A Study of Alectinib (CH5424802/RO5424802) in Participants With Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Alectinib (CH5424802/RO5424802) in Participants With Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC) (NCT01871805), a non-randomized phase 1, phase 2 study. The primary outcome is Number of Participants With Dose Limiting Toxicities (DLTs): Phase I.

2. Clinical Question

The study also included secondary outcomes concerning objective response, duration of response, disease control, disease progression, and progression-free survival. Some were assessed by investigators and others by an independent review committee, using RECIST v1.1. These outcomes address tumor response and disease course, while the primary Phase I endpoint concerns early toxicity. Their result values are not reported in the registry record.

3. Trial Design

This was a Phase I/II, multicenter study of alectinib in participants with ALK-rearranged non-small cell lung cancer previously treated with crizotinib. The registry records enrollment of 134 and lists the study as completed. The recorded study start was 2013-09-30, and the primary completion date was 2014-10-24. These dates describe the registry record; they do not supply additional follow-up information about individual participants.

The trial was non-randomized and open-label. Participants and investigators were not masked, and the registry describes a parallel model. In Phase I, cohorts received escalating oral doses of alectinib twice daily. Treatment was described as continuing until disease progression, death, or withdrawal for another reason. Phase II participants received the recommended Phase II dose determined from Phase I, with the same stated treatment-ending conditions. The adverse-event group labels include Phase I dose cohorts and a Phase II group labelled Alectinib 600 mg (Fed); the arm description itself identifies the Phase II dose as the recommended dose.

The Phase I primary endpoint was the number of participants with dose-limiting toxicities throughout Cycle 1, defined as 21 days. Secondary outcomes covered objective response in Phase I and Phase II, duration of response in Phase I, disease control in Phase II, and progression or progression-free survival in Phase II. Some Phase II progression and progression-free survival outcomes were assessed by an independent review committee, while others were assessed by investigators.

Because allocation was not randomized and the registry does not describe a control arm, dose cohorts should not be read as randomized treatment comparisons. Dose levels and study phases have different roles within the development program. The registry record does not report details of the allocation process beyond its non-randomized designation, nor does it report a sample-size justification or a statistical analysis plan.

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.

Phase I

Reasons for not completing this period:

Phase II

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Phase I safety population

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: Safety population included all participants who received any dose of alectinib.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose Limiting Toxicities (DLTs): Phase I, measured over Throughout Cycle 1 of Phase I (21 days).

The primary endpoint counts participants in the Phase I safety population who experienced a dose-limiting toxicity during Cycle 1, a period defined as 21 days. The registry lists specific toxicity criteria: severe hematologic toxicities, non-hematological toxicity of Grade 3 or higher subject to stated exceptions, and adverse events that led to treatment suspension for at least 7 days when the investigator could not rule out a relationship to alectinib. The definition also specifies conditions for interpreting liver enzyme elevations in participants with Grade 2 AST and/or ALT at baseline.

This endpoint is used in dose escalation to identify toxicities considered important when evaluating dose levels. In general, early dose-limiting toxicity information helps characterize tolerability during the defined observation period; it does not, by itself, describe every adverse event, later toxicity, or the balance of benefits and harms. The registry record does not report the number of participants who met the DLT definition, nor does it report a confidence interval or other estimate for this endpoint.

The endpoint is a participant count, not a measurement of the severity of every event or the total number of events. A participant meeting more than one criterion would still contribute to a count of participants with a DLT, rather than necessarily contributing multiple participants. Whether the analysis applied any additional rules for such cases is not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The record describes a Phase I/II study rather than a randomized efficacy comparison. Phase I used escalating alectinib doses, and Phase II used the recommended dose determined from Phase I. In general, dose escalation studies use information gathered at earlier dose levels to inform later dose decisions. The record does not state the escalation algorithm or other decision rules, so those details cannot be inferred from the design label alone.

What does the primary endpoint count?

The primary endpoint is a participant count: the number of people in the Phase I safety population who met the registry’s DLT definition during Cycle 1. The stated period is 21 days. The criteria include specified blood-count toxicities, non-hematological toxicity at Grade 3 or higher with listed exclusions, and treatment suspension of at least 7 days for adverse events that the investigator could not rule out as related to alectinib. The definition includes a separate qualification for participants with Grade 2 AST and/or ALT at baseline. This operational definition matters because changing event criteria or the observation period could change which participants count as having a DLT.

In general, a count of participants with an event differs from a count of all event occurrences: the participant is the unit counted for this endpoint. The registry does not report how many participants met the definition. It also does not describe the statistical method used to summarize or compare DLT counts, or state whether any interval estimates were calculated. Those analysis details are not reported in the registry record.

How should the non-randomized cohorts be understood?

Random assignment is a method for making treatment groups comparable, on average, with respect to measured and unmeasured participant characteristics. This study was explicitly non-randomized. Its Phase I cohorts represent dose escalation, and Phase II represents treatment at the recommended dose. Thus, an observed difference between dose groups would not automatically be an effect of dose. Participant characteristics, time in the study, phase-specific procedures, and other differences could contribute. The registry does not report an adjusted comparison intended to address these issues.

The study was open-label, meaning masking was absent. In general, lack of masking can affect decisions about care, reporting of subjective symptoms, and assessment of outcomes when assessors know the treatment. The registry identifies some secondary outcomes as investigator-assessed and others as assessed by an independent review committee. It does not provide enough information to evaluate how assessment procedures were implemented or whether assessors were masked to other information.

What do the response and time-to-event outcomes represent?

The listed secondary outcomes include objective response according to RECIST v1.1, duration of response, disease control, disease progression, and progression-free survival. RECIST v1.1 supplies the stated framework for classifying tumor response and progression. Investigator and independent-review-committee assessments are separate assessment sources, not interchangeable measurements. In general, an independent review can provide an assessment distinct from the treating investigator’s judgment, but it does not remove limitations arising from study design or incomplete outcome reporting.

Duration of response concerns the period of response, whereas progression-free survival concerns time until the defined progression event or death. The registry lists these outcomes but does not report their estimates, event counts, censoring details, or analysis methods. The definitions of time origin and censoring are not reported in the registry record. Without those details and the results, neither the size nor the precision of a time-to-event effect can be interpreted.

How do the planning illustrations relate to the trial?

The stated sample-size assumptions describe planning illustrations computed from an observed effect, not the study’s original design. They use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. In general, a planning calculation estimates the amount of information or enrollment that would be needed under its assumptions. It is not a measure of the probability that a result is true and is not observed power. The record does not report the trial’s own sample-size justification, and the non-randomized dose cohorts are not equivalent to an equal-allocation randomized comparison.

For general interpretation, a confidence interval describes uncertainty around an estimate under the method used to calculate it. A wider interval indicates less precision than a narrower interval, all else equal. A p-value measures how compatible data are with a null hypothesis under specified assumptions; it does not measure clinical importance. The registry record does not provide primary-endpoint estimates, confidence intervals, or p-values, so these concepts cannot be applied to a numerical DLT result from the record.

The registry lists 28 outcome measures and 4 analyses. That listing does not, by itself, establish which analyses were prespecified, which were primary in the analysis plan, or whether adjustment was made for multiple testing. Those details are not reported in the registry record.

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("Alectinib 300 mg (Fasted): Phase I", "Alectinib 460 mg (Fed): Phase I", "Alectinib 600 mg (Fed): Phase I (20/40/150 mg)", "Alectinib 760 mg (Fed): Phase I", "Alectinib 900 mg (Fed): Phase I (20/40/150 mg)")
n      <- c(7, 7, 13, 7, 13)
events <- c(0, 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  Alectinib 300 mg (Fasted): Phase I  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Alectinib 460 mg (Fed): Phase I  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Alectinib 600 mg (Fed): Phase I (20/40/150 mg)  13  0  0.0  0.0  24.7  0.0  22.8  0.2  23.2
ARM  Alectinib 760 mg (Fed): Phase I  7  0  0.0  0.0  41.0  0.0  35.4  0.3  36.9
ARM  Alectinib 900 mg (Fed): Phase I (20/40/150 mg)  13  2  15.4  1.9  45.4  4.3  42.2  4.7  42.8

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 28 outcome measures and 4 analyses, including outcomes addressing response, disease control, progression, and progression-free survival. When many outcomes or analyses are considered, the chance of obtaining apparently notable results by chance can increase. In general, a prespecified hierarchy or multiplicity adjustment can help define how such results should be interpreted. The registry record does not report whether outcomes were organized into a testing hierarchy, whether multiplicity adjustments were applied, or which analyses were prespecified.

Missing-data procedures are not reported in the registry record. The record does not explain how participants with unavailable response assessments, incomplete follow-up, or missing endpoint information were handled. For time-to-event outcomes, censoring rules and the treatment of incomplete follow-up are also not reported. These details matter because different handling choices can affect estimates and their precision.

The primary endpoint identifies the Phase I safety population, but the registry does not give the number analyzed for that endpoint or describe exclusions from the safety population. The analysis populations for the secondary outcomes are not specified in the registry record listed for the outcomes. Enrollment is recorded as 134, but that enrollment figure should not be treated as the number included in each endpoint analysis.

The record gives no sample-size justification, interim-analysis plan, or detailed statistical analysis plan. These items are not reported in the registry record. Their absence limits evaluation of whether the reported analyses, if available elsewhere in the record, followed prespecified methods.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pericardial effusion (15.4%), pneumonia (15.4%), nausea (14.3%), vomiting (14.3%), renal failure (14.3%).

The serious adverse-event figures are presented by labelled dose and phase groups. The registry reports participants at risk and participants affected by serious events, other events, and deaths for each group. These are descriptive counts, not randomized comparisons. The group sizes differ, and the study was non-randomized, so the figures do not establish that a particular dose caused a higher or lower event rate.

The listed serious-event terms include Pericardial effusion and Pneumonia at 15.4% each, and Nausea, Vomiting, Renal failure, and Gastroenteritis at 14.3% each. The denominator and calculation details for these percentages are not reported in the registry record. They should therefore be read as registry-listed percentages, not as directly comparable risks across groups.

The death counts are reported by group, but the record does not provide timing, cause, relationship to treatment, or follow-up duration for these deaths. The counts should not be interpreted as treatment-attributable deaths. The record also does not report exposure-adjusted event rates. In general, such rates can account for differences in time at risk; without exposure-time information, comparisons based on raw counts have important limitations.

Serious events are not the same as all adverse events, and a count of participants affected is not necessarily a count of event episodes. These figures describe safety reporting in the registry, not a complete account of each participant’s clinical course.

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

The registry record identifies a study of alectinib in participants with ALK-rearranged non-small cell lung cancer previously treated with crizotinib. Its Phase I primary question concerns the number of participants with DLTs during a defined 21-day cycle. The record gives detailed DLT criteria, but it does not report the observed primary-endpoint count. It therefore does not support a numerical conclusion about how often participants met that endpoint.

The record also lists secondary tumor-response and disease-course outcomes, as well as descriptive adverse-event counts. It does not report the secondary outcome estimates. The safety counts can describe what was recorded in the labelled groups, but they do not provide a randomized comparison or establish causation. The serious-event percentages have no reported denominator details in the record, and death counts lack timing and attribution information.

This study’s non-randomized, open-label design is important to what the evidence can establish. Without a randomized control group, differences between dose cohorts cannot be interpreted as controlled treatment effects. Likewise, the listed outcome names do not supply evidence of benefit or lack of benefit; results and their precision would be needed to characterize the outcomes.

In general, statistical interpretation depends on both the estimate and its uncertainty, along with the design and analysis methods. The registry does not report the DLT estimate, confidence intervals, hypothesis tests, missing-data procedures, or a multiplicity strategy. Those omissions mean that the posted record supports a description of the study structure and selected safety counts, but not a complete assessment of the magnitude or precision of its primary or efficacy outcomes. No medical conclusion about an individual’s treatment follows from these registry entries.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of how a dose-escalation safety question differs from a randomized treatment-effect question. Its primary endpoint is a participant count under a defined set of toxicity criteria during Cycle 1. That endpoint is suited to characterizing early dose-limiting toxicity, while the response and progression outcomes address other dimensions of the study. Keeping these questions distinct helps prevent a safety endpoint from being mistaken for an efficacy estimate.

The Phase I and Phase II components also have different roles. Phase I used escalating dose cohorts; Phase II used the recommended dose determined from Phase I. Because the study was non-randomized, comparisons among the cohorts do not carry the protection against confounding that random assignment is designed to provide. A dose-group difference could reflect differences in participants, phase, or other features, rather than dose alone.

The registry illustrates why outcome definitions and results must be considered together. A detailed DLT definition makes the endpoint interpretable, but without the observed count and uncertainty, its magnitude cannot be assessed. Similarly, listing RECIST v1.1 outcomes and assessment sources clarifies the intended measurements but does not reveal the response or progression results.

Finally, the record’s selected safety counts need context about exposure, timing, and attribution to support stronger comparisons. Those details are not reported. The study therefore offers a clear framework for asking early safety and later disease-outcome questions, while the registry information available for interpretation remains incomplete for quantifying those outcomes.

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 direct limitation is that the registry record does not report the observed result for the primary DLT endpoint. It also does not report the listed response, duration-of-response, disease-control, progression, or progression-free survival estimates. As a result, the outcome definitions and study structure can be described, but the magnitude and precision of those outcomes cannot be assessed from this record.

The study was non-randomized and open-label, with no randomized control group described. Dose cohorts should not be treated as exchangeable groups, and differences among them cannot be assigned to dose alone. The record does not report an adjusted analysis that would address potential differences between cohorts.

Further important analysis details are not reported in the registry record: the statistical analysis plan, sample-size justification, interim-analysis plan, missing-data handling, multiplicity procedures, and analysis population details beyond the Phase I safety population label for the primary endpoint. For time-to-event outcomes, the time origin and censoring rules are also not reported.

The safety information is limited to group-level counts, selected serious-event terms, percentages with unreported denominator details, and death counts without reported timing or attribution. Exposure duration and exposure-adjusted event rates are not reported. These omissions constrain comparisons across groups and interpretation of the listed deaths and adverse events.

The registry records enrollment of 134, but does not provide endpoint-specific analysis counts in the registry record listed. Enrollment should not be assumed to equal the number analyzed for any particular outcome.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of Alectinib (CH5424802/RO5424802) in Participants With Anaplastic Lymphoma Kinase (ALK)-Rearranged Non-Small Cell Lung Cancer (NSCLC) — NCT01871805.
• Registry record last updated 2018-08-21; status last verified 2018-07.
• Results first posted 2016-02-12.
• 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

The registry record describes a completed, multicenter, non-randomized, open-label Phase I/II study of alectinib in participants with ALK-rearranged non-small cell lung cancer previously treated with crizotinib. Enrollment is recorded as 134. Phase I involved escalating oral doses twice daily, and Phase II used the recommended dose determined from Phase I. The recorded study start was 2013-09-30, with primary completion on 2014-10-24.

The primary endpoint was the number of Phase I safety-population participants with DLTs throughout Cycle 1, defined as 21 days. The registry gives the DLT criteria but does not report the endpoint result. Secondary outcomes include response, disease control, progression, and progression-free survival. The record lists descriptive adverse-event counts by group, but it does not provide the efficacy estimates or enough safety context for causal comparisons. Key statistical details, including missing-data handling and multiplicity procedures, are not reported in the registry record.