A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations (NCT01647711), a na phase 1 study. The primary outcome is Percentage of Participants With Dose Limiting Toxicities.

2. Clinical Question

The study therefore combines a dose-finding question with an activity question. These questions are related but not interchangeable: toxicity during dose escalation informs selection of a regimen, while tumor response in the mutation-defined group concerns activity at the selected dose. The record identifies objective response rate as a secondary outcome, but does not give its result. It also lists pharmacokinetic and tumor-derived biological marker exploration among the secondary objectives. The available record does not establish how many participants entered each study part or which dose they received for response assessment.

3. Trial Design

This completed study is identified as NCT01647711. Its title describes intermittent administration of high doses of afatinib, and its official title calls it a Phase 1b study. The registry classifies the phase as Phase 1. Enrollment is recorded as 35 participants. The study began in 2012-07, had primary completion in 2015-09, and is listed as completed.

The design had two parts with different aims. Part A sought to establish the maximum tolerated dose of intermittent high-dose afatinib in patients with advanced solid tumors. Part B sought to assess response in patients with non-small cell lung cancer with EGFR T790M mutations, using the dose established in Part A or a lower dose. The description states that Part B concerned patients whose disease had progressed on prior therapy, but the further treatment wording in the arm description is incomplete in the registry record.

The intervention is listed as dose escalation followed by treatment with the maximum tolerated dose. Five afatinib dose cohorts appear in the safety results: 90mg, 120mg, 150mg, 160mg, and 200mg. The number of participants at risk for the serious adverse event summary differs across these cohorts. These cohorts are stages of a dose-finding design, not randomized study arms. Changes in participant characteristics, exposure, or cohort size can affect comparisons across doses, and the registry does not report an adjusted comparison between them.

The record lists no masking and no separate comparator group. It also lists 5 outcome measures and no analysis records. That does not establish what analyses were conducted outside the registry results record. The registry record does not report the detailed protocol, the planned sample-size justification, or a complete statistical analysis plan. The enrollment figure is not itself evidence that the study had a particular level of statistical power.

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: Afatinib was administered until disease progression, however patients experiencing clinical benefit were allowed to continue treatment for as long as judged beneficial by the investigator.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated set including patients eligible for MTD determination

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: Treated set which included all patients who took at least one dose of afatinib.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Dose Limiting Toxicities, measured over 28 days.

The primary endpoint is the percentage of participants with dose-limiting toxicities, based on investigator assessment. It applies to the treated set including patients eligible for maximum tolerated dose determination, and its stated timeframe is 28 days. The registry defines the maximum tolerated dose as the dose at which less than 2 of up to 6 patients developed a dose-limiting toxicity.

This endpoint is used in dose-finding because the objective is to identify a dose that meets a prespecified tolerability rule, rather than to compare the treatment with a control. An event indicator for each participant can be summarized as a count or a percentage within a dose cohort. The rule described in the record links the observed number of dose-limiting toxicities to dose selection. It should not be read as a general safety threshold for other settings.

The record gives the endpoint definition, population, and timeframe, but does not report the primary endpoint’s observed percentage, its dose-specific results, or the dose selected as the maximum tolerated dose. The serious adverse event counts listed elsewhere are not a substitute for the primary endpoint: the record does not state that every serious event was a dose-limiting toxicity, and the endpoint is specifically based on investigator assessment for dose-limiting toxicities.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint represent?

For a binary outcome such as whether a participant experienced a dose-limiting toxicity, the basic summary is the number with the event relative to the number assessed. A percentage expresses that observed fraction on a common scale. It is a descriptive estimate for the defined population and timeframe; it is not, by itself, a comparison with another treatment or proof that a dose caused an event.

In this trial the primary outcome is explicitly a percentage, and the registry supplies the endpoint definition and intended population. It does not supply the event count or the endpoint denominator. Therefore, a primary endpoint percentage cannot be reconstructed from the record. The serious adverse event totals are a different safety summary and should not be substituted for the dose-limiting toxicity count.

How does the dose-finding rule work?

The record defines maximum tolerated dose using a rule based on the number of patients who develop a dose-limiting toxicity: the selected dose is one at which less than 2 of up to 6 patients develop such an event. This is an operational decision rule. In general, a dose-escalation rule uses observed toxicity information to guide whether dosing proceeds, stops, or is selected for further study. The specific escalation steps, stopping boundaries beyond the stated definition, and any decision algorithm are not reported in the registry record.

The number of patients contributing to a dose cohort is important when interpreting this type of rule. A count from a small cohort is inherently limited in how much it can tell about the underlying event probability. That is a general feature of estimates from small samples, not an additional result for this study. The registry lists dose-specific safety denominators, but does not report dose-specific primary endpoint outcomes, so the stated maximum tolerated dose rule cannot be independently applied using the posted record.

What would an interval estimate add?

In general, a confidence interval describes the uncertainty around an estimated quantity under a statistical procedure. For a binary outcome, an interval around the event percentage would help show how precisely the observed percentage estimates the event frequency in the population represented by the study. It would not remove limitations caused by small cohorts, participant selection, incomplete outcome reporting, or the absence of a comparator.

No confidence interval for the primary endpoint is reported in the registry record. Nor are confidence intervals for objective response rate listed. Without an estimate and its denominator, readers cannot assess the precision of either outcome from the registry record. A narrow or broad interval should not be inferred from the overall enrollment alone, because the relevant number assessed may differ by endpoint and study part.

Why do dose cohorts not form a controlled comparison?

A randomized comparison aims to balance measured and unmeasured participant characteristics between assigned groups, on average. This trial is listed as single-group, with allocation not applicable and no masking. Its dose cohorts arise within a dose-escalation study rather than from random assignment to competing treatments. As a general matter, cohort-level differences can reflect who entered each cohort, when the cohort was enrolled, the number assessed, and other factors as well as dose.

The registry safety results give counts at risk and affected for each listed dose, but do not report a formal comparison across doses. It would therefore be inappropriate to interpret differences among those raw counts as adjusted evidence of a dose effect. The same caution applies to comparing the serious event terms across cohorts; the record does not provide an analysis accounting for cohort size or participant characteristics.

What is the role of secondary outcomes?

The registry lists objective response rate for patients with EGFR T790M mutations, the maximum concentration of afatinib on Day 3 of Course 1, and determination of the dosage for the Part B expansion cohort among the secondary outcomes. The brief summary also mentions exploration of tumor response, tumor-derived biological markers, and pharmacokinetic parameters. These outcomes serve different purposes: response describes tumor activity, pharmacokinetic measures describe drug exposure, and biomarker exploration can examine biological patterns. None is interchangeable with the primary dose-limiting toxicity endpoint.

The registry record does not report results for these secondary outcomes. In general, interpreting a collection of outcomes involves considering which were prespecified, how many were assessed, and whether analyses account for multiple comparisons. The record does not report a multiplicity procedure or a detailed analysis plan. It is therefore not possible to determine from the registry record which secondary findings, if any, were considered confirmatory.

What can planning illustrations establish?

Sample-size calculations are planning tools. In general, they describe the sample size associated with chosen assumptions about the effect to detect, significance level, allocation, and statistical method. A calculation based on an observed effect is a retrospective planning illustration, not evidence that the completed trial had a particular probability of finding a result. It is not observed power.

The registry record does not report its own sample-size justification. Any planning illustration tied to the observed effect must also be read cautiously when the primary effect estimate is not reported in the registry record. No sample-size result can replace the missing primary endpoint estimate, denominator, or uncertainty interval.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Afatinib 90mg", "Afatinib 120mg", "Afatinib 150mg", "Afatinib 160mg", "Afatinib 200mg")
n      <- c(6, 3, 7, 9, 5)
events <- c(1, 0, 0, 0, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Afatinib 90mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Afatinib 120mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Afatinib 150mg  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Afatinib 160mg  9  0  0.0  0.0  33.6  -0.0  29.9  0.3  30.8
ARM  Afatinib 200mg  5  2  40.0  5.3  85.3  11.8  76.9  11.8  77.7

11. Multiplicity, Missing Data and Analysis Populations

The trial lists multiple outcomes across dose finding, response, pharmacokinetics, and biological marker exploration. When several outcomes or comparisons are examined, the chance of finding at least one apparently notable result can increase. General approaches to multiplicity include identifying a primary outcome in advance, setting a hierarchy for secondary outcomes, or adjusting inference across a defined family of tests. The registry record identifies a primary endpoint and secondary outcomes, but does not report a multiplicity strategy or a complete statistical analysis plan.

The record lists no analysis records. This should be read as a limit of the posted registry information, not as proof that no analysis took place. It does mean that the registry record does not give inferential results, including estimates and uncertainty measures, for the listed outcomes.

Missing-data methods and outcome completeness are also not reported in the registry record. The primary endpoint specifies a treated population eligible for maximum tolerated dose determination, but the record does not give the number evaluated for that endpoint or explain how participants without an evaluable assessment were handled. The total enrollment of 35 cannot be assumed to be the denominator for every outcome. The record likewise does not report how many participants contributed to the Part B response assessment or to the pharmacokinetic outcomes.

In general, missing outcome data can affect both the denominator and the interpretation of an estimated event percentage or response rate. If the likelihood of an unobserved outcome differs between participants, a summary among those assessed may not represent all enrolled participants. The registry record does not provide enough information to determine whether missingness occurred, how it was addressed, or whether sensitivity analyses were conducted.

12. 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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: influenza (33.3%), dehydration (22.2%), small intestinal obstruction (18.2%), urosepsis (16.7%), hypoxia (16.7%).

The registry lists 14 of 35 participants in the all-participants group as affected by a serious adverse event and 35 of 35 as affected by an other adverse event. The dose-specific serious-event counts are 1 of 6 at 90mg, 1 of 3 at 120mg, 7 of 9 at 150mg, 4 of 11 at 160mg, and 1 of 6 at 200mg. The corresponding other-event counts are 6 of 6, 3 of 3, 9 of 9, 11 of 11, and 6 of 6. These are descriptive counts as recorded.

The listed serious adverse event terms include Influenza at 33.3%, Dehydration at 22.2%, Small intestinal obstruction at 18.2%, Urosepsis at 16.7%, Hypoxia at 16.7%, and Rash at 16.7%. The registry record does not explain in this summary whether participants could contribute to more than one term, so these percentages should not be summed or treated as mutually exclusive categories.

These safety summaries do not identify which events met the separate primary definition of a dose-limiting toxicity. They also do not establish comparative safety across dose levels, since the cohorts were not randomized control groups. Death counts are not reported in the registry record.

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

The record establishes that the study was designed to explore intermittent high-dose afatinib through dose escalation and then assess response in a mutation-defined non-small cell lung cancer group. Its primary endpoint was a dose-limiting toxicity percentage used in maximum tolerated dose determination. The record supplies an operational definition for that dose-selection rule and identifies a 28-day timeframe.

What the registry record does not establish is the observed primary endpoint percentage, the dose selected by the study, or the Part B response rate. It gives no confidence intervals or inferential analyses for these outcomes. Thus, the record cannot show how precisely toxicity or response was estimated, nor whether the response objective was met. Absence of those results in the registry record is not evidence that the outcomes were zero or that no analyses were performed.

The recorded safety counts describe participants affected by serious and other adverse events. They do not by themselves identify causation, establish a dose-related pattern, or tell whether a serious event met the primary endpoint definition. The fact that all 35 participants are listed as having an other adverse event is a descriptive registry entry; it does not by itself characterize severity, duration, or clinical importance.

The single-group dose-escalation structure is useful for a different question from a randomized treatment comparison. It can inform a dose-selection process using observed toxicity, but it does not estimate a treatment effect relative to a control group. The cohort counts should not be interpreted as causal comparisons or as proof of activity.

Accordingly, the strongest conclusions supported by the posted record concern the design, endpoint definition, enrollment, and the stated safety counts. Conclusions about the efficacy of afatinib, the maximum tolerated dose actually established, or the precision of the primary result require outcome information that is not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates a central distinction in early clinical research: dose finding and treatment-effect estimation are different statistical tasks. Part A was designed to establish a maximum tolerated dose using a dose-limiting toxicity rule. Part B was intended to assess response in patients with EGFR T790M mutations. The first task concerns dose selection under a safety criterion; the second concerns tumor response in a defined group. A single endpoint cannot answer both questions.

The study also shows why endpoint definitions and denominators are essential. The registry names the primary outcome, specifies the population and timeframe, and gives the rule used for dose selection. But without the event count and number assessed, the primary percentage cannot be interpreted or its uncertainty evaluated. Overall enrollment does not automatically supply the denominator for each endpoint.

Safety counts by dose can look like a dose comparison, but the design matters. These cohorts are not randomized controls, and participant numbers differ. The raw counts are informative descriptions of what the registry records, yet they do not isolate an effect of dose from differences in who was treated or how the study proceeded.

Finally, a record can contain detailed design information while leaving its principal outcome unreported. That distinction is important when assessing evidence: a clearly described endpoint is not itself an endpoint result. Statistical interpretation requires both a transparent definition and the observed data, along with enough information to assess precision, missingness, and analysis choices.

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 most consequential limitation of the registry record for interpreting this trial is that the primary endpoint result is not reported. The number of participants with dose-limiting toxicities, the primary endpoint denominator, and the dose selected as the maximum tolerated dose are not given. This prevents assessment of how the stated selection criterion was applied.

The record also does not report the objective response rate for patients with EGFR T790M mutations, despite identifying it as a secondary outcome and describing it as an aim of Part B. The number assessed for response and the uncertainty around any response estimate are not reported in the registry record. Pharmacokinetic and biomarker results are likewise absent from the posted information.

The overall enrollment figure does not describe the participant flow through both parts, the number treated at each dose for each endpoint, or the number included in each analysis. The safety summary has cohort-level denominators, but these cannot be assumed to apply to the primary endpoint or the Part B response analysis. The record does not report missing-data handling, reasons for withdrawal, or whether all enrolled participants received treatment.

Because this is a single-group dose-escalation study with no randomized comparator, it cannot provide a controlled estimate of treatment effect relative to another regimen. Differences among dose cohorts should be treated descriptively. Further limitations include the absence of a reported statistical analysis plan, sample-size justification, multiplicity approach, confidence intervals, and detailed analysis results. The absence of these details in the registry record limits independent evaluation; it does not establish that the study team did not address them elsewhere.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Intermittent, High-dose Afatinib to Determine the Maximal Tolerated Dose and Assess Activity of This Dose Against Non-small Cell Lung Cancer With T790M Mutations — NCT01647711.
• Registry record last updated 2017-01-31; status last verified 2016-12.
• Results first posted 2017-01-31.
• 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

NCT01647711 is a completed, single-group study of intermittent high-dose afatinib, with enrollment recorded as 35. Part A aimed to establish the maximum tolerated dose in patients with advanced solid tumors; Part B aimed to assess response in non-small cell lung cancer with EGFR T790M mutations. The primary endpoint was the percentage with investigator-assessed dose-limiting toxicities over 28 days, using a stated dose-selection rule based on less than 2 events among up to 6 patients.

The registry lists serious and other adverse event counts across five dose cohorts. It does not report the primary endpoint result, the selected maximum tolerated dose, or the response rate. No analysis records are listed, and the record does not provide confidence intervals, missing-data methods, or a detailed statistical analysis plan. The posted information therefore supports description of the study design and selected safety counts, but not a quantitative conclusion about the primary endpoint or response objective.