevant survival-analysis methods and assumptions are used. The posted results give a median and 95% confidence interval for each arm. The interval expresses uncertainty about the median estimate; it does not indicate the range of individual outcomes.

What does the log-rank test assess?

The registry reports log-rank tests for the two primary comparisons. In general, a log-rank test compares the event-time patterns across groups over follow-up, accounting for the timing of events and censored observations. It is not simply a test of whether the two reported medians differ. The p-value describes how compatible the observed test result is with a null model of no group difference, under the test’s assumptions. It does not give the probability that the null hypothesis is true, or measure the size or clinical importance of a difference.

The reported primary p-values are 0.24 for the KRAS-mutant comparison and 0.75 for the wild-type comparison. The registry does not report hazard ratios, confidence intervals for hazard ratios, or a detailed statistical analysis plan for these endpoints. Consequently, the posted primary results do not give a reported relative-effect estimate that would complement the medians.

How should the confidence intervals be read?

A confidence interval represents uncertainty in an estimated quantity under a statistical procedure. A wider interval indicates less precision than a narrower one, all else equal. For a median time, the interval concerns the estimated median, not the spread of individual progression times. Intervals from separate arms are not a substitute for a confidence interval on the treatment contrast. The registry reports arm-specific intervals but does not report a confidence interval for the difference between medians.

For the secondary disease-control outcome, the posted results include percentages and 95% confidence intervals. The additional recalculations use a risk difference, which expresses the difference between the two observed proportions on the probability scale. These are unadjusted recalculations from posted summary statistics, not the sponsor’s reported primary time-to-event analysis. Their p-values do not account for multiple comparisons, and their confidence intervals reflect the limited arm sizes. In general, sparse binary outcomes can produce substantial uncertainty, and a small p-value does not by itself establish that an effect is stable or reproducible.

Why does over-dispersion matter?

Over-dispersion is a general issue for count data when variability exceeds what a simple statistical model assumes. It can make standard errors too small if the extra variation is ignored. The registry record does not identify an over-dispersion analysis for the primary endpoint, which is a time-to-event outcome, or provide a count-model analysis for the outcomes listed. It would therefore be inappropriate to infer that a particular over-dispersion adjustment was used.

What do the planning illustrations mean?

The sample-size planning illustrations concern the secondary binary disease-control comparisons. They use the observed effect as a starting point and show planning under specified fractions of that effect. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. These are planning illustrations, not the trial’s original design justification and not observed power. They do not show the probability that this completed trial detected a real effect.

Planning from an observed effect is especially uncertain when the original groups are small, because an observed difference can be an unstable estimate of the effect a future study might encounter. The illustrations should therefore be read as conditional scenarios, not as validated requirements or evidence that the trial was adequately or inadequately sized. The registry record does not report the original sample-size justification, target effect, interim analyses, or a complete statistical plan.

For time-to-event planning, the record states that sample-size illustrations would use total events under a Schoenfeld approach, whereas other illustrations use participants per arm. The posted planning assumptions do not supply a trial-specific time-to-event planning analysis. These distinctions matter: event counts and participant counts are not interchangeable, and planning calculations do not describe the results actually observed.

10. Analyses Reported by the Sponsor

The sponsor’s reported primary analysis uses log-rank tests for the within-KRAS treatment comparisons. The registry gives p = 0.24 for the mutant comparison and p = 0.75 for the wild-type comparison. Those are the reported analyses for progression-free survival and should be distinguished from any simple recalculation based on arm-level summary statistics.

No recalculated hazard ratios or other relative time-to-event effects are presented because the registry record does not provide the summary information needed for such a recalculation. The posted primary results give arm-specific medians and confidence intervals, together with the sponsor’s log-rank p-values. The sponsor’s own analysis takes precedence for interpreting the primary time-to-event comparison; there is no stated discrepancy between a recalculation and that analysis.

The secondary disease-control comparisons include unadjusted recalculations from the posted counts and proportions. Those calculations are not sponsor-reported analyses in the registry record, and the registry does not list reported analyses for that outcome. They are descriptive supplementary calculations, not a replacement for the sponsor’s primary analysis or a fully adjusted analysis across outcomes. Their interpretation should account for uncertainty, the small group sizes, and the absence of a reported multiplicity plan.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary progression-free survival endpoint and several secondary outcomes. It reports two primary log-rank comparisons, one within each KRAS group. It also lists disease control or stabilization, overall survival, adverse events, and biological outcomes. Testing several outcomes and comparisons increases the chance of finding at least one nominally notable result by chance if each is assessed separately.

The record does not report a multiplicity adjustment, a prespecified hierarchy among secondary outcomes, or a strategy for controlling the overall false-positive rate. The unadjusted secondary p-values from recalculation should therefore be considered exploratory. The record also does not report interim analyses or a stopping rule, so no inference about interim monitoring can be made.

Missing-data handling and analysis populations are not sufficiently described in the registry record. In particular, the record does not state whether the primary analysis used an intention-to-treat population, a per-protocol population, or another defined set; how missing outcome assessments were handled; or how censoring was determined for progression-free survival. These details can affect the interpretation of randomized comparisons, especially when follow-up is incomplete or participants discontinue treatment.

Arm-level counts appear with the posted outcomes, but they do not establish the full analysis population or explain exclusions from any endpoint analysis. The registry enrollment figure should not be assumed to equal the number analyzed for every outcome. Without the analysis-population definitions and missing-data procedures, the degree to which the reported estimates preserve the benefits of randomization cannot be assessed fully.

The original sample-size justification and planned statistical analysis are also not reported in the registry record. The planning illustrations based on observed disease-control effects are not a substitute for those protocol details and should not be used to infer the trial’s original power or design intent.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: death nos (42.1%), fatigue (12.2%), dehydration (12.2%), diarrhea (12.2%), dyspnea (10.5%).

The safety record combines KRAS Mut 2 and WT KRAS 2 into one group for the reported adverse-event summary. In that combined group, 30 of 49 participants were reported with serious adverse events, and 49 of 49 were reported with other adverse events. The record lists 17 deaths in that group. For KRAS Mut 1, the corresponding figures are 6 of 11 with serious adverse events, 9 of 11 with other adverse events, and 4 deaths. For WT KRAS 1, they are 11 of 19, 18 of 19, and 8 deaths.

These figures describe events recorded in the registry; they do not establish that a treatment caused an event. The combined group includes participants from both KRAS status groups receiving the combination, so it does not provide separate safety summaries for mutant and wild-type participants on that regimen. The listed serious-event terms include Death NOS, fatigue, dehydration, diarrhea, dyspnea, and neoplasms benign, malignant and unspecified. A listed event term is not, by itself, evidence of causation or of the event’s relationship to study treatment.

Differences between these group summaries should be read cautiously because the group sizes differ and the registry record does not report a formal comparative safety analysis, exposure-adjusted rates, or attribution details. Counts and percentages are not a substitute for clinical assessment of individual events.

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

The primary results describe progression-free survival estimates in four treatment arms, organized into separate comparisons for KRAS-mutant and KRAS wild-type tumors. The registry reports median times, confidence intervals, and log-rank p-values. Neither reported p-value provides strong evidence of a difference between the randomized arms under conventional significance testing, but this does not prove that the treatments have identical effects.

The results also do not establish equivalence or non-inferiority. Those conclusions require an appropriate design, prespecified margins, and analyses reported for that purpose; such information is not reported in the registry record. The lack of a statistically notable difference is compatible with uncertainty about the size and direction of an effect, particularly when the estimates have broad confidence intervals and the trial groups are limited in size.

Nor do the results establish that KRAS status modifies treatment effect. The trial reports one treatment comparison within each mutation group, but no formal interaction analysis. A difference between two group-specific p-values would not show that the treatment effect differs between groups. The primary results should therefore be interpreted as two separate comparisons, not as a validated treatment-selection rule based on KRAS status.

The secondary outcomes offer additional descriptive information, but unadjusted secondary analyses carry less weight when many outcomes are considered and no multiplicity strategy is reported. The safety summaries document adverse events and deaths in the registry, without establishing treatment causation. The record also does not give enough information about analysis populations, missing data, or censoring to resolve all concerns about how the estimates were produced.

In general, a randomized phase II study can provide estimates that help characterize uncertainty and inform future research. Its results are not, by themselves, a complete account of clinical benefit, harm, or applicability beyond the enrolled population. These findings should be read as the posted statistical results of this study, with the limitations of the registry record kept in view.

14. Why This Trial Matters Statistically

This trial illustrates why a randomized study may still yield imprecise estimates. Randomization supports comparisons within the groups studied, but it does not guarantee narrow confidence intervals, especially when the number of participants in an arm is limited. The mutant monotherapy arm is smaller than the other primary arms, and its median estimate has appreciable uncertainty. Reporting confidence intervals alongside medians helps keep that uncertainty visible.

It also shows the importance of separating within-group treatment tests from questions about effect modification. The study makes two KRAS-specific comparisons, but a claim that KRAS status changes the treatment effect requires a direct interaction analysis. Without that analysis, the two p-values cannot be used as evidence that one mutation group responds differently from the other.

The secondary disease-control outcome illustrates a further statistical distinction: an unadjusted comparison based on proportions is not the same analysis as a time-to-event comparison. Different endpoints can provide complementary descriptions, but they can also appear to tell different stories because they measure different aspects of outcome and carry different uncertainty. Multiple outcomes make a prespecified analysis plan particularly important; that plan is not reported in the registry record.

Finally, the safety grouping illustrates how presentation choices affect interpretation. Combining the two combination arms allows a broader safety summary but prevents a separate reading by KRAS status. Together, these features make the record useful for examining uncertainty, endpoint distinctions, multiplicity, and the limits of conclusions drawn from phase II comparisons.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The registry record contains limited detail about the primary statistical analysis beyond the reported log-rank tests. It does not provide hazard ratios or confidence intervals for the treatment contrasts, a full analysis plan, censoring rules, or a clear account of the analysis populations. These omissions limit assessment of the effect’s magnitude and of how the time-to-event estimates were constructed.

The primary comparisons are split by KRAS status, but a formal interaction test is not reported. The results therefore cannot establish that KRAS status predicts a different relative treatment effect. The registry record also does not report a sample-size justification, so the precision of these comparisons cannot be assessed against the original design assumptions.

Several secondary outcomes are listed, but results are not available in the record for all of them. No multiplicity strategy is reported, and the recalculated disease-control comparisons are unadjusted. Any apparently notable secondary finding should therefore be considered exploratory. The planning illustrations based on observed secondary effects are also conditional and do not establish what a future study will observe.

The adverse-event summary combines the two combination arms and does not separate those participants by KRAS status. The record does not give a formal comparative safety analysis, treatment attribution, or exposure-adjusted safety rates. Thus, these data describe recorded events but cannot independently identify treatment-caused harms or support a detailed comparison between regimens.

Finally, the registry description does not report enough information about subsequent therapy, follow-up completeness, or missing outcome assessments to evaluate their influence on the results. The posted estimates should be interpreted within those reporting limits.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Randomized Phase II Study of AZD6244 (Mitogen-activated Protein Kinase Inhibitor) MEK-Inhibitor With Erlotinib in KRAS Wild Type Advanced Non-Small Cell Lung Cancer (NSCLC) and a Randomized Phase II Study of AZD6244 With Erlotinib in Mutant KRAS Adva... — NCT01229150.
• Registry record last updated 2017-05-23; status last verified 2017-04.
• Results first posted 2014-10-29.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT01229150 is a completed randomized phase II, parallel-group study with no masking. It enrolled participants with advanced non-small cell lung cancer and compared AZD6244 alone with AZD6244 plus erlotinib within KRAS-mutant and KRAS wild-type groups. The registry lists progression-free survival as the primary outcome.

The sponsor-reported log-rank p-values are 0.24 for the KRAS-mutant comparison and 0.75 for the wild-type comparison. The arm-specific medians and confidence intervals are imprecise, and the record does not report hazard ratios or a formal interaction test. Disease control or stabilization is a secondary outcome, with additional secondary outcomes including overall survival, adverse events, and biological measures.

Important details—including the original sample-size justification, multiplicity strategy, analysis populations, and missing-data procedures—are not reported in the registry record. The findings are best read as separate, uncertain within-group comparisons, with secondary recalculations treated as exploratory.