Sequencing of Stereotactic Ablative Body Radiotherapy in Combination With PD-1 Blockade Using Pembrolizumab in Metastatic Non-Small Cell Lung Carcinoma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Sequencing of Stereotactic Ablative Body Radiotherapy in Combination With PD-1 Blockade Using Pembrolizumab in Metastatic Non-Small Cell Lung Carcinoma (NCT03307759), a randomized phase 1 study. The primary outcome is Adverse Events Measured Using CTCAE Version 4.03.

2. Clinical Question

The clinical question is therefore about the safety of treatment sequencing in metastatic non-small cell lung cancer. The comparison changes the order in which SABR and pembrolizumab are given. The registry summary also describes the study as examining efficacy and biological effects, but the posted primary endpoint is a count of participants with high-grade treatment-related events.

The registry record lists response outcomes assessed with RECIST 1.1, irRECIST, PERCIST1.0, and Peter Mac metabolic response criteria, as well as overall survival and progression-free survival. Those outcomes address different questions from the primary safety endpoint. The registry record does not report analysis results for those secondary outcomes, so the primary result cannot establish comparative efficacy or survival.

3. Trial Design

This was a phase Ib, randomized, open-label, parallel-group trial sponsored by Peter MacCallum Cancer Centre, Australia. The registry record identifies the condition as non-small cell lung cancer and describes the study as involving metastatic disease. Enrollment was 13. The record gives a study start date of 2017-12-07, a primary completion date of 2022-01-31, and a status of terminated.

The two groups differed in treatment order. In the SABR Plus Pembrolizumab group, SABR was followed by pembrolizumab. In the Pembrolizumab Plus SABR group, pembrolizumab was followed by SABR after cycle 1. The registry describes allocation as randomized and the model as parallel. Masking is listed as none, so the record does not describe blinding of participants or study personnel.

Posted primary endpoint counts are available for both groups. The SABR Plus Pembrolizumab group had 0 participants with the specified primary event among 5 participants; the Pembrolizumab Plus SABR group had 1 among 8. These are descriptive group counts. The registry record does not report a statistical analysis for the comparison, and it does not report confidence intervals or a hypothesis-test result.

The study status is important context: the record lists the trial as terminated. The reason for termination is not reported in the registry record, so it should not be inferred from the enrollment or outcome counts. The protocol’s planned enrollment, intended allocation ratio, and reasons for the sample size are also not reported in the registry record.

The registry lists six secondary outcome measures, including response under several criteria, overall survival, and progression-free survival. It records no analyses for those outcomes. The absence of posted analyses does not establish that no analyses were conducted; it means the registry record does not provide them. Further details about random sequence generation, allocation concealment, treatment adherence, and analysis populations 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

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 Adverse Events Measured Using CTCAE Version 4.03, measured over Up to 24 months after commencement of treatment.

The primary endpoint is the number of participants with grade 3 treatment-related adverse events, determined using CTCAE version 4.03. The registry describes grade 3 treatment-related events as high-grade toxicities and gives a timeframe of up to 24 months after commencement of treatment. The measure is a participant count: it records whether participants experienced the specified type of event over the stated follow-up period, rather than counting every event episode.

Safety outcomes are used to characterize harms observed during treatment and follow-up. A high-grade treatment-related event is a specific classification: it is not interchangeable with every adverse event, every serious adverse event, or a death. The primary endpoint’s treatment-related attribution and grade criteria distinguish it from the separate serious adverse event summaries in the registry.

The posted count is 0 participants with grade 3 treatment-related adverse events in the SABR Plus Pembrolizumab group, among 5 participants, and 1 in the Pembrolizumab Plus SABR group, among 8 participants. These counts do not by themselves show the full range, timing, duration, or clinical course of adverse events. Those details are not reported in the registry record.

A participant count is straightforward to interpret but provides limited information about uncertainty, particularly when the group counts are small. The registry record does not post an interval estimate or a statistical comparison for this endpoint. It also does not report the specific event terms contributing to the primary endpoint counts. Therefore, the result describes the posted count under the stated definition; it is not a complete accounting of safety or a comparative estimate with quantified precision.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry design information describes a randomized, open-label, parallel-group phase Ib study. The posted primary endpoint is a count of participants with grade 3 treatment-related adverse events, with group-specific counts and group sizes. The registry record does not report an inferential statistical analysis for this endpoint. The methods below explain what the design and outcome summaries mean in general, without attributing unreported procedures to the investigators.

What does randomization mean?

In general, randomization uses an assignment process intended to make treatment groups comparable at the time of allocation, apart from chance variation. It does not guarantee that groups will be identical, especially in a study with limited enrollment. The record labels allocation as randomized, but details of sequence generation and allocation concealment are not reported in the registry record. The allocation ratio is also not reported.

A parallel-group design means participants are assigned to a treatment group and the groups are compared over the study. Here, the groups correspond to the two sequences: SABR followed by pembrolizumab, or pembrolizumab followed by SABR after cycle 1. Open-label status means the registry lists masking as none. It does not, by itself, establish whether outcome assessors were masked; that detail is not reported in the registry record.

How should a participant count be read?

For a binary endpoint such as whether a participant experienced a specified event, the count gives the number meeting the event definition, while the group size gives the number assessed or enrolled for that group as recorded. In general, a count is a direct description of observed participants, but it does not convey uncertainty on its own. Statistical methods can use the count and denominator to estimate an event proportion and uncertainty around it. No such interval estimate is posted for the primary result, and no new estimate is calculated.

The primary measure is the number of participants with grade 3 treatment-related adverse events under CTCAE version 4.03, up to 24 months after commencement of treatment. An event count is not necessarily an event-episode count. If a participant experiences multiple events, a participant-level endpoint can still count that participant once. Whether multiple events were handled in that way is inherent in the registry’s stated participant measure; more detailed event-level methods are not reported.

What does a confidence interval add?

In general, a confidence interval expresses the uncertainty in an estimate under a statistical model and analysis procedure. It gives a range of values compatible with the data and method, rather than only a single point estimate. Its width depends on features including the amount of information in the data and the variability of the outcome. The registry record does not report a confidence interval for the primary endpoint. A reader should therefore avoid treating the observed counts as if they precisely identify the underlying event frequency.

A p-value, when used, addresses how compatible data are with a specified null model under stated assumptions. It does not measure the size or clinical importance of an effect. No p-value or hypothesis test for the primary endpoint is reported in the registry record. The analysis plan, including any prespecified test, model, or adjustment, is not reported either.

Why distinguish the outcome definitions?

Safety outcomes can be classified in several ways. Grade describes severity under a grading system; treatment-related attribution concerns whether an event is considered related to treatment; serious adverse event status follows a separate seriousness classification. These labels answer different questions. The registry’s primary endpoint combines grade and treatment-related attribution, while its separate safety summary reports serious adverse events and other adverse events. Without event-level cross-tabulation, one cannot determine which serious events also met the primary endpoint definition.

The secondary response outcomes also use different criteria: RECIST 1.1, irRECIST, PERCIST1.0, and Peter Mac metabolic response criteria. In general, differing criteria can classify response using different measurement and interpretation rules. Their results should not be assumed interchangeable. The registry record lists these outcomes but does not report their analyses, so no comparison among the criteria can be made from the posted results.

What can planning calculations tell us?

Planning illustrations based on observed effects are not the same as a trial’s original sample-size justification or an estimate of observed power. In general, such illustrations ask how many participants might be needed under specified assumptions to detect an effect of a chosen size using a stated significance level and allocation approach. The registry record states that its planning illustrations use a two-sided significance level of 0.05, equal allocation, a normal approximation, and fractions of the observed effect; it distinguishes participant-per-arm calculations from total event calculations for time-to-event outcomes. These are planning assumptions, not evidence that the trial was designed or analyzed using those assumptions.

The registry record does not report the trial’s own sample-size justification, planned enrollment, or statistical plan. It also does not report an observed-power analysis. Planning values should not be interpreted as proof that the completed study had sufficient information to answer its clinical question. In general, uncertainty is assessed through the estimates and intervals from the actual analysis, not by treating a retrospective planning illustration as observed power.

The record lists no analyses for the secondary outcomes. It does not describe the analysis populations, missing-data methods, handling of withdrawals, or whether any interim analyses were planned. Those methods can affect how results are interpreted, but their absence from the registry record means no particular approach should be assumed.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary safety outcome and six secondary outcome measures. The secondary measures cover response under several criteria, overall survival, and progression-free survival. Each outcome can address a different clinical or biological question. When many outcomes are examined, the chance of observing an apparently notable result by chance can increase if results are interpreted without regard to multiplicity. In general, study plans may address this through prespecified outcome hierarchies or statistical adjustments, but such methods are not reported in the registry record.

The record lists no analyses for the secondary outcomes. No multiplicity strategy, testing sequence, or adjustment is reported. Therefore, no claim about controlling the overall error rate or prioritizing secondary results can be made. The absence of posted analyses should not be taken to mean that the outcomes were not collected or analyzed; it means results are not reported in the registry record.

Missing-data handling is not reported in the registry record. The record does not explain how participants who withdrew, had incomplete follow-up, or lacked an outcome assessment were handled. It also does not report analysis populations, such as whether analyses included all randomized participants or only participants meeting specified criteria. No assumptions about missing outcomes or exclusions should be added to the posted counts.

For the primary endpoint, the registry gives group counts and group sizes, but it does not provide a participant flow or further detail about endpoint availability. The reported timeframe is up to 24 months after commencement of treatment. The record does not clarify whether follow-up was complete for every participant or how differences in follow-up were handled. These omissions limit interpretation of the observed safety counts and the unreported secondary outcomes.

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

Serious events with the highest arm-level rate: cortical thinning (20.0%), hip pain (20.0%), pericardial effusion (20.0%), reaccumulation of pericardial effusion (20.0%), diabetic ketoacidosis (12.5%).

The registry’s serious adverse event summary reports 2 affected participants among 5 at risk in the SABR Plus Pembrolizumab group and 3 among 8 at risk in the Pembrolizumab Plus SABR group. It reports 0 affected participants for other adverse events in each group. The registry also lists deaths: 1 in the SABR Plus Pembrolizumab group and 4 in the Pembrolizumab Plus SABR group.

These serious-event counts are separate from the primary endpoint of grade 3 treatment-related adverse events. Seriousness, severity grade, and attribution to treatment are different classifications. The record does not establish that the listed serious events were grade 3 or treatment-related, nor does it state that the listed deaths were caused by treatment. The cause and timing of deaths are not reported in the registry record.

The registry lists serious-event terms with percentages: Cortical thinning, Hip pain, Pericardial effusion, and Reaccumulation of pericardial effusion at 20.0% each; Diabetic ketoacidosis and Non ST elevation myocardial infarct at 12.5% each. These terms and percentages should be read as registry summaries, not as evidence of causal attribution. The record does not provide enough detail to establish how the terms overlap within participants or how they relate to the primary endpoint.

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

The result establishes what the registry record reports for the primary safety measure: 0 participants with grade 3 treatment-related adverse events in the SABR Plus Pembrolizumab group, among 5 participants, and 1 in the Pembrolizumab Plus SABR group, among 8. It also establishes that the registry lists serious adverse events and deaths separately. These are descriptive findings for the enrolled groups under the record’s definitions.

The result does not establish that either treatment sequence is safer. No comparative estimate, confidence interval, or statistical test is reported for the primary outcome. The observed counts alone do not quantify how uncertain a difference between sequences may be, and the limited enrollment means the record gives only a restricted view of safety outcomes.

The result also does not establish whether the sequences differ in tumor response, progression-free survival, or overall survival. Those outcomes appear among the listed secondary measures, but analyses are not reported in the registry record. The study summary describes efficacy and biological effects as interests of the study; that description is not itself evidence of an efficacy result.

The record does not explain why the trial was terminated. It would be unsupported to attribute termination to adverse events, lack of efficacy, recruitment difficulty, or any other cause. Nor does the record report enough about eligibility, follow-up completeness, missing data, or analysis populations to judge how these features may have affected results.

In general, a randomized comparison can be informative when its design, outcome definitions, analysis, and uncertainty are reported. Here, the posted information supports a narrow account of the primary event counts and selected safety summaries. It does not support a definitive comparative conclusion about the two schedules or a treatment recommendation. Further conclusions would require analyses and contextual details not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable because it compares treatment sequence rather than simply listing a treatment against no treatment. The randomized, parallel-group design assigns participants to SABR followed by pembrolizumab or pembrolizumab followed by SABR after cycle 1. That makes the order of the two interventions the central contrast described in the registry.

The primary endpoint is also distinct from the secondary response and survival outcomes. It is a participant count for grade 3 treatment-related adverse events under CTCAE version 4.03, over a stated follow-up period. Keeping this definition separate from serious adverse events, response criteria, and deaths is essential to avoid treating different clinical measures as if they meant the same thing.

The record illustrates the difference between a randomized design and a precise estimate. Randomization is a design feature, but the posted primary result consists of 0 of 5 participants in one group and 1 of 8 in the other, with no reported interval or formal comparison. The study’s design therefore does not, by itself, turn descriptive counts into a conclusive estimate of the difference between sequences.

The registry lists several response measures based on different criteria, along with survival outcomes, but provides no analyses for them. This highlights why outcome registration and outcome reporting are both important: readers need results and analysis details to assess what was learned, not just a list of planned or tracked measures. The record also does not report multiplicity methods, missing-data handling, or analysis populations.

Finally, the terminated status and enrollment of 13 give important context without explaining the reason for termination. The record supports transparent description of the posted results, while also showing how much interpretation depends on analysis details and uncertainty estimates. Its statistical value lies in documenting a randomized sequencing study and its reported safety counts, not in establishing a definitive comparative effect.

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 registry record reports enrollment of 13 and lists the trial as terminated. It does not report why the trial was terminated, the planned enrollment, or whether the completed enrollment met the intended design. These omissions prevent conclusions about the reasons for the size of the study or the consequences of termination.

The primary result is a small set of participant counts, without a confidence interval, p-value, or other inferential comparison. The record does not report an analysis plan, sample-size justification, or prespecified method for comparing the groups. The allocation ratio and details of randomization and allocation concealment are also not reported. These gaps limit assessment of the strength and precision of the primary comparison.

Further eligibility details and outcome-specific analysis populations are not reported. Neither are missing-data methods, participant flow, treatment adherence, or completeness of follow-up. Although the endpoint timeframe is stated as up to 24 months after commencement of treatment, the record does not explain how follow-up differences or incomplete outcome assessments were handled.

The registry lists serious adverse events, other adverse events, deaths, and serious-event terms separately, but does not provide detailed event-level information linking those categories to the primary endpoint. The cause and timing of deaths, event attribution, and overlap among listed terms are not reported in the registry record. The secondary response and survival outcomes are listed without posted analyses. Taken together, the available record supports description of the reported counts, but not a broad assessment of comparative safety or efficacy.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Sequencing of Stereotactic Ablative Body Radiotherapy in Combination With PD-1 Blockade Using Pembrolizumab in Metastatic Non-Small Cell Lung Carcinoma — NCT03307759.
• Registry record last updated 2025-09-15; status last verified 2025-08.
• Results first posted 2025-09-15.
• 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 NCT03307759 as a randomized, open-label, parallel-group phase Ib study of treatment sequencing for metastatic non-small cell lung cancer. One group received SABR followed by pembrolizumab; the other received pembrolizumab followed by SABR after cycle 1. Enrollment was 13, and the record lists the trial status as terminated.

The primary endpoint was the number of participants with grade 3 treatment-related adverse events under CTCAE version 4.03, up to 24 months after treatment commenced. The posted counts were 0 among 5 participants in the SABR Plus Pembrolizumab group and 1 among 8 in the Pembrolizumab Plus SABR group. Separate serious adverse event and death counts are also listed.

Six secondary outcomes are listed, including response, overall survival, and progression-free survival, but no analyses are reported for them. The registry record does not report a formal statistical comparison for the primary endpoint, a sample-size justification, missing-data methods, or the reason for termination. The posted results therefore support a descriptive account of safety counts, not a definitive comparison of the two schedules.