Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab or MGA012 in Refractory Cancer: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab or MGA012 in Refractory Cancer (NCT02475213), a non-randomized phase 1 study. The primary outcome is Number of Participants With Dose-limiting Toxicities (DLT) After Administration of Enoblituzumab and Pembrolizumab or Retifanlimab.

2. Clinical Question

3. Trial Design

This was a phase 1, open-label, non-randomized, sequential study sponsored by MacroGenics. It enrolled 146 participants and is recorded as completed. The registry gives a start date of 2015-07 and a primary completion date of 2021-08-18. Because treatment assignment was not randomized and masking was absent, the cohorts are best understood as parts of a dose-escalation and combination study, not as arms of a controlled efficacy comparison.

Cohorts 1, 2, and 3 received enoblituzumab with pembrolizumab. The enoblituzumab schedules were 3 mg/kg IV weekly, 10 mg/kg IV weekly, and 15 mg/kg IV weekly, respectively; pembrolizumab was 2 mg/kg IV every 3 weeks in each. Cohort 4 received enoblituzumab 15 mg/kg IV with retifanlimab 375 mg IV every 3 weeks. Separate melanoma, urothelial cancer, NSCLC, and SCCHN cohorts used enoblituzumab 15 mg/kg IV weekly with pembrolizumab 2 mg/kg IV every 3 weeks.

The primary endpoint covered participants in Cohorts 1-4 who were evaluable for dose-limiting toxicity during the first 42 days of treatment. The registry also lists pharmacokinetic outcomes, including concentration, clearance, distribution, and terminal half-life measures, as well as anti-drug antibody outcomes. It describes assessment of potential anti-tumor activity, but efficacy results are not reported in the registry record. Further details about cohort entry, dose-escalation decisions, and the number of participants assigned to each cohort are not reported in the registry record.

With sequential, non-randomized cohorts, later or distinct cohorts may differ in ways beyond the treatment combination. The registry does not establish that participants in one cohort were comparable to those in another. Thus, observed safety counts should be read as descriptive cohort summaries rather than estimates of comparative treatment effects.

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.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Participants in Cohorts 1-4 are evaluable for DLT during the first 42 days of 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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Dose-limiting Toxicities (DLT) After Administration of Enoblituzumab and Pembrolizumab or Retifanlimab, measured over Study Day 1-42, for Cohorts 1-4..

The primary endpoint is the number of participants with dose-limiting toxicities after receiving enoblituzumab with pembrolizumab or retifanlimab. The registry defines a dose-limiting toxicity as a severe side effect related to study treatment that may cause dose interruption, dose reduction, or withdrawal of treatment. The assessment period is Study Day 1-42, and the specified population is participants in Cohorts 1-4 who are evaluable for dose-limiting toxicity during the first 42 days of treatment.

In a phase 1 dose-escalation setting, this kind of endpoint is used to describe whether serious treatment-related toxicities arise within a defined early observation window. It can inform decisions about dose levels and further study, although the registry does not report the decision rules used in this study. A count of affected participants is a direct descriptive measure; interpretation also depends on how many participants were assessed and how the endpoint was defined and attributed.

The primary endpoint result itself is not reported in the registry record. The adverse-event figures listed elsewhere in the record do not replace that result: those summaries concern serious and other adverse events by cohort, and the registry does not identify them as the primary dose-limiting toxicity analysis.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a non-randomized, sequential, open-label phase 1 design. That design matters for interpretation: participants were not assigned randomly to comparable groups, and treatment was not masked. The study’s stated primary endpoint is a count of participants with dose-limiting toxicity over Study Day 1-42 in Cohorts 1-4. The registry does not report the count for that endpoint, the statistical analysis methods, or the rules that governed dose escalation.

What does a participant count express?

A count describes how many participants experienced a defined event in a specified population and observation period. It is not, by itself, a measure of how precisely the event frequency is known. The number assessed matters: the same count can have different implications when it comes from groups of different sizes. A percentage can help convey a frequency, but a percentage without its denominator and population definition can be difficult to interpret. General statistical principle: uncertainty around an event frequency is usually greater when fewer participants contribute information.

Here, the primary measure is explicitly a participant count, and its population is limited to people in Cohorts 1-4 who were evaluable for dose-limiting toxicity during the first 42 days. The total enrollment of 146 is not the denominator for that endpoint unless the analysis population and outcome data establish that it is. Those endpoint details are not reported in the registry record. The listed adverse-event denominators are cohort-specific safety counts and should not be substituted for a primary endpoint denominator.

Why is the observation window important?

An event count is tied to the period in which events are observed. The primary endpoint’s window is Study Day 1-42. It therefore describes the specified early period, not necessarily the entire treatment course or all follow-up. General statistical principle: when participants have different lengths of observation, a simple count may not capture the full time at risk. The registry does not report additional exposure-adjusted analyses for the primary endpoint, so no such interpretation can be made.

What does sequential allocation imply?

In a sequential study, cohorts can be enrolled or treated in sequence, and dose levels can differ across groups. General statistical principle: comparisons across non-randomized groups can be confounded when groups differ in treatment, eligibility, disease type, or other characteristics. Randomization is one way to balance measured and unmeasured factors on average; this study is explicitly non-randomized. Cohort counts can still describe the observed participants, but should not be treated as controlled estimates of a treatment contrast. No comparative analysis is reported in the registry record.

The three initial pembrolizumab cohorts have different listed enoblituzumab doses, while Cohort 4 combines enoblituzumab with retifanlimab. The named tumor cohorts have their own cohort identities and shared listed pembrolizumab regimen. These distinctions mean that dose, combination partner, and cancer cohort are not interchangeable features. Any apparent differences in the adverse-event summaries should be interpreted with this design context in mind.

How should uncertainty and significance be understood?

A confidence interval, in general, is a range of values produced by a statistical method to express uncertainty about an estimate. It describes the precision of an estimate under assumptions of that method; it does not guarantee that the true value lies inside any one interval. No confidence intervals for the primary endpoint or adverse-event summaries are reported in the registry record. Likewise, no hypothesis tests, p-values, or model-based estimates are reported. Without these results, there is no basis to characterize the primary endpoint as statistically significant or to quantify its precision.

General statistical principle: lack of a reported test is not evidence that groups are equivalent. This point is particularly relevant for a non-randomized study, where a formal comparison would also require a clearly defined contrast and appropriate adjustment for the design. The registry record lists no analyses and does not report a prespecified comparative hypothesis.

What do the other outcomes add?

Listed secondary outcomes include mean maximum and trough concentrations, area under the concentration-time curve from time 0 to Day 7, clearance, volume of distribution at steady state, terminal half-life, and the number of participants developing anti-drug antibodies. These outcomes address drug exposure and immune response rather than the primary count of dose-limiting toxicities. The registry lists 18 outcome measures in total, but does not report results for these measures or analyses associated with them.

General statistical principle: concentration and pharmacokinetic summaries depend on how samples are collected, which participants contribute data, and how missing measurements are handled. The registry record does not report those analysis details or the estimates themselves. The brief summary also mentions potential anti-tumor activity, but the available record does not provide efficacy estimates. Accordingly, the methods information supports understanding what was intended to be assessed, but not conclusions about the magnitude or precision of the findings.

The record includes a planning illustration framework based on a fraction of an observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such illustrations are prospective planning aids, not observed trial outcomes or observed power. The numerical sample-size illustrations and the effect estimate underlying them are not reported in the registry record. The study’s own sample-size justification is not reported in the registry record.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Cohort 1", "Cohort 2", "Cohort 3", "Cohort 4")
n      <- c(6, 3, 3, 12)
events <- c(1, 0, 0, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Cohort 1  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Cohort 2  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 3  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Cohort 4  12  0  0.0  0.0  26.5  0.0  24.2  0.2  24.7

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 18 outcome measures, including the primary dose-limiting toxicity count and secondary pharmacokinetic and anti-drug antibody measures. It does not report a multiplicity adjustment, a hierarchy for testing outcomes, or a statistical plan for interpreting several outcomes together. Because no analyses are listed, the registry record does not establish whether any formal testing was performed or how multiple comparisons were addressed. General statistical principle: when many outcomes or comparisons are examined, the chance of a misleading positive finding can increase unless the analysis plan accounts for multiplicity. That general concern cannot be resolved from this record.

Missing-data methods are not reported in the registry record. The record specifies that participants in Cohorts 1-4 are evaluable for the primary endpoint during the first 42 days, but does not explain how participants who discontinue early, have incomplete follow-up, or lack evaluable toxicity information were handled. It also does not report missingness for the listed pharmacokinetic or antibody outcomes. Without those details, the endpoint population and the impact of incomplete data cannot be fully assessed.

Analysis populations beyond the stated dose-limiting toxicity-evaluable group are not reported in the registry record. In particular, the record does not describe an intention-to-treat population, a per-protocol population, or rules for including participants in individual outcome analyses. The total enrollment of 146 should therefore be kept distinct from the endpoint-specific evaluable population. The number analyzed for each outcome, and any exclusions or reasons for exclusion, are not reported in the registry record.

The study’s sample-size justification, interim analysis approach, and prespecified statistical analysis plan are also not reported in the registry record. The planning illustration described in the record is not a substitute for those protocol details or for observed endpoint results.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: atrial fibrillation (33.3%), adrenal insufficiency (33.3%), pyrexia (33.3%), dizziness (33.3%), cytokine release syndrome (16.7%).

The serious adverse-event summaries give, for each cohort, the number of participants at risk and the number affected. Cohort 1 lists 1 affected among 6 at risk; Cohort 2 lists 1 among 3; Cohort 3 lists 2 among 3; the Melanoma Cohort lists 8 among 17; the Urothelial Cancer Cohort lists 4 among 21; the NSCLC Cohort lists 14 among 40; the SCCHN Cohort lists 18 among 43; and Cohort 4 lists 3 among 12. These figures are cohort-specific descriptive counts, not randomized comparisons.

The record also lists other adverse events, with 6 of 6 in Cohort 1, 3 of 3 in Cohort 2, 3 of 3 in Cohort 3, 17 of 17 in the Melanoma Cohort, 21 of 21 in the Urothelial Cancer Cohort, 40 of 40 in the NSCLC Cohort, 42 of 43 in the SCCHN Cohort, and 12 of 12 in Cohort 4. Death counts are listed by cohort, but causal attribution is not reported in the registry record.

Top serious-event terms include atrial fibrillation, adrenal insufficiency, pyrexia, and dizziness at 33.3% each, cytokine release syndrome at 16.7%, and infusion related reaction at 14.0%. The denominator and cohort context for these term percentages are not reported in the registry record. Event counts do not establish that an event was caused by treatment, and the serious-event summaries are not equivalent to the primary dose-limiting toxicity endpoint.

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

The registry record establishes that this completed phase 1 study evaluated enoblituzumab with pembrolizumab or retifanlimab in several cancer cohorts and lists adverse-event summaries by cohort. It also states that dose-limiting toxicity was assessed over Study Day 1-42 in Cohorts 1-4. However, the number of participants with the primary endpoint is not reported in the registry record. This prevents a direct summary of the primary safety result and limits what can be said about the endpoint’s observed frequency.

The adverse-event counts are useful as descriptive reports of events among the participants at risk in each listed cohort. They do not show that one treatment combination is safer than another. The design was non-randomized, cohorts differed in dose, combination partner, or cancer type, and their sizes varied. The record provides no adjusted comparisons or uncertainty intervals. These figures also cannot be interpreted as causal treatment effects: the registry does not establish for each listed event that treatment caused it.

The listed deaths should be read with similar care. The record gives death counts by cohort but does not state that these deaths were related to study treatment. Neither the cohort death counts nor the adverse-event counts can be used as a substitute for a treatment-attributed mortality analysis, which is not reported in the registry record.

The record’s description of pharmacokinetic, anti-drug antibody, and potential anti-tumor assessments indicates what the study sought to evaluate, but the corresponding results are not reported in the registry record. No conclusion about anti-tumor activity, drug exposure, or immune response can be drawn from the outcome descriptions alone. Likewise, the completed status does not by itself indicate what the results were or how the study’s objectives were met.

In general, an absence of reported results is not evidence that an outcome did not occur. It means that the result cannot be assessed from the registry record. The available information supports understanding the study’s purpose, cohort structure, and some safety counts, while leaving the primary endpoint result, analysis methods, and outcome precision unresolved.

14. Why This Trial Matters Statistically

This study is statistically informative as an example of why the design and the outcome definition must be considered together. The primary endpoint was a count of participants with dose-limiting toxicity during a fixed early period, while the study also included distinct cancer cohorts and combinations. Clear definitions of the analysis population and observation window are essential to interpreting such a count. The registry does identify the Cohorts 1-4 population and the Study Day 1-42 period, but does not report the endpoint result itself.

The non-randomized, sequential design also illustrates the distinction between descriptive safety reporting and comparative inference. Cohorts can be useful for documenting what occurred among participants receiving a particular regimen. But without randomization and a defined control comparison, differences among cohorts cannot be attributed to treatment alone. Here, groups differ by dose, combination partner, or cancer cohort, and no statistical comparisons are reported.

The record additionally underscores the importance of reporting denominators, missing-data handling, and analysis populations. Adverse-event counts are listed with cohort-specific numbers at risk, whereas the primary endpoint’s number evaluated and affected is absent. The listed top serious-event percentages are not accompanied by their denominator or cohort context. Such details affect how readers judge precision and generalizability.

Finally, listing outcomes is not the same as reporting their findings. The record identifies pharmacokinetic and anti-drug antibody measures and mentions potential anti-tumor activity, yet does not provide the numerical results or analyses. For clinical research, accessible endpoint results and analysis methods are necessary to assess what the study established, how uncertain the estimates are, and how findings should be compared with other evidence.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

A major limitation of the available record is that it does not report the primary dose-limiting toxicity result, despite identifying the endpoint, the observation period, and the evaluable population. The registry also lists no analyses. Consequently, the central safety question cannot be quantified from the posted record, and there is no reported uncertainty estimate for the primary endpoint.

The study was open-label and non-randomized, with sequential cohorts. No like-for-like randomized control comparison is described. Differences across cohort summaries may reflect differences in regimen, tumor type, cohort composition, or group size. The record does not provide adjustment methods or comparative estimates that could address such differences.

The available safety summaries have additional limits. The record gives serious adverse-event counts and other adverse-event counts by cohort, and reports deaths by cohort, but does not provide treatment-attribution details for the deaths. The top serious-event terms are accompanied by percentages, but their denominator and cohort context are not reported in the registry record. No confidence intervals or statistical comparisons are listed for these summaries.

Other key reporting details are absent: the sample-size justification, interim analysis approach, statistical analysis plan, missing-data methods, and analysis populations beyond the stated primary endpoint population are not reported in the registry record. Although the record lists 18 outcome measures and describes pharmacokinetic and anti-drug antibody outcomes, their results are unavailable. The brief summary also refers to potential anti-tumor activity without reporting efficacy estimates. These limitations restrict both the precision of interpretation and the conclusions that can be drawn from the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety Study of Enoblituzumab (MGA271) in Combination With Pembrolizumab or MGA012 in Refractory Cancer — NCT02475213.
• Registry record last updated 2025-08-11; status last verified 2025-08.
• Results first posted 2025-08-11.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT02475213 is a completed phase 1, open-label, non-randomized, sequential study sponsored by MacroGenics. It enrolled 146 participants and evaluated enoblituzumab combined with pembrolizumab or retifanlimab across dose-escalation and cancer-specific cohorts. The registry lists a start date of 2015-07 and a primary completion date of 2021-08-18.

The primary endpoint was the number of participants with dose-limiting toxicities during Study Day 1-42 in Cohorts 1-4. The endpoint result is not reported in the registry record. Cohort-specific serious and other adverse-event counts and death counts are listed, but they do not constitute a randomized comparison or replace the primary endpoint result. The record also lists pharmacokinetic and anti-drug antibody outcomes, without reporting their results. Statistical methods, missing-data procedures, and the study’s sample-size justification are not reported in the registry record.