A Study of Alectinib (RO5424802) in Participants With Non-Small Cell Lung Cancer Who Have Anaplastic Lymphoma Kinase (ALK) Mutation and Failed Crizotinib Treatment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Alectinib (RO5424802) in Participants With Non-Small Cell Lung Cancer Who Have Anaplastic Lymphoma Kinase (ALK) Mutation and Failed Crizotinib Treatment (NCT01801111), a na phase 1, phase 2 study. The primary outcome is Recommended Phase 2 Dose (RP2D) of Alectinib.

2. Clinical Question

The clinical question therefore has two related parts: what dose was intended for continued study, and what outcomes were assessed among participants receiving alectinib after crizotinib treatment. The registry record identifies safety and efficacy as study aims and lists secondary outcomes involving objective response, duration of response, progression-free survival, progression or death, and death from any cause. It does not provide numerical results for those secondary outcomes in the record.

Because participants were not randomized between alectinib and a control treatment, the study design does not establish a comparative treatment effect. Outcome descriptions can identify what was planned for assessment, but without reported estimates they do not show the magnitude or precision of any outcome. The primary dose endpoint also cannot be interpreted as a dose-selection result from this trial: the record says it was not analyzed.

3. Trial Design

This was an open-label, non-randomized, multicenter Phase I/II trial. The registry record lists a single-group model, no masking, and an enrollment of 138. It gives the study status as completed, with a start date of 2013-06-20 and a primary completion date of 2014-10-24. The allocation is listed as NA, and the record cautions that the study is not a randomized comparison.

The brief study description divides treatment into parts. In Part 1, cohorts were to receive escalating oral doses of alectinib. Part 2 was to use the recommended Phase 2 dose determined in Part 1. Treatment in those parts was described as continuing at the same dose until disease progression. In Part 3, after progression, participants without an EGFR mutation were to be offered continued alectinib; participants with EGFR mutations were to be offered alectinib with erlotinib. The arm description in the registry record is truncated, so further details of treatment implementation are not reported in the registry record.

The study’s open-label format means that masking was not used. Its non-randomized, single-group structure means that participants were not assigned to a concurrent control arm for a treatment comparison. Consequently, outcomes observed among participants cannot by themselves separate treatment effects from other explanations, including the course of disease or differences in participant characteristics. This is a general limitation of single-group studies, not a finding about any particular outcome in this trial.

The registry lists 36 outcome measures and 3 analyses. It does not report the full analysis methods or explain how those analyses relate to the listed outcome measures. The stated primary outcome was recommended Phase 2 dose during Cycle 1, up to 28 days; the registry says this endpoint was not analyzed in this study because the dose was confirmed in study NP28761 (NCT01871805). Enrollment, design, and outcome descriptions therefore need to be distinguished from analyzable results: the number enrolled and the planned measurements do not supply the missing endpoint estimates.

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: Part 1 of study was planned to determine recommended Phase 2 dose (RP2D) of alectinib to be used in Part 2. During the conduct of Part 1 for this study, RP2D was confirmed in Study NP28761 (NCT01871805). Hence Part 1 participants were merged into Part 2. Part 3 was post-progression treatment period.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The endpoint was not analyzed in this study as the RP2D was confirmed in study NP28761 (NCT01871805).

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: Analysis was performed on safety population, which included all participants who received at least one dose of alectinib.

6. Primary Endpoint

The registry lists the primary outcome as Recommended Phase 2 Dose (RP2D) of Alectinib, measured over Cycle 1 (up to 28 days).

The primary endpoint was the recommended Phase 2 dose of alectinib. The registry describes the relevant timeframe as Cycle 1, up to 28 days, and says that dose determination was to be based on the safety and tolerability profile of the study treatment. Dose-finding endpoints serve a different purpose from endpoints such as tumor response or survival: they are intended to identify a dose for later study that can be carried forward in light of observed safety and tolerability.

In this record, however, the endpoint was not analyzed. The registry states that the recommended Phase 2 dose was confirmed in study NP28761 (NCT01871805). It therefore does not report a dose estimate, a dose-selection rule, or trial-specific safety and tolerability results used to determine the dose. The endpoint’s purpose can be described, but its result cannot be reconstructed from the information recorded for this study.

This distinction matters when reading the trial’s Phase I/II designation. The planned primary endpoint does not automatically become an observed result simply because the study was designed to assess it. Nor can the reported enrollment or adverse-event counts substitute for an analysis of dose selection. The registry record identifies the intended measurement and explains why it was not analyzed; it does not provide the analysis that would be needed to evaluate a dose chosen from this trial.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary endpoint represent?

The primary endpoint was the recommended Phase 2 dose of alectinib, with dose determination based on the safety and tolerability profile during Cycle 1, up to 28 days. In general, a dose-finding endpoint is used to guide the dose carried forward into later research. It is conceptually different from an endpoint that measures tumor response or time until progression: a dose-selection question concerns the treatment regimen to study, while response and time-to-event questions concern participant outcomes.

Here, the distinction between intended endpoint and analyzed endpoint is decisive. The registry says the recommended Phase 2 dose was confirmed in study NP28761 (NCT01871805), and that this endpoint was not analyzed in this study. No dose estimate or supporting dose-selection analysis is reported in the registry record. General descriptions of dose-finding methods cannot fill that gap; they explain the purpose of such endpoints, not what this trial found.

How does the study design affect interpretation?

The trial was open-label, non-randomized, multicenter, and single-group. In general, randomization aims to make treatment groups comparable in expectation, while masking can reduce some forms of knowledge-related influence on assessment or care. Neither a randomized control group nor masking is recorded for this study. The design therefore supports a descriptive account of outcomes among treated participants, but it does not provide a randomized estimate of the difference between alectinib and a control treatment.

This is not a claim that a single-group study has no statistical value. Such a design can document observed outcomes and safety events in its enrolled population. The important point is the scope of inference: without a concurrent randomized comparator, observed outcomes cannot isolate the causal contribution of treatment from other factors. This general limitation applies regardless of whether an outcome is favorable, unfavorable, common, or rare.

What do uncertainty measures ordinarily convey?

In general, a confidence interval describes the uncertainty around an estimated quantity under the assumptions of the analysis. A narrower interval indicates greater precision for that estimate, while a wider interval indicates less precision. An interval does not correct bias from study design, guarantee that the model is appropriate, or establish that a result is clinically important. A point estimate without an uncertainty measure can leave readers unable to judge how compatible the data are with a range of values.

The registry record does not report a confidence interval or numerical primary endpoint estimate for this trial because the primary endpoint was not analyzed. It also does not report numerical estimates for the secondary outcome descriptions in the record. Thus, general explanations of confidence intervals should not be mistaken for a claim that such intervals were calculated or reported for this study.

What do the listed secondary outcomes measure?

Objective response is a category-based outcome. The record describes response as complete response or partial response and names assessments by an independent review committee or by the investigator for specified populations. In general, response assessments depend on the criteria and assessment process used. The registry names RECIST v1.1 for the progression-or-death outcome, but the numerical response results and detailed analysis methods are not reported in the registry record.

Duration of response concerns how long a response persists, whereas progression-free survival concerns time until a defined progression event or death, according to the outcome definition. Time-to-event analyses generally account for the fact that some participants may not have had the event by the end of observation. They may be censored, meaning their event time is not fully observed; the exact censoring rules and analysis procedures for this trial are not reported in the registry record. This general explanation does not imply that a particular estimator or model was used.

What are the planning illustrations?

The record describes planning illustrations computed from an observed effect, rather than as the trial’s own design calculation. Their stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is set at a stated fraction of the observed effect. For time-to-event planning, the quantity is the total number of events; for other outcomes, it is participants per arm.

These calculations are hypothetical planning aids, not observed power. They do not change the design of this study, which is recorded as single-group and non-randomized, and do not establish that the trial enrolled enough participants to detect a particular effect. The registry record does not report the original sample-size justification. It also does not report enough detail to assess the source, uncertainty, or suitability of the observed effect used in the planning illustrations.

Why does over-dispersion matter in general?

For count outcomes, a statistical model may assume a particular relationship between the average count and its variability. Over-dispersion occurs when observed variability exceeds what a model assumes. If ignored, uncertainty estimates can be too small, making results appear more precise than they are. This is a general statistical concern; the registry record does not identify an over-dispersion assessment or a count model for this study. It should not be inferred that such an analysis was performed.

More broadly, statistical interpretation depends on knowing the endpoint definitions, analysis population, handling of missing observations, model, and uncertainty estimates. The registry record reports some outcome titles and design details, but the analysis plan and several implementation details are not reported in the registry record. Consequently, methods can be explained in general terms, while trial-specific claims must remain limited to the documented information.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 36 outcome measures and 3 analyses, including several response outcomes assessed by different reviewers or in different participant groups, as well as duration of response, progression-free survival, progression or death, and death from any cause. When multiple outcomes or analyses are examined, the chance of obtaining at least one apparently notable result can increase. General approaches to multiplicity include defining a primary outcome in advance, adjusting significance thresholds, or treating secondary findings as exploratory. The registry record does not report a multiplicity strategy, a hierarchy of secondary outcomes, or whether any adjustments were made.

The stated primary endpoint was the recommended Phase 2 dose, but it was not analyzed in this study because the dose was confirmed in study NP28761 (NCT01871805). The registry record does not say whether another outcome was designated as a primary analysis after that endpoint was not analyzed. It also does not report the statistical analysis plan needed to determine how outcomes and analyses were prioritized.

Missing-data methods are not reported in the registry record. For an outcome with incomplete observation, the approach to missing values can affect both the estimate and its uncertainty. For time-to-event outcomes, the treatment of participants whose event time is not fully observed is especially relevant; the record does not provide the censoring rules or details of follow-up for these analyses. Analysis populations for the listed outcomes are also not fully described in the record.

These omissions do not establish that the investigators failed to plan for multiplicity or missing data. They mean only that the registry record does not report how those issues were handled. Without those details and numerical results, it is not possible to assess the robustness of outcome estimates or the degree to which selective reporting could influence interpretation.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: hyperbilirubinaemia (2.2%), dyspnoea (2.2%), pulmonary embolism (2.2%), constipation (1.4%), pneumonia (1.4%).

The registry reports safety counts for the alectinib group, with 138 participants at risk for both serious and other adverse events. It records 39 participants affected by serious adverse events, 133 affected by other adverse events, and 75 deaths. These are descriptive counts. They do not, by themselves, indicate whether an event was caused by treatment or how the observed counts compare with another treatment or background risk.

The registry lists selected serious adverse-event terms and percentages: Hyperbilirubinaemia, 2.2%; Dyspnoea, 2.2%; Pulmonary embolism, 2.2%; Constipation, 1.4%; Pneumonia, 1.4%; and Alanine aminotransferase increased, 1.4%. These are listed as serious-event terms, not as a complete account of every event. The record does not report whether an individual participant could contribute to more than one term or provide a detailed account of event timing and duration.

In general, serious adverse events and other adverse events are different reporting categories; the counts should not be combined or treated as interchangeable. The registry record does not report the attribution of these events to study treatment in the information. The death count is a safety descriptor and should not be interpreted as a treatment effect without a defined comparison and relevant outcome analysis.

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

The record establishes that a completed, open-label, non-randomized, multicenter Phase I/II study enrolled 138 participants with non-small-cell lung carcinoma in a study of alectinib after crizotinib treatment. It describes dose escalation in Part 1, use of a recommended Phase 2 dose in Part 2, and treatment offers after progression that depended on EGFR mutation status. It also identifies the outcomes the study was intended to assess.

The record does not establish a primary dose-selection result from this study. The recommended Phase 2 dose endpoint was not analyzed because the dose was confirmed in study NP28761 (NCT01871805). The registry record does not report numerical results for the secondary outcome descriptions in the information, so response, duration of response, progression-free survival, and other listed outcomes cannot be characterized in terms of their estimated magnitude or precision from this record.

The adverse-event counts describe what was recorded among participants in the alectinib group: 39 participants with serious adverse events, 133 with other adverse events, and 75 deaths, with selected serious-event terms also listed. These figures do not demonstrate that alectinib caused an event, nor do they show how event frequency would compare with a control treatment. A single-group design has no randomized treatment contrast to support that conclusion.

In general, a treatment effect is best interpreted using a clearly defined comparison, an appropriate analysis, and an estimate with uncertainty. The study’s design and the absence of reported outcome estimates in the registry record limit that kind of inference. The documented study aims and safety counts remain useful descriptive information, but they should not be extended into conclusions that the record does not support.

Planning illustrations based on an observed effect are also not evidence that an effect was observed with a particular precision in this trial. Their assumptions describe hypothetical two-arm planning, whereas the study is recorded as single-group. They are not observed power and cannot replace trial-specific endpoint results or an explanation of the original design rationale.

13. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a planned primary endpoint and the endpoint actually analyzed. The primary endpoint concerned selection of a recommended Phase 2 dose using safety and tolerability during Cycle 1, up to 28 days. The registry explicitly states that it was not analyzed in this study because the dose was confirmed in study NP28761 (NCT01871805). Recognizing that distinction prevents the study’s stated aim from being mistaken for a reported result.

The study also illustrates why design labels matter. Open-label, non-randomized, single-group studies can describe outcomes and adverse events among enrolled participants, but do not provide the balance created by random assignment to a control group. This constrains comparative inference even when enrollment and follow-up have been completed. The record’s warning that the study is not a randomized comparison is central to interpreting its scope.

Another statistical issue is the breadth of listed outcomes. The registry names 36 outcome measures and 3 analyses, including multiple response assessments and time-to-event outcomes. Interpreting a collection of outcomes requires knowing how they were prioritized, how multiplicity was addressed, and which analysis populations were used. Those details are not reported in the registry record, so the outcome list alone cannot establish the strength of evidence for any particular secondary result.

Finally, the safety counts and planning illustrations answer different questions. The adverse-event figures are descriptive records for the alectinib group, while planning illustrations use stated hypothetical assumptions about a two-arm study. Neither supplies the missing primary endpoint analysis or a comparative treatment effect. Keeping those categories separate is essential for sound statistical reading.

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 primary endpoint was not analyzed in this study. The registry says the recommended Phase 2 dose was confirmed in study NP28761 (NCT01871805), so no trial-specific dose estimate or dose-selection analysis is reported in the registry record. This limits interpretation of the Phase I dose-finding objective in this record.

The study was open-label, non-randomized, and single-group. It did not include a randomized control comparison, and the registry cautions that the arms are not a like-for-like control comparison. Consequently, the design does not support a randomized estimate of the difference between alectinib and another treatment. This limitation is specific to the recorded design, not a claim about the quality of outcome assessment.

The registry lists 36 outcome measures and 3 analyses, but does not report the numerical results for the secondary outcomes described in the record. The statistical analysis plan, multiplicity approach, missing-data handling, and analysis populations are not reported in the registry record. These omissions limit assessment of precision, robustness, and the interpretation of multiple outcomes.

The safety information is also limited in scope. Counts and selected serious-event terms are reported, but attribution to treatment, event timing, overlap between event categories, and detailed follow-up are not reported in the registry record. The arm description is truncated, so additional treatment details are not available in the record.

Planning illustrations are based on an observed effect and specified assumptions, not the trial’s own design justification. The original sample-size justification is not reported in the registry record. The illustrations therefore should not be used to infer observed power or to resolve the lack of reported endpoint estimates.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of Alectinib (RO5424802) in Participants With Non-Small Cell Lung Cancer Who Have Anaplastic Lymphoma Kinase (ALK) Mutation and Failed Crizotinib Treatment — NCT01801111.
• Registry record last updated 2018-11-02; status last verified 2018-10.
• Results first posted 2016-05-26.
• 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

NCT01801111 is a completed, open-label, non-randomized, multicenter Phase I/II study of alectinib in participants with non-small cell lung cancer and an ALK mutation who had failed crizotinib treatment. The registry records a single-group model and enrollment of 138. The study started on 2013-06-20 and reached primary completion on 2014-10-24.

The primary endpoint was the recommended Phase 2 dose of alectinib, based on safety and tolerability during Cycle 1, up to 28 days. The registry states that this endpoint was not analyzed because the dose was confirmed in study NP28761 (NCT01871805). The record lists 36 outcome measures and 3 analyses, but numerical results for the secondary outcomes are not reported in the information.

For the alectinib group, the registry reports 39 participants with serious adverse events, 133 with other adverse events, and 75 deaths among 138 participants at risk. The design does not provide a randomized treatment comparison.