Reirradiation With Pembrolizumab in Locoregional Inoperable Recurrence or Second Primary Squamous Cell CA of the Head and Neck: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Reirradiation With Pembrolizumab in Locoregional Inoperable Recurrence or Second Primary Squamous Cell CA of the Head and Neck (NCT02289209), a na phase 2 study. The primary outcome is Progression Free Survival.

2. Clinical Question

The clinical question is whether this combined regimen can be described in terms of progression-free survival and safety in the enrolled population. Because the design has one group, any observed outcome would describe participants treated in this trial; it would not by itself establish how outcomes compare with another treatment. The open-label design means masking was not used, but the record does not describe how that feature affected assessment or reporting.

The registry also lists secondary outcomes including best overall response rate, clinical benefit rate, time to in-field disease progression, overall survival, and quality of life measured with EORTC QLQ-C30 at several specified assessments. Results for these outcomes are not reported in the registry record. The entry therefore establishes the questions the study set out to assess, but does not provide a complete account of the corresponding observed outcomes.

3. Trial Design

This is a phase II, single-group trial of reirradiation combined with open-label pembrolizumab in patients with locoregional inoperable recurrence or a second primary squamous cell carcinoma of the head and neck. The registry record lists enrollment of 48 and study status as completed. Allocation is listed as NA, and masking as none. There is no randomized comparator group in the described design.

The regimen is described as reirradiation at 1.2 Gy BID for 5 days a week for 5 weeks, together with MK-3475, the generic name pembrolizumab. Pembrolizumab is described as 200mg intravenously every 3 weeks until 3 months post completion of reirradiation. The record identifies reirradiation as a radiation intervention and MK-3475 as a drug intervention.

The registry lists a start date of 2016-03-09 and a primary completion date of 2023-08-31. These dates describe the registered study timeline; they do not supply information about the timing or conduct of individual analyses. The record does not report the protocol’s sample-size justification, an interim-analysis plan, or a detailed statistical analysis plan.

With no separate control arm, the study can describe outcomes among participants receiving the combination, but cannot isolate the contribution of either component or establish comparative effects against another approach. This is a design limitation, not a finding about the regimen. The record lists 15 outcome measures, including the primary progression-free survival outcome and secondary response, progression, survival, and quality-of-life outcomes. It does not report results for those outcomes in the information available for this analysis.

The primary endpoint population is described as all treated patients who were radiologically evaluable and experienced disease progression. That wording does not explain how participants without documented progression, participants who were not radiologically evaluable, or deaths before documented progression were handled in the endpoint analysis. The analysis population and handling of such cases 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

Analysis population for the primary outcome, as defined in the registry: All treated patients who were radiologically evaluable and experienced disease progression.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Progression Free Survival, measured over Up to 36 months (after starting reirradiation and MK-3475).

Progression-free survival measures the time from initiation of treatment to the first of disease progression or death. The registry defines progression according to RECIST 1.1: at least a 20% increase in the sum of target-lesion diameters, using the smallest sum on study as reference, together with an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression. The stated assessment timeframe is up to 36 months after starting reirradiation and MK-3475.

A time-to-event endpoint retains information about how long participants remain without a recorded event, rather than reducing follow-up to a simple count of events. In general, this can be useful when follow-up duration varies or when the timing of progression or death matters to the clinical question. A median is the time by which half of the analyzed population has had an event, under the method used to estimate the time-to-event distribution. A confidence interval communicates uncertainty around that estimate.

The record identifies the endpoint as a median with a 95% confidence interval, but the median and interval are not reported in the registry record. Its stated analysis population is all treated patients who were radiologically evaluable and experienced disease progression. That description appears narrower than a full treated population, and the record does not explain the analysis set or how participants without documented progression were treated. Those details matter for interpreting a time-to-event estimate and cannot be inferred from the endpoint definition alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes the primary endpoint as progression-free survival, summarized by a median and 95% confidence interval. The following statistical explanations are general; they do not imply that a particular analysis method was used in this trial unless the registry record states it.

What a time-to-event endpoint represents

In general, a time-to-event endpoint records the duration from a defined starting point to a specified event. Here, the starting point is treatment initiation, and the event is disease progression or death, whichever occurs first. Combining progression and death into one endpoint makes either outcome count as an event. The registry’s definition of progression refers to RECIST 1.1 and includes a stated increase in target-lesion measurements or the appearance of new lesions.

Time-to-event analyses can account for participants whose event has not been observed by the end of their available follow-up. In general, their information is not equivalent to saying that they will never experience the event; it indicates that the event time is not known within the observed period. The method used to handle incomplete follow-up, and the number of participants with such follow-up, are not reported in the registry record.

How to understand a median and confidence interval

In general, the median event time is a point on the estimated time-to-event distribution: half the population is estimated to have experienced the event by that time, subject to the analysis method and follow-up. A median is not an average, and it does not describe every participant’s individual outcome. The registry specifies a 95% confidence interval for the median. In general, a confidence interval describes uncertainty in an estimate under the assumptions of the statistical method. A narrower interval indicates greater precision than a wider interval, but the interval cannot be interpreted without its endpoints and the method used to calculate it.

Although the registry states that the endpoint is to be reported as a median with a 95% confidence interval, neither the estimate nor the interval is reported in the registry record. The method for estimating the time-to-event distribution and confidence interval is also not reported. Thus, the intended summary can be explained, but its observed value and precision cannot be assessed from the registry information.

Event definition and measurement

The registry identifies progression using RECIST 1.1 criteria. For target lesions, it specifies at least a 20% increase in the sum of diameters, measured against the smallest sum on study, and an absolute increase of at least 5 mm. It also counts the appearance of one or more new lesions as progression. The endpoint includes death even if progression has not been recorded first. The registry does not provide details about assessment schedules, independent review, or handling of disagreements in radiological assessment; these details are not reported in the registry record.

Single-group design and comparative inference

General statistical principle: a single-group study estimates outcomes among people who received the study regimen, but it lacks a concurrent control group to separate the regimen’s association with outcomes from other influences. The design is listed as single group, with allocation NA and no masking. Consequently, it does not support a randomized comparison. The record does not report an external comparator or a comparative estimate.

The registry’s general sample-size assumptions describe planning illustrations based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set as a stated fraction of the observed effect. For time-to-event illustrations, the stated quantity is total events using the Schoenfeld method; other illustrations use participants per arm. These are planning assumptions, not the trial’s own design justification and not observed power. No resulting planning counts or sample-size justification are reported in the registry record. In addition, no observed effect estimate for the primary endpoint is reported there, so the underlying observed effect cannot be examined from this record.

Multiplicity and analysis reporting

Multiplicity arises in general when several outcomes, comparisons, or repeated tests are examined, because the chance of at least one apparently notable result can increase as testing expands. The registry lists one primary endpoint and multiple secondary outcomes, including response, clinical benefit, time to in-field progression, overall survival, and quality-of-life assessments. It does not report a multiplicity adjustment or a prespecified hierarchy for interpreting these outcomes. No analyses are listed in the registry record. A detailed statistical plan, including any planned subgroup or interim analyses, is not reported in the registry record.

Why analysis-population details matter

The registry identifies the primary endpoint population as treated patients who were radiologically evaluable and experienced disease progression. General principle: a time-to-event analysis needs a clearly defined population that includes people with and without an observed event, along with rules for follow-up and censoring. The registry wording does not explain how participants without progression were handled, how deaths were counted in relation to radiological evaluability, or whether all enrolled or treated participants were included. Those analysis details are not reported in the registry record, limiting assessment of the endpoint definition’s implementation.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists progression-free survival as the primary outcome and several secondary outcomes: best overall response rate, clinical benefit rate, time to in-field disease progression, overall survival, and quality of life using EORTC QLQ-C30 at baseline, Cycle 3, Cycle 9, and 12 Months. It also lists 15 outcome measures in total. The registry record does not report a multiplicity strategy, such as adjustment for multiple statistical tests or a hierarchy for interpreting secondary outcomes. Without those details, the status of any potential secondary finding cannot be evaluated as confirmatory or exploratory.

Missing-data methods are not reported in the registry record. The record does not describe how missing quality-of-life assessments, incomplete radiological evaluations, or loss to follow-up were handled. For progression-free survival, it does not specify the censoring rules or provide the number of participants with incomplete event follow-up. These details are relevant to understanding how observed follow-up contributes to an estimate.

The stated primary endpoint population is all treated patients who were radiologically evaluable and experienced disease progression. The registry does not clarify how that population definition relates to participants without an observed event or to all treated participants. It does not identify an intention-to-treat, per-protocol, or other analysis population. Therefore, the endpoint’s analysis set and the treatment of participants who do not meet the stated description are not reported in the registry record.

The registry lists no analyses. It also does not report a detailed statistical analysis plan, interim-analysis plan, or prespecified subgroup analyses. Absence of these details from the registry record does not establish what may have been done outside the record; it means the posted information does not permit those procedures to be assessed.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: aspiration (16.7%), pneumonitis (10.4%), death nos (6.2%), cardiac arrest (4.2%), gastrointestinal disorders - other, specify (4.2%).

For the Reirradiation + MK-3475 group, the registry lists 48 participants at risk for serious adverse events and 27 affected. It lists 48 at risk for other adverse events and 46 affected. The record also lists 37 deaths. These are separate reported safety figures; the death count does not indicate, by itself, whether deaths were attributed to treatment or how they relate to the adverse-event categories.

The registry reports serious adverse-event terms with percentages: Aspiration, 16.7%; Pneumonitis, 10.4%; Death NOS, 6.2%; Cardiac arrest, 4.2%; Gastrointestinal disorders - Other, specify, 4.2%; and Vomiting, 4.2%. These percentages describe the reported terms, but the detailed event counts, denominator for each term, and whether participants could contribute more than one event are not reported in the registry record.

Adverse-event summaries describe events observed in a study group; they do not alone establish causation. The registry information does not identify which events were considered related to treatment or describe their timing, duration, severity grading rules, or outcomes. The figures should therefore be read as reported safety observations, not as proof that the regimen caused a listed event or that an event was unrelated.

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

The registry record establishes that a phase II, single-group trial evaluated reirradiation combined with pembrolizumab in patients with inoperable locoregional recurrence or a second primary squamous cell carcinoma of the head and neck. It gives the treatment schedule, names progression-free survival as the primary endpoint, defines progression, and lists selected safety counts and serious adverse-event terms. These details describe the study’s intended question and the information recorded about its conduct.

The record does not report the median progression-free survival or its 95% confidence interval. It therefore does not allow readers to assess the observed primary endpoint value or how precisely it was estimated. Results for the listed secondary outcomes are also not reported in the registry record. The listed safety figures provide counts and term percentages, but do not establish treatment causation or provide the fuller clinical context needed to interpret individual events.

The single-group design has no concurrent randomized comparator. As a general statistical principle, outcomes observed in one group cannot by themselves show what the same population’s outcomes would have been under another treatment. Nor can this design separate the contribution of reirradiation from the contribution of pembrolizumab. No comparative efficacy conclusion is supported by the design and information in the registry record.

These limitations do not mean that the study had no useful purpose. A single-group phase II study can describe outcomes and generate information for further research. But the registry information is insufficient to determine the magnitude or precision of the primary endpoint result, assess secondary endpoint findings, or make a comparative treatment judgment. The appropriate interpretation is limited to the registered design, endpoint definitions, and posted safety information, while recognizing that unreported results and methods cannot be reconstructed.

13. Why This Trial Matters Statistically

This trial raises several important statistical issues for clinical research. First, progression-free survival is a time-to-event outcome, so interpreting it requires more than knowing whether progression or death occurred. The timing of events, completeness of follow-up, and treatment of participants without an observed event all contribute to the analysis. The registry defines the endpoint and its progression criteria, but does not report the estimate, its confidence interval, or the detailed analysis methods.

Second, the single-group design sets a clear boundary on interpretation. It can describe outcomes among participants who received reirradiation with pembrolizumab, but it does not provide a randomized control group for estimating a comparative effect. This distinction matters when moving from a description of observed outcomes to claims about how the regimen compares with another approach.

Third, the registry lists multiple secondary outcomes, including response, clinical benefit, progression, survival, and quality of life. Considering multiple outcomes makes a prespecified statistical plan important. The registry does not report a multiplicity approach or analysis hierarchy, so the intended role of secondary findings cannot be determined from the record.

Finally, the safety information illustrates the difference between reporting an event and attributing it to treatment. Counts and percentages are useful descriptions, but require context about event definitions, denominators, severity, timing, and causality assessment. Those details are not reported in the registry record. Together, these issues show why clear endpoint reporting, transparent analysis populations, and complete results are central to a sound statistical interpretation.

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 limitation for interpreting the trial’s efficacy is that the registry record does not report the primary progression-free survival estimate or its 95% confidence interval. Without those values, the observed outcome and its precision cannot be described. The record also does not report results for the listed secondary outcomes, including response, clinical benefit, in-field progression, overall survival, and quality of life.

The trial is listed as a single-group study, with no masking and allocation NA. It therefore has no randomized comparator in the registry description. This prevents a like-for-like comparison and limits interpretation to outcomes observed in the treatment group. The design also cannot separate the effects of reirradiation and pembrolizumab.

The stated primary endpoint population is limited in wording to treated patients who were radiologically evaluable and experienced disease progression. The registry does not clarify how participants without documented progression were included, how censoring was handled, or whether the endpoint analysis used all treated participants. Missing-data methods, radiological assessment schedules, and analysis-population definitions are not reported in the registry record.

The record lists no analyses and does not provide a detailed statistical analysis plan, multiplicity approach, or interim-analysis plan. It also does not report the trial’s sample-size justification. The safety figures lack detail about event-level counts, event-specific denominators, treatment relationship, and the relationship between the listed deaths and adverse-event categories. These limitations apply to the information in the registry record; they do not establish what information may exist outside it.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Reirradiation With Pembrolizumab in Locoregional Inoperable Recurrence or Second Primary Squamous Cell CA of the Head and Neck — NCT02289209.
• Registry record last updated 2025-03-06; status last verified 2025-02.
• Results first posted 2025-03-06.
• 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

The registry record describes NCT02289209, a completed phase II, single-group, open-label trial of reirradiation with pembrolizumab for locoregional inoperable recurrence or a second primary squamous cell carcinoma of the head and neck. Enrollment is listed as 48. The regimen combines reirradiation with MK-3475, also called pembrolizumab.

The primary endpoint is progression-free survival, defined from treatment initiation to progression or death, whichever occurs first, with progression criteria based on RECIST 1.1. The record specifies a median and 95% confidence interval as the endpoint summary, but the estimate and interval are not reported in the registry record. Results for the listed secondary outcomes are also not reported.

Safety reporting lists 27 of 48 participants affected by serious adverse events, 46 of 48 affected by other adverse events, and 37 deaths. Serious adverse-event terms and percentages are listed, but causal attribution and detailed event-level information are not reported in the registry record. The single-group design offers no randomized comparison.