This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study to Test the Safety and How Radium-223 Dichloride an Alpha Particle-emitting Radioactive Agent Works in Combination With Pembrolizumab an Immune Checkpoint Inhibitor in Patients With Stage IV Non-small Cell Lung Cancer With Bone Metastases (NCT03996473), a randomized phase 1 study. The primary outcome is Number of Participants With Treatment-emergent Adverse Events in Phase 1.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT03996473 |
| Phase | Phase 1 |
| Condition | Carcinoma, Non-Small-Cell Lung |
| Allocation | Randomized |
| Design model | Sequential |
| Masking | None (open label) |
| Enrollment | 8 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Bayer |
| Results posted | Yes |
2. Clinical Question
Population
Participants with stage IV non-small cell lung cancer and bone metastases. The study description included people who had not received systemic therapy for advanced disease or whose disease had progressed after prior PD-1/PD-L1 checkpoint blockade. The safety analysis set included participants who received at least one administration of study treatment.
Intervention
Radium-223 dichloride combined with pembrolizumab. In Phase 1, the planned regimen specified radium-223 dichloride at 55 kBq/kg every 6 weeks and pembrolizumab every 3 weeks.
Comparator
The Phase 1 results list one treatment group, Radium-223 + Pembrolizumab. Pembrolizumab alone and combination-treatment groups were planned for Phase 2, but whether those cohorts began is not reported in the registry record.
Primary question
How many participants in Phase 1 experienced a treatment-emergent adverse event during the stated observation period? The primary endpoint counts participants with such events, whether or not the event was considered related to treatment.
The registry describes the broader purpose as evaluating safety and testing efficacy of the combination in participants with advanced disease and bone metastases. It also lists tumor-response outcomes, duration of response, disease control, progression-free survival, and overall survival. Those listed outcomes indicate what the study intended to assess, not what was observed: numerical results for them are not reported in the registry record.
The record identifies the study as randomized, open-label, and sequential, but the Phase 1 primary outcome data contain only one treatment group. The registry does not report enough information to determine how randomization was implemented or whether a comparison was made in the completed portion. With no posted comparative efficacy results, the principal question that can be answered from the results is descriptive: what adverse-event counts were recorded for the treated participants?
3. Trial Design
This was a Phase 1 study with a randomized allocation label, no masking, and a sequential model. The record lists an enrollment of 8 and status of terminated. The study began on 2020-03-06, and the primary completion date is 2021-04-14. These registry fields describe the study record; they do not establish how many participants entered each planned cohort or why the study was terminated. The reason for termination is not reported in the registry record.
The listed Phase 1 regimen combined radium-223 dichloride at 55 kBq/kg every 6 weeks with pembrolizumab every 3 weeks. Planned Phase 2 regimens included combination treatment at a maximum tolerated dose to be determined in Phase 1, as well as a pembrolizumab-alone comparator in one planned cohort. Whether the dose-finding decision was reached or any Phase 2 cohort enrolled participants is not reported in the registry record. The Phase field identifies the study as PHASE1.
The primary outcome was the number of participants with treatment-emergent adverse events in Phase 1, assessed in a safety analysis set consisting of participants who received at least one administration of study treatment. Its timeframe was up to 218 days. The adverse-event summary lists one group, Radium-223 + Pembrolizumab, with 7 participants at risk for serious events and 7 at risk for other events. This is a small treated group, and the registry does not give comparative results for the primary endpoint.
The study description refers to efficacy measures, including response under RECIST v1.1 and time-to-event outcomes. However, the record lists no analyses and provides no numerical efficacy results. It is therefore important to distinguish the planned scope of the study from the results that are actually available in the registry record. The record does not report the protocol-level statistical plan, randomization procedure, dose-escalation rules, or the reason for early termination.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Before assignment: Overall, 10 participants were screened. Of them, 2 participants were screen failures. 8 participants were assigned to study treatment, of which 7 received the study treatment and 1 participant never received the treatment in the Phase 1.
Treatment Assignment
| Stage | Radium-223 Dichloride + Pembrolizumab |
|---|---|
| STARTED | 8 |
| COMPLETED | 0 |
| NOT COMPLETED | 8 |
Reasons for not completing this period:
| Reason | Radium-223 Dichloride + Pembrolizumab |
|---|---|
| Withdrawal by Subject | 1 |
| Progressive disease | 6 |
| Study drug never administered | 1 |
Active Follow-up
| Stage | Radium-223 Dichloride + Pembrolizumab |
|---|---|
| STARTED | 1 |
| COMPLETED | 0 |
| NOT COMPLETED | 1 |
Reasons for not completing this period:
| Reason | Radium-223 Dichloride + Pembrolizumab |
|---|---|
| Death | 1 |
Long-term Follow-up
| Stage | Radium-223 Dichloride + Pembrolizumab |
|---|---|
| STARTED | 6 |
| COMPLETED | 1 |
| NOT COMPLETED | 5 |
Reasons for not completing this period:
| Reason | Radium-223 Dichloride + Pembrolizumab |
|---|---|
| Death | 5 |
Analysis population for the primary outcome, as defined in the registry: Safety analysis set (SAF): included all participants who received at least 1 administration of study treatment.
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 (SAF): includes all participants who received at least 1 administration of study treatment.
| Characteristic | Unit | Radium-223 Dichloride + Pembrolizumab |
|---|---|---|
| Participants analysed | 7 | |
| Age, Continuous | years | 63.6 (SD 10.7) |
| Sex: Female, Male: Female | Participants | 5 |
| Sex: Female, Male: Male | Participants | 2 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 |
| Race (NIH/OMB): Asian | Participants | 0 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 |
| Race (NIH/OMB): White | Participants | 7 |
| Race (NIH/OMB): More than one race | Participants | 0 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 0 |
6. Primary Endpoint
The registry lists the primary outcome as Number of Participants With Treatment-emergent Adverse Events in Phase 1, measured over Up to 218 days.
| Element | Registry entry |
|---|---|
| Result type | Count Of Participants |
| Measure of spread | not applicable |
| Unit | Participants |
| Endpoint classification | Binary Endpoint |
The primary endpoint counts participants with treatment-emergent adverse events in Phase 1. The registry defines a treatment-emergent adverse event as an untoward medical occurrence that arose or worsened after study treatment began and through the end-of-treatment visit, whether or not it was considered related to treatment. The end-of-treatment visit was defined as 30 [+7] days after the last dose. Severity was summarized overall and by the maximum grade experienced, according to NCI CTCAE v.5.0. The stated timeframe for this endpoint was up to 218 days.
A participant count is useful for describing how many treated participants experienced an event during the observation window. It is a safety-focused measure: events do not have to be judged treatment-related to qualify. That broad definition can capture the range of medical occurrences arising during treatment, while not establishing that the study drug caused them. A count also does not by itself describe event duration, recurrence, seriousness, or the clinical context of each occurrence.
The endpoint uses the safety analysis set, defined as participants who received at least one administration of study treatment. The record lists 7 participants at risk for the adverse-event summaries, compared with an overall enrollment of 8. The reason the enrolled and safety counts differ is not reported in the registry record. The posted primary endpoint is a count rather than a comparison between groups, and no inferential analysis of it is reported in the registry record.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The posted safety summary is descriptive. In the Radium-223 + Pembrolizumab group, 7 participants were listed as at risk for serious adverse events and 2 as having serious adverse events. For other adverse events, 7 were listed at risk and 7 as having events. The record also lists 6 deaths. These figures should be read as counts from a small treated group, not as estimates from a controlled comparison. The registry does not state that the reported deaths were caused by treatment.
The serious-event terms listed in the record are acute kidney injury, bone pain, rectal haemorrhage, and respiratory failure, each with a reported value of 14.3%. The registry does not provide additional detail in this summary about the timing, course, seriousness criteria, or treatment attribution for individual events. Nor does the listing establish whether participants experienced more than one listed term. The percentages should therefore be understood as the registry reports them, without treating the terms as mutually exclusive or combining them.
The difference between the total enrollment of 8 and the 7 participants included in the safety summaries matters for interpretation. The endpoint population was defined by receipt of at least one treatment administration. The reason one enrolled participant was not included in the reported at-risk counts is not reported in the registry record. With such a small safety set, each participant contributes substantially to the overall pattern; the summary is not a precise estimate of event frequency in a broader population.
No statistical analyses are reported in the registry record, and the primary outcome is framed as a participant count. There is no posted confidence interval, adjusted estimate, or test comparing treatment groups. The trial record also does not provide an efficacy estimate that could be weighed against the safety findings. The planned efficacy outcomes are not substitutes for observed results, and their numerical findings are not reported.
Because the study is terminated and the record identifies a Phase 1 study, the findings describe the limited results posted for the treated group. They do not show how the combination compares with pembrolizumab alone or another treatment, nor do they establish whether the observed events were more or less frequent than they would have been without the combination. A small, uncontrolled safety summary can describe what was recorded, but it cannot isolate treatment effects from the participants’ underlying illness or other factors. The reason for termination and any additional analysis outside the registry record are not reported in the registry record.
9. Statistical Methods Explained
The statistical information available is limited to the registry’s endpoint definition, population description, and posted counts. No statistical analysis is listed. The record does not report a statistical analysis plan, a sample-size justification, planned interim analyses, or details of any dose-escalation rules. These omissions mean that the inferential procedures and decision criteria used by the investigators cannot be reconstructed from the registry record.
What does a participant count measure?
A count reports how many people in a defined analysis population experienced an outcome. For this primary endpoint, the outcome is having at least one treatment-emergent adverse event during the stated observation period. Counting participants differs from counting every event occurrence: a participant with multiple events may still contribute once to a count of participants with any event. The registry’s endpoint title uses a participant count, but the posted summary does not give event-level histories or detailed participant-level data.
The safety analysis set includes those who received at least one administration of study treatment. Defining the population this way ties the safety summary to exposure to the study treatment, rather than to everyone enrolled. The record lists 8 enrolled and 7 at risk for the adverse-event summaries. It does not report why these numbers differ. This uncertainty should remain explicit rather than being resolved by assuming a particular reason for non-inclusion.
What does treatment-emergent mean?
The registry defines treatment-emergent events by their timing: they arise or worsen after treatment starts and are followed through the end-of-treatment visit, specified as 30 [+7] days after the last dose. This temporal definition does not mean an event was caused by treatment. The endpoint includes events whether or not they were considered related. In general, temporal association and causal attribution are different concepts: an event can occur during a treatment period without the record establishing that treatment produced it.
The registry says severity was summarized overall and by the maximum grade experienced, using NCI CTCAE v.5.0. The posted primary outcome summary does not provide a full distribution of grades. Consequently, the event counts should not be read as a severity profile. A count of participants with any event alone cannot show how intense or persistent an event was, or whether the same participant experienced several different events.
Why does a small group limit interpretation?
When a study includes few participants, the observed counts can describe what happened to those participants, but they provide limited information about how often similar events would occur in a wider population. In general, estimates based on small samples are uncertain, and one participant’s outcome can have a large influence on the observed pattern. No confidence intervals are reported for these adverse-event counts, so the registry does not quantify their statistical precision.
The record identifies one group in the primary outcome summary. A comparison of groups would require reported results for the groups being compared and an analysis suitable for the outcome and design. The record does not provide such a comparison. Although allocation is labelled randomized, that label alone does not supply a treatment contrast or explain how participants were assigned in the reported Phase 1 group. There is no basis in the posted outcome data for estimating a comparative treatment effect.
How should the planned efficacy measures be treated?
The registry lists response outcomes under RECIST v1.1 and measures including duration of response, disease control, progression-free survival, and overall survival. These names identify outcomes of interest, but they are not results. No efficacy analysis is reported in the registry record. In general, response outcomes describe tumor change according to specified criteria, while time-to-event outcomes concern the time until a defined event. Their interpretation depends on the analysis population, event definitions, follow-up, and handling of censoring. Those analysis details and numerical findings are not reported in the registry record.
The registry’s record of 0 analyses reinforces the distinction between registered outcomes and reported analyses. It does not mean that no analysis was conducted outside the registry; such a conclusion cannot be drawn from this record. The statistical plan, missing-data methods, and any adjustment for multiple outcomes are not reported in the registry record. Therefore, the posted counts support descriptive reading only. General concepts such as confidence intervals, comparative tests, and time-to-event methods explain what could be used in a fuller analysis, but no such results should be inferred from the information recorded.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists numerous secondary outcomes, including best tumor response, objective response rate, duration of response, disease control, progression-free survival, and overall survival. It also lists 14 outcome measures overall. When multiple outcomes are assessed, general statistical practice considers whether and how to address the possibility of chance findings across those outcomes. The registry record does not report a multiplicity plan, hierarchy of outcomes, or adjustment method. Since numerical efficacy analyses are not reported, there are no posted estimates to interpret in light of multiplicity.
The record does not report how missing outcome data were handled, whether participants were censored in time-to-event analyses, or whether follow-up differed among participants. These details matter in general because incomplete observation can affect estimates, especially when outcomes depend on follow-up time. The registry lists progression-free survival and overall survival as Phase 2 outcomes, but no numerical results or analysis methods for them are reported in the registry record.
The primary endpoint population is the safety analysis set, consisting of participants who received at least one administration. The record lists 7 participants at risk for the adverse-event summary and 8 enrolled. It does not report the reason for the difference or describe any missing safety observations. The registry also does not report an intention-to-treat efficacy population or another analysis population for the planned efficacy outcomes.
The distinction between absent analyses and missing participant data is important. The registry record contains no analyses, but that alone does not establish whether data were missing or whether analyses occurred elsewhere. The handling of missing data, analysis populations beyond the stated safety set, and multiplicity procedures are not reported in the registry record.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Radium-223 + Pembrolizumab | 2 | 7 | 28.6% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Radium-223 + Pembrolizumab | 6 of 7 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Radium-223 + Pembrolizumab | 7 of 7 |
Most frequent serious adverse event terms
| Event term | Organ system | Radium-223 + Pembrolizumab |
|---|---|---|
| Acute kidney injury | Renal and urinary disorders | 1 of 7 |
| Bone pain | Musculoskeletal and connective tissue disorders | 1 of 7 |
| Rectal haemorrhage | Gastrointestinal disorders | 1 of 7 |
| Respiratory failure | Respiratory, thoracic and mediastinal disorders | 1 of 7 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Radium-223 + Pembrolizumab |
|---|---|---|
| Asthenia | General disorders | 3 of 7 |
| Nausea | Gastrointestinal disorders | 3 of 7 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 2 of 7 |
| Constipation | Gastrointestinal disorders | 2 of 7 |
| Cough | Respiratory, thoracic and mediastinal disorders | 2 of 7 |
| Decreased appetite | Metabolism and nutrition disorders | 2 of 7 |
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | 2 of 7 |
| Pyrexia | General disorders | 2 of 7 |
| Vomiting | Gastrointestinal disorders | 2 of 7 |
| Weight decreased | Investigations | 2 of 7 |
Serious events with the highest arm-level rate: acute kidney injury (14.3%), bone pain (14.3%), rectal haemorrhage (14.3%), respiratory failure (14.3%).
The safety summary lists the Radium-223 + Pembrolizumab group with 7 participants at risk for serious events, 2 participants with serious events, 7 at risk for other events, and 7 with other events. The record also lists 6 deaths. These are participant counts in the posted registry summary. The registry does not state that deaths were treatment-related, and the broad treatment-emergent definition includes events whether or not they were considered related to treatment.
The serious-event terms listed are acute kidney injury, bone pain, rectal haemorrhage, and respiratory failure, each reported as 14.3%. These entries should be read as separate listed terms, not added together to create a total. The record does not explain whether a participant could contribute to more than one term, nor does it provide individual case details or event timing. It also does not give the serious-event definition in the posted summary.
These counts describe a small safety population and do not provide a comparison with another group. They cannot determine how many events were caused by treatment or estimate the risk in a broader population. The reason for the difference between enrollment and the at-risk counts is not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The results establish that the registry reports adverse-event counts for a treated Phase 1 group: 2 participants with serious adverse events among 7 at risk, 7 participants with other adverse events among 7 at risk, and 6 deaths. They also identify four serious-event terms, each listed at 14.3%. These are observations recorded for this study group, not evidence by themselves about the cause of an event or the comparative safety of the combination.
The primary endpoint has a broad treatment-emergent definition. An event qualifies if it arises or worsens after treatment begins within the specified follow-up period, even when it is not considered related to treatment. This makes the endpoint useful for recording events during treatment, but it does not isolate events attributable to study drugs. The registry does not provide enough case-level context to assess each event’s timing, grade, course, or attribution.
The record does not report comparative efficacy results. Although the study description and registered outcomes refer to tumor response and survival-related measures, no numerical results for those outcomes are posted. The registry therefore does not establish the size or precision of any effect on tumor response, disease control, progression-free survival, or overall survival.
Nor does the record establish a comparison between the combination and pembrolizumab alone. A pembrolizumab-alone cohort was planned for Phase 2, but whether that cohort enrolled participants is not reported. The primary outcome summary lists only the combination group. A randomized allocation label does not, on its own, provide a usable comparison when corresponding group results and an analysis are absent.
In general, a study result needs to be interpreted in light of its population, design, follow-up, and analysis. Here, the safety set is small, the study is terminated, and the statistical analysis details are not reported. These limits mean the counts are best understood as descriptive registry findings for the participants included, rather than definitive estimates of treatment effects or risks for other people.
13. Why This Trial Matters Statistically
This trial illustrates why a registered study’s design and its posted results must be distinguished. The registry describes a broader program, including a planned Phase 2 comparator and several efficacy outcomes, while the posted primary safety summary contains one treatment group and no analyses. Planned comparisons and outcomes do not become evidence unless results are reported and can be interpreted.
It also highlights the role of the analysis population. The study enrolled 8 participants, while the adverse-event summaries list 7 at risk. The primary endpoint explicitly concerns the safety analysis set of participants who received at least one treatment administration. Without a reported explanation for the difference, readers cannot assume why an enrolled participant is absent from that set. Clear population definitions help keep counts interpretable.
The endpoint’s definition is another important statistical detail. Treatment-emergent events are events that arise or worsen during a specified period after treatment begins, regardless of whether they are considered related. This distinction prevents a temporal safety count from being mistaken for a causal estimate. The serious-event terms and death count likewise need to be read as descriptive observations, not as proof of treatment causation.
Finally, the record underscores the limits of small samples and absent inferential results. Counts in a small group can convey what was observed, but they do not provide a precise population estimate or a comparison. No confidence intervals, tests, or efficacy estimates are reported in the registry record. Understanding those gaps is part of sound statistical interpretation, particularly when a study is terminated and the posted results do not cover the full set of planned questions.
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 study is listed as terminated, and the reason for termination is not reported in the registry record. The record identifies the study as Phase 1 and reports an enrollment of 8, but the safety summaries include 7 participants at risk. The reason for this difference is not reported. This limits assessment of how the enrolled group relates to the participants whose safety outcomes are summarized.
Only one group appears in the primary safety summary. The planned Phase 2 description includes a pembrolizumab-alone cohort, but whether that cohort began or enrolled participants is not reported. No comparative efficacy or safety analyses are reported in the registry record, so the randomized allocation label cannot be used to infer a treatment contrast from the posted results.
The primary outcome is a broad count of treatment-emergent events, including events not considered related to treatment. The record does not provide participant-level details, a full severity distribution, event timing, or the basis for individual attribution. It lists 6 deaths but does not state whether they were related to treatment. The serious-event terms are reported without further case context.
The registry lists efficacy outcomes but no numerical results or analyses. It does not report the statistical analysis plan, sample-size justification, interim analyses, multiplicity procedures, missing-data methods, or details of the planned randomization. It is also not reported whether the planned Phase 2 maximum tolerated dose was determined. These omissions prevent assessment of the full intended design and the precision or robustness of any efficacy findings. The limitations concern what can be concluded from the registry record and do not establish whether additional information exists elsewhere.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study to Test the Safety and How Radium-223 Dichloride an Alpha Particle-emitting Radioactive Agent Works in Combination With Pembrolizumab an Immune Checkpoint Inhibitor in Patients With Stage IV Non-small Cell Lung Cancer With Bone Metastases — NCT03996473.
- Registry record last updated 2024-10-10; status last verified 2024-07.
- Results first posted 2024-10-10.
- 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.
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18. Record Summary
The registry record describes a randomized, open-label, sequential Phase 1 study of radium-223 dichloride plus pembrolizumab in stage IV non-small cell lung cancer with bone metastases. The study enrolled 8 participants and is listed as terminated. The stated primary endpoint was the number of participants with treatment-emergent adverse events in Phase 1, assessed in a safety population of participants who received at least one treatment administration.
The safety summary lists 7 participants at risk for adverse events, 2 with serious adverse events, 7 with other adverse events, and 6 deaths. Four serious-event terms are listed, each at 14.3%. The registry lists efficacy outcomes, but numerical efficacy results and statistical analyses are not reported. The reason for termination, the reason for the difference between enrollment and the safety count, and the status of the planned Phase 2 cohorts are not reported in the registry record.