This page separates posted trial information from statistical interpretation. The ClinicalTrials.gov record reports eight outcome measures and results, but no formal statistical analyses are included in the posted results.
View CheckMate-358 on ClinicalTrials.gov
1. Trial at a Glance
CheckMate-358 is a completed randomized, parallel-design phase 1/2 study investigating nivolumab and nivolumab combination therapy in virus-associated tumors and various advanced cancer. The ClinicalTrials.gov record describes five arms, four registered primary endpoints, eight posted outcome measures, and total enrollment of 578 participants.
| Feature | CheckMate-358 |
|---|---|
| Trial name | CheckMate-358 |
| Brief title | An Investigational Immuno-therapy Study to Investigate the Safety and Effectiveness of Nivolumab, and Nivolumab Combination Therapy in Virus-associated Tumors |
| Phase | Phase 1/2 |
| Status | COMPLETED |
| Therapeutic area | Oncology |
| Condition | Various Advanced Cancer |
| Allocation | RANDOMIZED |
| Design model | PARALLEL |
| Masking | NONE |
| Primary purpose | TREATMENT |
| Enrollment | 578.0 |
| Arms | 5 |
| Interventions | Nivolumab; Ipilimumab; Relatlimab; Daratumumab |
| Lead sponsor | Bristol-Myers Squibb |
| Sponsor type | INDUSTRY |
| Start | 2015-10-13 |
| Primary completion | 2021-03-19 |
| ClinicalTrials.gov identifier | NCT02488759 |
2. Clinical Question
The ClinicalTrials.gov record describes a study investigating the safety and effectiveness of nivolumab and nivolumab combination therapy in virus-associated tumors, within a broader condition description of various advanced cancer. Because the ClinicalTrials.gov record does not provide a single pooled comparator regimen or a single efficacy hypothesis spanning all five arms, the statistical question is best understood at the level of the registered cohorts and endpoints rather than as one conventional two-arm superiority comparison.
Population
Participants enrolled under the condition description Various Advanced Cancer, including a neoadjuvant cohort and metastatic cohorts represented in the posted safety data.
Interventions
The ClinicalTrials.gov record lists nivolumab, ipilimumab, relatlimab, and daratumumab as interventions.
Design question
The trial used randomized allocation with a parallel design and no masking.
Primary questions
The registered primary endpoints focus on drug-related adverse events, serious adverse events, surgery delay in the neoadjuvant cohort, and investigator-assessed objective response rate in the metastatic setting.
3. Trial Design
These design descriptors matter statistically because randomization creates the basis for comparing assigned groups, while the parallel design means participants are evaluated within their assigned study pathways rather than being described as a crossover or factorial experiment. The absence of masking also means that neither participants nor investigators were assigned a blinded treatment condition according to the registry's masking field.
Study timeline
Study start
The trial began on October 13, 2015.
Primary completion
The registry lists March 19, 2021 as the primary completion date.
Current trial status in the ClinicalTrials.gov record
The trial status is listed as COMPLETED.
4. Endpoints
The ClinicalTrials.gov record identifies four registered primary endpoints. All four are binary endpoints in the registry-reported endpoint classification. The registry also states that results were posted for each of these four primary endpoints.
| Primary endpoint | Time frame | Endpoint type | Definition reported in registry data |
|---|---|---|---|
| Neoadjuvant: Number of Participants With Drug-Related Select Adverse Events (AEs) | From first dose to 30 days post last dose (Up to 2 months) | Binary | Number of participants with any grade of drug-related select adverse events including endocrine, gastrointestinal, hepatic, pulmonary, renal, skin, and hypersensitivity AEs in the neoadjuvant cohort. |
| Neoadjuvant: Number of Participants With Drug-Related Serious Adverse Events (SAEs) | From first dose to 30 days post last dose (Up to 2 months) | Binary | Number of participants with any grade of drug-related serious adverse events in the neoadjuvant cohort. |
| Neoadjuvant: Rate of Surgery Delay | Day 29 | Binary | Percentage of participants in the neoadjuvant cohort with surgery delayed > 4 weeks from the planned surgery date or planned start date for chemoradiation due to a drug-related adverse event. The registry-reported definition identifies HPV positive squamous cell carcinoma of the head and neck, HPV negative squamous cell carcinoma of the head and neck, and cervical cancer among the diseases assessed. |
| Metastatic: Investigator-Assessed Objective Response Rate (ORR) | From the date of first dose to the date of the initial objectively documented tumor progression or the date of the last reported assessment in the registry wording | Binary | Percentage of participants with a best overall response of confirmed complete response or partial response using RECIST 1.1 criteria. |
Why the endpoint structure matters
These endpoints are not all measuring the same clinical construct. The first two quantify adverse-event occurrence, the third captures an operational consequence of toxicity in the neoadjuvant setting, and the fourth measures tumor response in metastatic disease. Treating all four as if they were interchangeable efficacy endpoints would obscure the actual statistical structure of the trial.
5. Statistical Analysis Status
The ClinicalTrials.gov record states that Results Posted = Yes, but no formal statistical analyses were posted. That distinction is important. A registry can contain posted outcome data without supplying the formal treatment-comparison analysis objects needed to reproduce a complete inferential analysis.
6. Posted Primary Endpoint Results and Planned Analysis
The registry indicates that results were posted for all four registered primary endpoints. However, because the ClinicalTrials.gov recordset does not include formal statistical analyses, the appropriate approach is to distinguish the reported outcome definitions from the statistical methods that would ordinarily be used for those binary outcomes.
Neoadjuvant drug-related select adverse events
Registered endpoint
Number of participants with any grade of drug-related select adverse events
Time frame: From first dose to 30 days post last dose (Up to 2 months)
The endpoint is a participant-level binary outcome: a participant either meets the registry definition of having at least one qualifying drug-related select adverse event during the specified observation window or does not. The ClinicalTrials.gov record confirms that results were posted for this endpoint, but do not provide a numerical result or formal statistical comparison in the posted results.
For a randomized comparison, an analysis might report event proportions by arm together with a risk difference, risk ratio, odds ratio, or an appropriate exact or asymptotic confidence interval. The correct choice depends on the prespecified analysis plan, sample size, number of arms, and comparison structure.
Neoadjuvant drug-related serious adverse events
Registered endpoint
Number of participants with any grade of drug-related serious adverse events
Time frame: From first dose to 30 days post last dose (Up to 2 months)
The registry defines this endpoint as the number of participants with any grade of drug-related serious adverse events in the neoadjuvant cohort. The ClinicalTrials.gov record states that results were posted but does not provide a formal comparative analysis.
Neoadjuvant rate of surgery delay
Registered endpoint
Surgery delay > 4 weeks because of a drug-related adverse event
Binary endpoint expressed as a percentage of participants in the neoadjuvant cohort
This endpoint has a particularly clear operational definition. It is not simply a measure of whether an adverse event occurred; it asks whether surgery was delayed by more than four weeks from the planned surgery date or planned start date for chemoradiation because of a drug-related adverse event. That distinction makes the endpoint clinically different from the broader adverse-event measures.
Metastatic investigator-assessed ORR
Registered endpoint
Confirmed complete response or partial response using RECIST 1.1 criteria
Assessment begins at first dose and continues to initial objectively documented tumor progression or the last reported assessment in the registry wording.
The registry-reported definition identifies objective response rate as the percentage of participants whose best overall response is confirmed complete response or partial response under RECIST 1.1. The record also specifies two interpretive thresholds: an ORR in excess of 10% is considered of clinical interest, while an ORR of 25% or greater is considered of strong clinical interest.
7. Clinical Biostats Interpretation: Why No Effect Estimate Is Reported
A binary endpoint can support a clear effect estimate, but only when the underlying event counts, denominators, and comparison framework are available. The registry-reported CheckMate-358 data do not provide the statistical-analysis records needed to establish such a comparison for the four registered primary endpoints.
The absence of a reported hazard ratio, odds ratio, confidence interval, or p-value in the ClinicalTrials.gov record does not mean that the trial had no statistical analysis. It means that those formal analyses are not contained in the trial-data object in the ClinicalTrials.gov record.
Calculating a new p-value from incomplete registry information could produce a number that appears authoritative while answering a different question from the prespecified analysis. An educational statistical analysis should distinguish what is documented from what would normally be calculated.
8. Safety Results: Serious Adverse Events by Arm
the ClinicalTrials.gov record reports serious adverse events by named arm or cohort. These data are the clearest numerical safety results provided in the trial data.
| Arm / cohort | Affected | At risk |
|---|---|---|
| Metastatic Monotherapy | 59 | 113 |
| Metastatic Combo A | 130 | 195 |
| Metastatic Combo B | 99 | 133 |
| Metastatic Combo C | 5 | 8 |
| Metastatic Combo D | 5 | 6 |
| Neoadjuvant | 40 | 123 |
The denominators vary substantially across these reported groups. That matters when interpreting raw event counts: an affected count cannot be compared directly across groups without considering the corresponding number at risk. The ClinicalTrials.gov record also do not identify a formal statistical comparison among these safety groups.
9. Safety Analysis Explained
What does "affected / at risk" represent?
The affected count is the number of participants experiencing the reported serious adverse-event outcome, while the at-risk value is the denominator reported with that result. Together, they provide the basic ingredients for an observed event proportion.
Why should counts and denominators be shown together?
A count without its denominator is difficult to interpret. For example, 5 events could represent a very different safety frequency depending on whether the underlying group contained 6 participants or a substantially larger population. The registry-reported CheckMate-358 data explicitly provide both values, which allows the reader to see the scale of each cohort.
What statistical comparison would normally be used?
For a simple binary safety outcome, investigators might compare proportions using a risk difference, risk ratio, or odds ratio, with a confidence interval. With small expected cell counts, exact methods may be preferable. In a multi-arm trial, however, the correct comparison must follow the prespecified analysis plan rather than being selected after looking at the observed counts.
Why is "statistically different" not the same as "clinically different"?
A statistical test addresses evidence against a specified null hypothesis. Clinical interpretation additionally depends on the magnitude of the difference, the seriousness and reversibility of the events, the precision of the estimate, and the broader benefit-risk context. A p-value alone cannot supply that context.
10. Statistical Methodology
Binary endpoint analysis
All four registered primary endpoints are classified as binary in the ClinicalTrials.gov record. Binary endpoints reduce an outcome to two states according to a prespecified definition. For this trial, those definitions include presence or absence of selected drug-related adverse events, presence or absence of drug-related serious adverse events, whether surgery was delayed by more than four weeks for the specified reason, and whether a participant achieved a confirmed complete or partial response.
where x is the number of participants meeting the endpoint definition and n is the relevant analysis denominator.
Risk difference
When two groups are compared, the risk difference is the difference between their observed event probabilities. It is directly interpretable on the probability scale and answers the question of how much the event frequency differs between groups.
A risk difference of zero corresponds to equal observed event probabilities. The ClinicalTrials.gov record does not provide enough information to calculate a prespecified CheckMate-358 risk difference for the primary endpoints.
Risk ratio
A risk ratio compares event probabilities multiplicatively. A value below 1 indicates a lower observed event probability in the numerator group relative to the reference group, while a value above 1 indicates a higher probability.
Odds ratio
An odds ratio compares the odds of an event rather than the event probabilities themselves. Odds ratios can be useful in binary-outcome models, but they should not be casually described as risk ratios, particularly when the outcome is common.
Confidence intervals
A confidence interval describes statistical uncertainty around an estimated quantity under the chosen model and sampling framework. It is more informative than a point estimate alone because it shows how precisely the study estimates the underlying effect. No confidence intervals for the CheckMate-358 primary endpoints are reported in the ClinicalTrials.gov record.
Multiplicity in a multi-endpoint, multi-arm study
CheckMate-358 has four registered primary endpoints and five arms. Whenever several hypotheses or comparisons are evaluated, the distinction between an individual nominal p-value and the overall familywise error rate becomes important. A formal multiplicity strategy would need to be specified in the statistical analysis plan. The ClinicalTrials.gov record does not report such a strategy, so none is assumed here.
11. Statistical Methods Explained
Why is randomization important in CheckMate-358?
Randomization assigns participants to study groups using a chance-based allocation mechanism. Its statistical value is that, in expectation, measured and unmeasured baseline factors are balanced across randomized groups. This supports causal interpretation of between-group comparisons when the trial is analyzed according to the randomized assignment and the prespecified design.
Why are the primary endpoints analyzed as binary outcomes?
The registry definitions convert each primary endpoint into a yes-or-no participant outcome. A participant either has a qualifying drug-related select adverse event or does not; either has a qualifying serious adverse event or does not; either experiences the specified surgery delay or does not; and either achieves a confirmed complete or partial response or does not.
Why is ORR different from progression-free survival?
ORR asks whether a participant achieves a specified tumor response. It does not directly incorporate the amount of time until progression. A time-to-event endpoint such as progression-free survival would instead account for the timing of progression or another specified event and for censoring. The registry-reported CheckMate-358 primary metastatic endpoint is ORR, not a time-to-event endpoint.
Why does RECIST 1.1 matter for ORR?
The response endpoint is only reproducible if "response" has a defined operational rule. The registry definition specifies RECIST 1.1 and requires a best overall response of confirmed complete response or partial response. That standardization reduces ambiguity in deciding whether a participant meets the binary response endpoint.
Why should the surgery-delay endpoint not be treated as an ordinary adverse-event rate?
The surgery-delay endpoint adds a clinical consequence and a time threshold to the adverse-event concept. It requires the surgery to be delayed by more than four weeks from the planned date or planned start date for chemoradiation and attributes the delay to a drug-related adverse event. That makes it a distinct endpoint rather than a duplicate count of adverse events.
Why can the safety groups not simply be ranked by event count?
Because the denominators differ. The reported serious-adverse-event counts range from 5 to 130, but the corresponding groups range from 6 to 195 participants at risk. Comparing raw counts without denominators would therefore be statistically misleading. Even comparing proportions would require caution because several groups are small.
12. What the Registry Data Can and Cannot Establish
| Question | What the ClinicalTrials.gov record establishes | What they do not establish |
|---|---|---|
| Was the study randomized? | Yes. The allocation field is RANDOMIZED. | The exact randomization ratio or allocation algorithm. |
| How many participants were enrolled? | 578.0. | Exact arm-specific enrollment for all five arms. |
| How many arms were specified? | 5. | A complete arm-to-intervention mapping. |
| Were results posted? | Yes. | A complete formal statistical-analysis record. |
| What primary endpoints were registered? | Four binary endpoints are listed. | Formal hypothesis-test results for those endpoints. |
| Are safety counts available? | Yes, serious adverse-event affected/at-risk counts are posted on ClinicalTrials.gov for six named groups or cohorts. | Confidence intervals, p-values, or prespecified pairwise safety comparisons. |
| Is a treatment-effect estimate available? | Not in the posted results. | Hazard ratios, risk ratios, odds ratios, risk differences, or corresponding confidence intervals. |
13. Limitations
- No formal statistical analyses reported: the statistical-analysis array is empty even though the registry indicates that results were posted.
- Incomplete arm mapping: the registry-reported profile identifies five arms and lists four interventions, while the serious-adverse-event data contain six named groups or cohorts. The ClinicalTrials.gov record does not provide enough detail to construct a definitive one-to-one arm map.
- No arm-specific enrollment table: the overall enrollment is 578.0, but the ClinicalTrials.gov record does not give a complete allocation of those participants across the five randomized arms.
- No confidence intervals: the registry-reported statistical data contain no confidence intervals for the primary endpoints or safety estimates.
- No p-values: the registry-reported statistical data contain no formal hypothesis-test p-values.
- No prespecified multiplicity strategy: the ClinicalTrials.gov record does not describe how multiple primary endpoints or multiple treatment comparisons were handled.
- No stratification information: the ClinicalTrials.gov record does not specify stratification factors, so none are assumed.
- No interim-analysis information: the ClinicalTrials.gov record does not report an interim monitoring plan or alpha-spending method.
- No missing-data strategy: the ClinicalTrials.gov record does not specify imputation, missing-response handling, or censoring rules for the posted outcomes.
- No Bayesian methodology: the ClinicalTrials.gov record does not identify Bayesian analyses or prior distributions.
- Small safety cohorts: the groups with 8 and 6 participants at risk are too small for raw counts alone to provide a stable comparative safety assessment.
- Endpoint heterogeneity: adverse events, surgery delay, and objective tumor response address different clinical questions and should not be collapsed into a single efficacy or safety measure.
14. Why This Trial Matters Statistically
CheckMate-358 is a useful statistical teaching case because its registry structure illustrates a problem that appears frequently in complex clinical research: the presence of reported outcomes does not necessarily mean that the public registry record contains every component needed to reconstruct the formal inferential analysis.
| Concept | How it appears in CheckMate-358 |
|---|---|
| Randomization | The trial allocation is listed as RANDOMIZED. |
| Parallel design | The design model is PARALLEL. |
| Binary endpoints | All four registered primary endpoints are classified as binary in the ClinicalTrials.gov record. |
| Safety analysis | Serious adverse-event counts and denominators are reported for named groups and cohorts. |
| Response analysis | Metastatic ORR is defined using confirmed complete response or partial response under RECIST 1.1. |
| Denominator awareness | Safety counts must be interpreted alongside their corresponding at-risk denominators. |
| Multiplicity | Four primary endpoints and five arms create a setting where formal multiplicity handling could be important. |
| Analysis transparency | Posted results and formal statistical analyses are distinct fields in the ClinicalTrials.gov record. |
| Small-sample inference | Several reported safety cohorts have very small denominators, limiting the stability of percentage estimates. |
15. Endpoint-Specific Statistical Interpretation
Select adverse events
This endpoint measures whether a participant experienced at least one qualifying drug-related select adverse event during the specified follow-up period. It is fundamentally a binary safety outcome.
Serious adverse events
This endpoint captures the occurrence of any drug-related serious adverse event in the neoadjuvant cohort during the defined observation window.
Surgery delay
This endpoint measures a clinically consequential delay exceeding four weeks when the delay is attributed to a drug-related adverse event.
Objective response
ORR measures the proportion achieving confirmed complete or partial response under RECIST 1.1 rather than measuring time until progression or death.
16. How a Formal Analysis Could Be Structured
The following describes the statistical logic that would ordinarily accompany the endpoints posted on ClinicalTrials.gov. It is not a reconstruction of the CheckMate-358 statistical analysis plan.
Step 1: Define the analysis population
The analysis would first identify which participants belong in the denominator for each endpoint. Safety endpoints may use an exposed or treated population, whereas efficacy analyses can follow the randomized population or another prespecified response-evaluable population. The ClinicalTrials.gov record does not specify the complete analysis-population definitions.
Step 2: Calculate the observed event proportion
For each binary endpoint, the number of participants meeting the endpoint definition is divided by the appropriate denominator. This provides the basic observed rate for each arm or cohort.
Step 3: Quantify uncertainty
A confidence interval can be constructed around each proportion. With small denominators, exact binomial intervals may be considered rather than relying on large-sample normal approximations.
Step 4: Define the comparison
In a multi-arm randomized study, the comparison must be prespecified. Possible approaches include comparison against a reference arm, pairwise comparisons, or a global multi-arm hypothesis. The ClinicalTrials.gov record does not specify which approach was prespecified for the four primary endpoints.
Step 5: Address multiplicity
If several hypotheses are tested, the statistical plan may control the familywise type I error rate using a hierarchical testing strategy, alpha allocation, adjustment procedures, or another prespecified method. No such strategy is reported here.
Step 6: Report effect size and precision
A complete results presentation would ideally include the observed proportions, an interpretable effect measure, its confidence interval, and the corresponding hypothesis-test result where applicable. The registry-reported CheckMate-358 statistical-analysis data do not contain those quantities.
17. Understanding the Posted Safety Counts
The chart above displays the reported number of affected participants, not a risk-adjusted or percentage comparison. It is intentionally not presented as a ranking of safety risk because the denominators differ substantially among the reported groups.
18. Randomization as the Central Design Concept
The trial's statistical concepts identifies Randomization as the key statistical concept associated with this trial. Randomization is especially important in a study with multiple treatment pathways because it provides the framework for comparing groups while reducing systematic allocation bias.
However, randomization does not automatically solve every statistical problem. The analysis still needs a clearly defined estimand, an appropriate analysis population, valid endpoint definitions, adequate handling of missing observations, and an explicit strategy for multiple comparisons when several hypotheses are considered.
Randomization tells us how treatment assignment was generated. It does not, by itself, tell us which statistical test should be used for every endpoint. The endpoint definition and prespecified analysis plan determine the appropriate inferential method.
19. Primary Endpoint Thresholds and Interpretation
The metastatic ORR endpoint includes explicit interpretive thresholds in the registry definition. These thresholds are particularly useful for teaching the distinction between an observed response proportion and a prespecified benchmark.
| ORR threshold | Registry wording | Statistical interpretation |
|---|---|---|
| In excess of 10% | Considered of clinical interest | An observed ORR above this threshold would meet the registry's stated descriptive criterion. The ClinicalTrials.gov record does not provide a formal hypothesis-test result against this threshold. |
| 25% or greater | Considered of strong clinical interest | An observed ORR at or above this threshold would meet the registry's stated descriptive criterion. This does not by itself establish statistical significance. |
This distinction is important. A clinical-interest threshold is not automatically equivalent to a null hypothesis, and crossing a descriptive threshold does not by itself establish a confidence interval or p-value. Formal inference requires the observed data, the specified null hypothesis, and the prespecified statistical method.
20. Limitations of Registry-Based Statistical Reconstruction
ClinicalTrials.gov is designed to provide structured information about clinical studies, including their design and outcome measures. It is not necessarily a complete substitute for the statistical analysis plan, protocol, participant-level dataset, or full clinical-study report.
For CheckMate-358, this limitation is particularly relevant because the ClinicalTrials.gov record contains a rich set of endpoint definitions and safety counts but an empty formal statistical-analysis array. A responsible educational analysis therefore has to resist the temptation to fill the gaps with assumptions.
What can be described
The design, population description, enrollment, number of arms, interventions, endpoint definitions, time frames, posted-result status, and registry-reported safety counts.
What should not be inferred
Formal effect estimates, confidence intervals, p-values, multiplicity adjustments, interim-analysis rules, missing-data methods, or exact arm-level statistical comparisons not contained in the ClinicalTrials.gov record.
21. Related Tutorials
Learn more about the methods used in this trial:
22. Related Statistical Calculators
23. Sources
- ClinicalTrials.gov: CheckMate-358, NCT02488759.
- Linked publication record reported with the trial data: PubMed PMID 39889250.
- Linked publication record reported with the trial data: PubMed PMID 38608691.
- Linked publication record reported with the trial data: PubMed PMID 38340723.
- Linked publication record reported with the trial data: PubMed PMID 34083421.
- Linked publication record reported with the trial data: PubMed PMID 32324435.
Continue through the Clinical Biostats statistical pathway
Explore the underlying trial-design and binary-outcome concepts used to interpret randomized clinical studies.
24. Record Summary
CheckMate-358 is a completed randomized, parallel-design phase 1/2 oncology study with 578.0 enrolled participants, five arms, four registered primary endpoints, and eight posted outcome measures. The primary endpoints are binary and span drug-related select adverse events, drug-related serious adverse events, surgery delay in the neoadjuvant cohort, and investigator-assessed objective response rate in the metastatic setting.
The most important statistical lesson from the ClinicalTrials.gov record is the distinction between reported outcomes and reported statistical analyses. The trial data confirm that results were posted, but the registry-reported statistical-analysis array is empty.