A Study Exploring the Safety and Efficacy of INCAGN01949 in Combination With Immune Therapies in Advanced or Metastatic Malignancies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Exploring the Safety and Efficacy of INCAGN01949 in Combination With Immune Therapies in Advanced or Metastatic Malignancies (NCT03241173), a non-randomized phase 1, phase 2 study. The primary outcome is Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs).

2. Clinical Question

3. Trial Design

This was a Phase 1/2, non-randomized, unmasked, parallel-group study of INCAGN01949, alone or with immune therapies, in advanced or metastatic malignancies. The study enrolled 52 participants. It began on 2017-10-09, had primary completion on 2019-09-17, and is recorded as completed. The sponsor was Incyte Biosciences International Sàrl.

Phase 1 used dose escalation and safety expansion groups. Dose escalation evaluated INCAGN01949 with nivolumab, with ipilimumab, or with both nivolumab and ipilimumab. The nivolumab combination dose-escalation groups used INCAGN01949 at 70, 200, 350, or 700 mg with nivolumab 240 mg. The ipilimumab groups used the same listed INCAGN01949 doses with ipilimumab 1 mg/kg. A triple-combination group used INCAGN01949 with nivolumab 3 mg/kg and ipilimumab 1 mg/kg. Safety expansion included run-in dosing in some groups, followed by combination treatment.

Phase 2 included INCAGN01949 with nivolumab in participants described as PD-1/PD-L1 refractory with gastric cancer, squamous cell carcinoma of the head and neck, non-small cell lung cancer, or renal cell carcinoma. Another part included INCAGN01949 alone, with nivolumab, or with both nivolumab and ipilimumab in participants with those malignancies.

The non-randomized design means treatment assignment was not described as random. No masking was used. The registry record does not report the allocation process, the rationale for assigning participants to particular groups, or a formal comparator strategy. Because the groups may differ in treatment and participant characteristics, their outcomes should not be treated as controlled estimates of comparative efficacy or safety.

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 15 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full Analysis Set (FAS): all participants enrolled in the study who received ≥ 1 dose of INCAGN01949, nivolumab, or ipilimumab

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 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase 1: Number of Participants With Treatment-emergent Adverse Events (TEAEs), measured over up to 17.4 months.

The Phase 1 primary endpoint counts participants with treatment-emergent adverse events (TEAEs), with the timeframe recorded as up to 17.4 months. The registry defines an adverse event as an untoward medical occurrence associated with drug use, whether or not considered drug related, that occurs after informed consent. Abnormal laboratory values or test results count as adverse events only when they induce clinical signs or symptoms, are considered clinically meaningful, require therapy, or require a change in study drug. A TEAE is an adverse event first reported or a pre-existing event that worsens after the first dose of study drug.

This endpoint is used to describe the observed safety experience during treatment. Counting participants with at least one qualifying event gives a participant-level summary; it is not the same as counting the total number of event episodes or measuring event severity, duration, or causality. A TEAE is defined by its timing in relation to study treatment, not by a determination that the drug caused it.

The stated analysis population is the Full Analysis Set, comprising enrolled participants who received at least one dose of INCAGN01949, nivolumab, or ipilimumab. The registry record identifies the measure and its definition, but a total count for this primary endpoint is not reported in the registry record in the registry record. The serious-event counts listed separately should not be substituted for the primary TEAE result: they describe serious adverse events and other listed safety categories, rather than a reported total for all TEAEs.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical details available for interpretation are limited. The record identifies a participant count as the primary Phase 1 measure and gives its definition, timeframe, and analysis population. The statistical analysis plan, the method for summarizing the primary endpoint, and any inferential model are not reported in the registry record.

What does a participant count represent?

In general, a participant-level binary outcome records whether each participant did or did not experience a defined event during the specified observation period. The result can be expressed as the number of participants with an event and the number assessed. This differs from an event count, since one participant may have more than one event. It also differs from a time-to-event measure, which uses information about when events occur and how long participants are followed.

The primary outcome is described as the number of participants with TEAEs. That is a count-based safety endpoint, but the registry entries do not include a reported primary-endpoint count. The serious adverse event and other adverse event figures are separate descriptive safety summaries. They should not be assumed to supply a missing all-TEAE endpoint value.

Why does the group structure matter?

In general, random allocation helps balance measured and unmeasured participant characteristics across treatment groups, on average. This study was non-randomized. As a result, even observed differences between groups cannot by themselves distinguish a treatment effect from differences in who entered each group, the treatment received, or other factors. The groups also include distinct combinations and doses, so they are not interchangeable controls.

The parallel-group label means the study included groups assigned to different treatment regimens rather than describing a single sequence for every participant. It does not make the groups randomized or establish that their results can be compared without adjustment. The adjustment methods, if any, are not reported in the registry record.

How should uncertainty be understood?

In general, a confidence interval is a range of values compatible with the observed data under a specified statistical method. It conveys uncertainty around an estimate; it does not guarantee that the true value lies in the interval, nor does it correct for design limitations such as non-random assignment. Confidence intervals for the safety counts are not reported in the registry record in the registry record. The small group sizes mean that a change in the experience of one participant can substantially change a group count, so the observed counts should be interpreted cautiously.

In general, over-dispersion occurs when variability in data exceeds what a chosen statistical model expects. It can make standard errors too small if ignored. The registry entries do not report an over-dispersion assessment or a model for these safety outcomes. Since the reported primary measure is a participant count rather than a continuous response, no distributional assumption for a continuous mean should be inferred from the endpoint description.

What do the planning illustrations mean?

In general, sample-size calculations estimate how many participants would be needed under stated assumptions to detect a specified effect with a chosen probability of statistical significance. The planning illustration associated with this study is described as using the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; its target effect is a stated fraction of the observed effect. The calculation is not the trial’s own design justification, and its assumptions do not describe the actual non-randomized, multi-group study. The numerical planning results are not reported in the registry record.

Such illustrations are not observed power. In general, observed power is not a substitute for an uncertainty interval or a clear presentation of the estimated effect. A planning calculation based on an observed effect is particularly dependent on the estimate used as its starting point. It should be treated as a hypothetical design aid, not as evidence that the completed study had a particular probability of detecting an effect.

For binary outcomes, the calculated participants-per-arm values depend on the assumed control and intervention event probabilities, the target difference, significance level, allocation, and analysis method. The stated illustration specifies some assumptions, but the exact effect fractions and resulting numeric sample sizes are not reported in the registry record. The record does not report that the completed trial had equal allocation between two arms; that condition belongs to the planning illustration only.

What cannot be inferred from the listed analyses?

The registry record reports no analyses in the registry record. A lack of a reported analysis does not show that no analysis was conducted; it means the analytic details and results are not reported in the registry record. No p-values, adjusted estimates, confidence intervals, or treatment-effect estimates should be inferred from the counts. The listed secondary outcomes establish that response, duration, disease control, and progression-free survival were measured or planned as outcomes, but they do not supply their findings.

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("Phase 1, Dose Escalation: INCAGN01949 70 mg + Nivo", "Phase 1, Dose Escalation: INCAGN01949 200 mg + Niv", "Phase 1, Dose Escalation: INCAGN01949 350 mg + Niv", "Phase 1, Dose Escalation: INCAGN01949 700 mg + Niv", "Phase 1, Dose Escalation: INCAGN01949 70 mg + Ipil", "Phase 1, Dose Escalation: INCAGN01949 200 mg + Ipi")
n      <- c(4, 4, 5, 5, 4, 5)
events <- c(4, 4, 5, 5, 4, 5)
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  Phase 1, Dose Escalation: INCAGN01949 70 mg + Nivo  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Phase 1, Dose Escalation: INCAGN01949 200 mg + Niv  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Phase 1, Dose Escalation: INCAGN01949 350 mg + Niv  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6
ARM  Phase 1, Dose Escalation: INCAGN01949 700 mg + Niv  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6
ARM  Phase 1, Dose Escalation: INCAGN01949 70 mg + Ipil  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Phase 1, Dose Escalation: INCAGN01949 200 mg + Ipi  5  5  100.0  47.8  100.0  56.6  100.0  54.1  99.6

11. Multiplicity, Missing Data and Analysis Populations

The study lists multiple outcomes, treatment groups, combinations, and doses. When many outcomes or comparisons are examined, the chance of obtaining an apparently notable result by chance can increase. In general, multiplicity procedures can control that risk by defining which comparisons are primary or by adjusting inference across multiple tests. The multiplicity strategy, if any, is not reported in the registry record. No claim about adjusted or unadjusted testing can be made in the registry record.

The registry record identifies the Phase 1 TEAE endpoint and the Full Analysis Set, defined as all enrolled participants who received at least one dose of INCAGN01949, nivolumab, or ipilimumab. Other analysis populations, such as a per-protocol or efficacy population, are not reported in the registry record. The record does not report how participants were handled in analyses if they discontinued, missed assessments, or had incomplete follow-up.

Missing-data methods are not reported in the registry record. In general, missing outcomes can affect interpretation if the likelihood of missingness is related to participant health, treatment, or outcome. Whether data were missing, how much was missing, and whether any imputation or sensitivity analysis was used are not reported in the registry record. The timeframe for the primary endpoint is up to 17.4 months, but the registry entries do not establish that every participant was observed for that full period.

Interim analyses, stopping rules, and the statistical analysis plan are not reported in the registry record. They should not be inferred from the Phase 1 dose-escalation and safety expansion labels. Those design descriptions identify study components, but do not state the formal statistical rules used to make decisions during the trial.

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: malignant neoplasm progression (50.0%), small intestinal obstruction (33.3%), adrenal insufficiency (25.0%), constipation (25.0%), dehydration (25.0%).

The Phase 1 safety figures record 28 of 52 participants as affected by serious adverse events, 52 of 52 as affected by other adverse events, and 33 deaths. The counts are descriptive and should be interpreted in their recorded categories. The serious adverse event group counts range from 1 to 4 affected participants, with 3 to 6 participants at risk in the listed treatment groups.

These figures do not show whether an event was judged related to a study drug. The relationship between the recorded deaths and study treatment is not reported in the registry record. Nor do the counts indicate how many event episodes occurred, how long events lasted, or their severity distribution. A participant count can include a person with more than one event, and the registry entries do not establish whether serious and other event categories were mutually exclusive.

The listed serious-event terms include malignant neoplasm progression at 50.0%, small intestinal obstruction at 33.3%, and adrenal insufficiency, constipation, dehydration, and dyspnoea at 25.0% each. The denominator and calculation basis for these percentages are not reported in the registry record. These terms and percentages are not, on their own, estimates of treatment-attributable risk. The small groups and non-randomized design also mean that comparisons between regimens are descriptive rather than controlled safety contrasts.

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

The results describe a Phase 1/2 investigation of INCAGN01949 as a single agent and in combinations with nivolumab and ipilimumab among people with advanced or metastatic malignancies. The posted safety counts show that adverse events were recorded in the Phase 1 groups, including serious events and deaths. They do not provide a randomized comparison, and they do not establish whether an event or death was caused by treatment.

The study’s primary endpoint is defined as the number of participants with TEAEs in Phase 1, through up to 17.4 months, in the Full Analysis Set. The total result for that endpoint is not reported in the registry record in the registry record. The serious-event figures offer related safety context but are not a substitute for the primary endpoint count.

The registry also lists objective response rate, duration of response, disease control rate, duration of disease control, and progression-free survival as secondary outcomes. Their numerical results are not reported in the registry record in the registry record. Therefore, the available information does not establish the magnitude or precision of any antitumor effect. It also does not support conclusions about comparative effectiveness among the different combinations or doses.

In general, a trial can generate useful descriptive information without supporting causal comparisons. Here, non-randomized assignment and small treatment groups limit how far group differences can be interpreted. The planned sample-size illustrations, which use an observed effect and stated assumptions, do not demonstrate that the study was adequately powered, and they are not observed power. A sample-size planning calculation cannot replace a reported effect estimate with uncertainty intervals.

The evidence described is consequently narrow: it records treatment exposure and safety observations in the study population, while leaving key comparative and efficacy questions unanswered. These limitations do not negate the observations; they define the scope within which they can be interpreted. The registry record does not report a basis for concluding that any regimen is better or worse than another.

14. Why This Trial Matters Statistically

This study is statistically notable for the questions its design and reporting raise, rather than for a randomized estimate of treatment effect. It evaluates multiple regimens and doses across Phase 1 dose escalation, safety expansion, and Phase 2 treatment groups. Such a structure can describe safety observations and explore outcomes across groups, but non-random allocation makes direct comparisons vulnerable to differences in participant composition and treatment assignment.

The group sizes are small: the listed Phase 1 groups have 3 to 6 participants at risk, while the total enrollment is 52. In general, estimates from small groups are imprecise, and each participant’s outcome can have a visible influence on a group count. The posted counts should therefore be understood as observations in these particular groups, not as stable estimates for a broader population.

The distinction between a time-defined adverse event and a treatment-caused adverse reaction is also important. TEAE classification depends on when an event occurs relative to first dose, whereas causality requires a separate judgment. The registry definition makes that distinction explicit. The reported death count, without attribution details, cannot be interpreted as a count of treatment-related deaths.

Finally, the study records several secondary outcomes that could address tumor response and disease control, but their results are not reported in the registry record in the registry record. For statistical interpretation, endpoint definitions and safety counts alone are not enough to assess efficacy. Estimates, uncertainty measures, analysis populations, and handling of missing data would be needed for a more complete assessment; these details are not reported in the registry record.

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.

The principal trial-specific limitation is the non-randomized design. Treatment groups are not like-for-like controls, so differences among their outcomes cannot be attributed to treatment without strong assumptions and appropriate analyses. The registry record does not report a randomized comparator or adjustment strategy. The Phase 1 groups also differ by combination, dose, or study component, complicating direct comparisons.

The listed group sizes are small, with 3 to 6 participants at risk per Phase 1 group. Counts in groups this small are highly sensitive to individual outcomes and provide limited precision. Although total enrollment was 52, those participants were distributed across multiple treatment groups; the registry record does not report the number enrolled in each Phase 2 group in the registry record.

The primary endpoint definition and population are stated, but its overall TEAE result is not reported in the registry record in the registry record. The available safety figures distinguish serious events, other events, and deaths, but do not report event attribution, severity distributions, event duration, or a complete account of recurrent events. The denominator and basis for the listed serious-event term percentages are not reported in the registry record.

Results for the listed response, disease-control, and progression-free survival outcomes are not reported in the registry record in the registry record. Also not reported are confidence intervals, the statistical analysis plan, multiplicity procedures, missing-data methods, interim analyses, and additional analysis populations. These omissions limit assessment of precision, robustness, and the extent to which the reported outcomes could be compared across groups.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study Exploring the Safety and Efficacy of INCAGN01949 in Combination With Immune Therapies in Advanced or Metastatic Malignancies — NCT03241173.
• Registry record last updated 2022-09-27; status last verified 2022-09.
• Results first posted 2022-09-27.
• 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

NCT03241173 is a completed Phase 1/2, non-randomized, unmasked, parallel study sponsored by Incyte Biosciences International Sàrl. It enrolled 52 participants with advanced or metastatic malignancies and investigated INCAGN01949 alone and in combinations with nivolumab and ipilimumab. The study began on 2017-10-09 and reached primary completion on 2019-09-17.

The Phase 1 primary endpoint was the number of participants with TEAEs, assessed through up to 17.4 months in the Full Analysis Set. The posted Phase 1 safety counts include 28 of 52 participants with serious adverse events, 52 of 52 with other adverse events, and 33 deaths. The registry record does not report the overall primary TEAE result, efficacy outcome results, or key statistical analysis details in the registry record. The non-randomized groups do not provide like-for-like control comparisons.