Efficacy and Safety of Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Efficacy and Safety of Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (NCT03206918), a na phase 2 study. The primary outcome is Overall Response Rate (ORR) by Independent Review Committee (IRC).

2. Clinical Question

The study focuses on response in relapsed or refractory CLL/SLL, rather than a randomized comparison of treatment strategies. The endpoint combines several categories of best response, including complete and partial response categories, with criteria specified separately for CLL and SLL. Independent review is part of how the primary outcome was assessed; the registry record does not provide further detail about the review process or adjudication.

3. Trial Design

NCT03206918 is a completed, multicenter, open-label, single-arm Phase 2 study sponsored by BeiGene. Its official title describes an evaluation of the safety and efficacy of BGB-3111, a BTK inhibitor, in relapsed or refractory CLL/SLL. The intervention listed in the record is zanubrutinib. Enrollment is recorded as 91.

The brief summary describes screening, a single-arm treatment phase, and follow-up. Participants had histologically documented CLL/SLL that had relapsed after or was refractory to at least one prior treatment regimen. The primary outcome timeframe is up to 1 year and 4 months. The registry record lists the study start as 2017-03-09, primary completion as 2018-06-15, and status as completed.

Because there is no concurrent control group, the design describes outcomes among participants receiving zanubrutinib but does not support a direct randomized contrast. Open-label conduct means treatment masking was absent; the record separately identifies an Independent Review Committee for the primary response assessment. These design features answer different questions: independent assessment concerns outcome evaluation, while masking concerns whether treatment assignment was concealed from participants or study personnel.

The registry lists secondary outcomes including progression-free survival, duration of response, time to response, investigator-determined overall response, and adverse events. The primary endpoint is overall response rate as determined by the Independent Review Committee. Detailed protocol procedures, the rationale for the enrollment target, and the full statistical analysis plan are 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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified Safety Analysis Set: All participants in the safety analysis set who had confirmed Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

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 Analysis Set: All participants who received any dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate (ORR) by Independent Review Committee (IRC), measured over Up to 1 year and 4 months.

The primary endpoint is the count of participants whose best response met the registry definition of overall response rate, assessed by an Independent Review Committee. For CLL, the definition includes complete response, complete response with incomplete marrow recovery, nodular partial response, partial response, and partial response with lymphocytosis, under the modified IWCLL guidelines. For SLL, it uses the Revised Criteria for Response for Malignant Lymphoma. The endpoint therefore applies disease-specific response criteria rather than treating CLL and SLL as though they had identical assessment rules.

Response endpoints are used to describe whether participants reached a prespecified category of tumor response during the assessment period. A count is a direct description of the number meeting the definition; a rate would additionally express that count relative to an analysis population. The registry record labels the primary outcome as a count of participants, but does not report the observed count or rate. It also does not give the component response counts or explain how missing or unevaluable assessments were handled.

In general, an overall response endpoint can summarize response status, but it does not by itself describe how long a response lasts or whether progression-free survival differs from that under another treatment. Those are separate questions reflected in the listed secondary outcomes. The registry record specifies a timeframe of up to 1 year and 4 months for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a count: the number of participants who achieved a qualifying best response. A count is interpretable only alongside a clear definition of who was eligible for assessment and what counted as an event. The registry identifies the primary endpoint population as the Modified Safety Analysis Set, described as participants in the safety analysis set with confirmed CLL/SLL. It does not report the number included in that analysis set or the number with evaluable response assessments.

In general, a response rate expresses the event count in relation to an analysis denominator. The rate is useful for describing the frequency of response in a population, while the count preserves the raw number of participants meeting the endpoint. Neither can be reconstructed because the observed response count and denominator are not reported. No unadjusted recalculation can be made from the registry entries, and no estimate should be inferred from enrollment alone.

A confidence interval describes the range of values reasonably compatible with an estimate under a stated statistical model and sampling assumptions. It helps readers judge precision; it does not resolve design limitations such as the absence of a comparator. The record does not report a confidence interval for the primary outcome. Without an estimate, interval, or analysis denominator, the uncertainty around the response endpoint cannot be quantified from this record.

The Independent Review Committee assessment is part of the endpoint definition. In general, independent outcome assessment can help separate outcome classification from investigator expectations, but the label alone does not reveal the review procedures, blinding arrangements, adjudication rules, or handling of disagreement. Those details are not reported in the registry record. The study itself is listed as open-label and unmasked; this does not establish whether the committee was masked to treatment or other information.

The registry identifies modified IWCLL guidelines for CLL and Revised Criteria for Response for Malignant Lymphoma for SLL. Different disease-specific criteria can be important because the clinical manifestations and response assessments may differ. For this study, the record states which criteria define response but does not provide the assessment schedule, the measurements used at visits, the rules for confirming response, or the handling of participants whose disease classification changed or could not be confirmed.

For a binary endpoint, statistical methods may estimate the response probability and its uncertainty. The exact estimator, confidence-interval method, and any hypothesis test are not reported in the registry record. It would therefore be inappropriate to attribute a particular test or interval procedure to the trial. More generally, the choice of method can affect interval width, especially when event counts are limited or estimates are near the boundaries of the possible range; this general point does not establish that either circumstance applied.

The record includes a separate planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. For non-time-to-event outcomes, that illustration is expressed as participants per arm; time-to-event illustrations use a total number of events. The record says the detectable effect is a stated fraction of the observed effect. These are planning assumptions, not observed trial outcomes, and they are not the design of this single-arm study. The observed effect and the resulting illustrative sample-size values are not reported in the registry entries, so the illustration cannot be evaluated numerically. It should not be interpreted as observed power or as evidence that the study was adequately powered.

In general, planning calculations depend on assumptions about the target effect, variability or event rate, allocation, significance level, and statistical model. A change in any of these assumptions can change a planning estimate. The registry record does not report the trial's own sample-size justification, target response rate, power target, or whether a formal hypothesis test was planned. The planning illustration therefore cannot fill those gaps.

The single-arm structure is especially important to the methods interpretation. A one-group estimate can describe the observed response experience under the study conditions, but it cannot directly estimate a treatment contrast against usual care, placebo, or another active therapy. Any external comparison would require a separately justified source of control data and assumptions about comparability; the registry record does not describe such an analysis. No adjusted comparison or causal estimate is reported.

For time-to-event outcomes such as progression-free survival and duration of response, general methods account for both event occurrence and follow-up time, including censoring when an event has not been observed by the end of observation. The registry lists those outcomes, but it does not give their results, censoring rules, analysis methods, or follow-up summaries. No survival estimate or event-time comparison can be inferred from the outcome names alone.

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("Zanubrutinib")
n      <- c(91)
events <- c(80)
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  Zanubrutinib  91  80  87.9  79.4  93.8  79.6  93.1  79.6  93.1

11. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and several secondary outcomes, including multiple response and time-to-event measures, as well as adverse events. Considering many outcomes can raise a multiplicity issue: when several statistical tests are conducted, the chance of at least one apparently notable result can increase. In general, a prespecified testing hierarchy or adjustment method may address that concern. The registry record does not report whether formal hypothesis tests were planned, how endpoints were ordered for testing, or whether any multiplicity adjustment was used. No conclusion about control of multiplicity is possible from the outcome list alone.

The primary analysis population is described as the Modified Safety Analysis Set, but the record does not report the number analyzed or the rules for inclusion beyond the stated description. It also does not report how missing response assessments, withdrawals, unevaluable participants, or incomplete follow-up were handled. These details matter because exclusions and missing outcomes can affect both the denominator and interpretation of a response estimate. No imputation method or sensitivity analysis is reported.

For the time-to-event outcomes, the record does not state censoring rules or how participants lost to follow-up were treated. It does not report interim analyses, stopping rules, or the complete statistical analysis plan. These items are not assumed to have been absent from trial operations; they are not reported in the registry record. Consequently, the endpoint list and population definition do not by themselves establish how the final analyses were conducted.

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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (24.2%), lung infection (7.7%), upper respiratory tract infection (4.4%), bronchitis (3.3%), hepatitis b (3.3%).

The safety record lists a zanubrutinib group with 91 participants at risk for the serious adverse-event summary and 47 participants recorded as affected. It also lists 11 deaths. These are registry entries, not evidence by themselves that an event was caused by zanubrutinib. The record details do not describe causality assessments, event timing, duration, severity grading, or whether deaths were considered treatment-related.

The listed serious adverse-event terms and percentages are pneumonia, 24.2%; lung infection, 7.7%; upper respiratory tract infection, 4.4%; bronchitis, 3.3%; hepatitis B, 3.3%; and gastroenteritis, 2.2%. These are term-specific figures as recorded. The denominator for those percentages is not reported in the registry record, so they should not be reverse-engineered into counts or treated as a complete accounting of all serious events. The list is described as top serious terms and does not establish that other serious events did not occur.

In general, safety counts and percentages require context about the population, observation period, event definitions, and attribution. The registry record gives an adverse-event timeframe only indirectly through the primary outcome timeframe and does not establish that all participants had identical observation. The listed figures therefore describe the record, not a comparative safety profile.

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

This study addresses a response question in participants with relapsed or refractory CLL/SLL who received zanubrutinib in a multicenter, open-label Phase 2 study. The primary response definition is explicit and uses an Independent Review Committee assessment, with separate criteria for CLL and SLL. The record also identifies secondary outcomes spanning disease control, response timing, investigator-assessed response, and adverse events.

What cannot be concluded from the registry entries is the observed response result. There is no primary count, rate, confidence interval, or p-value reported. The endpoint definition does not show how many participants responded, how uncertain an estimate would be, or whether results differed across disease subgroups. The adverse-event entries likewise do not establish comparative risk or causation.

The absence of a randomized comparator limits what the design can say about treatment effects relative to another option. An outcome observed in a single treatment group may be informative as a description of participants in that study, but it does not isolate the effect of treatment from all other influences. This does not negate the descriptive purpose of the study; it sets a boundary on comparative interpretation.

In general, a statistically precise estimate and a clinically important effect are not the same concept. Precision concerns uncertainty in an estimate, whereas clinical importance requires interpretation in the context of the condition, response definition, patient priorities, and available alternatives. The registry record does not provide the response estimate or the contextual evidence needed to make those judgments. No medical recommendation follows from the design details or adverse-event listing alone.

The record's planning assumptions are also distinct from findings. A planning illustration based on an observed effect does not report the effect itself, establish that the trial achieved a target precision, or provide observed power. Because the numeric illustration and primary outcome result are absent from the registry entries, the central statistical result remains unquantified.

14. Why This Trial Matters Statistically

The study is statistically notable for pairing a clearly specified, disease-specific response definition with a single-arm design. The endpoint definition allows readers to understand what would count as a response and who belongs to the stated primary analysis population. That clarity is useful even when the outcome value itself is not reported in the registry record.

The distinction between a count, a rate, and a comparative effect is central. The primary outcome is described as a count of participants, while a rate would require a denominator and a treatment effect would require a comparator or other defensible comparative framework. The registry entries do not report the response count or denominator for the endpoint and do not include a control group. These gaps sharply limit quantitative interpretation without changing what the study set out to measure.

The record also illustrates why endpoint definitions and statistical results must be read separately. A named response criterion establishes the classification rule, but not the observed result, uncertainty, or robustness to missing data. Similarly, listing secondary outcomes identifies topics of interest but does not indicate their findings or whether their analyses were adjusted for multiplicity.

The safety information offers counts and term percentages, but lacks key context such as the denominator for each term and attribution details. This reinforces the general statistical principle that event frequencies are most interpretable when accompanied by clear population, follow-up, and event-definition information.

Finally, the stated planning assumptions are not interchangeable with the design actually used. The illustration describes two-arm planning under equal allocation and a normal approximation, whereas the trial is a single-group study. Distinguishing a planning scenario from an observed trial analysis prevents a design calculation from being mistaken for evidence about efficacy or achieved statistical power.

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 primary limitation for interpreting the registry entries is that the primary outcome value is not reported. The record defines overall response but gives no observed count, rate, denominator, confidence interval, or test result. Consequently, the magnitude and precision of the primary finding cannot be assessed. The listed enrollment of 91 does not substitute for the analyzed population or establish how many participants had evaluable response assessments.

The study has no concurrent comparator and is open-label. It can describe outcomes during the study, but it cannot provide a randomized treatment contrast. Independent Review Committee assessment is specified for the primary endpoint, yet the record does not report the committee's masking status, detailed assessment procedures, or handling of disagreement. The relationship between independent and investigator response assessments is also not reported.

The registry record does not give the statistical analysis plan, sample-size justification, interim-analysis procedures, missing-data methods, censoring rules, or multiplicity strategy. These omissions prevent assessment of whether reported analyses, if available elsewhere, followed prespecified procedures. The endpoint population is defined in words, but its analyzed size is not reported.

The safety entries list affected participants, deaths, and serious-event terms, but do not provide the denominator for each term percentage, event timing, treatment attribution, or a full accounting of adverse events. Since this is a single-arm record, the listed safety figures cannot be interpreted as a comparative estimate of risk. These are limits of the information reported in the registry record, not claims about what was or was not collected during the study.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Efficacy and Safety of Zanubrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma — NCT03206918.
• Registry record last updated 2024-10-26; status last verified 2024-10.
• Results first posted 2020-09-25.
• 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

NCT03206918 is a completed, multicenter, open-label, single-arm Phase 2 study of zanubrutinib in relapsed or refractory CLL/SLL. The registry records enrollment of 91 and identifies overall response rate by Independent Review Committee as the primary outcome, with a timeframe of up to 1 year and 4 months. CLL and SLL response definitions are based on different named criteria. Secondary outcomes include progression-free survival, duration of response, time to response, investigator-determined overall response, and adverse events.

The registry entries do not report the primary response result or its uncertainty. Safety entries include 47 participants affected by serious adverse events, 11 deaths, and listed serious-event term percentages; the term-specific denominator and event attribution are not reported. The single-arm design supports description of study outcomes but does not provide a randomized comparison.