CD40 Agonistic Antibody APX005M (Sotigalimab) in Combination With Nivolumab: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for CD40 Agonistic Antibody APX005M (Sotigalimab) in Combination With Nivolumab (NCT03123783), a non-randomized phase 1, phase 2 study. The primary outcome is Phase 2 Evaluate the Objective Response Rate (ORR) by RECIST 1.1 and iRECIST in Each Cohort / Group.

2. Clinical Question

The study was intended to assess safety and efficacy of the combination, with the Phase 1 portion also intended to establish the maximum tolerated dose and recommended Phase 2 dose of APX005M with nivolumab. These are stated study aims, not results. The registry record does not report whether those dose-selection aims were met. The Phase 2 question is descriptive for each listed cohort: it concerns the observed response proportion under the combination, rather than a treatment effect relative to a concurrent control. Without cohort-level response estimates and their uncertainty, the primary question cannot be answered from the posted information.

3. Trial Design

This is a completed, open-label Phase 1-2 study with non-randomized allocation and a sequential model. The registry records enrollment of 140. The study began on 2017-07-10, and the primary completion date is 2020-11-16. The stated status is completed. These registry entries describe the study record; they do not provide a comparison of outcomes between randomized treatment groups.

In Phase 1b, APX005M was escalated across dose levels of 0.03 mg/kg, 0.1 mg/kg, and 0.3 mg/kg, each in combination with nivolumab 360 mg every 3 weeks. The brief summary describes this stage as a dose-escalation study intended to establish the maximum tolerated dose and recommended Phase 2 dose. The registry record does not report the escalation rules, dose-limiting toxicity definition, or the decision process used to select a dose.

Phase 2 used expansion cohorts at APX005M 0.3 mg/kg with nivolumab 360 mg every 3 weeks. Cohort 1 comprised immunotherapy-naïve, metastatic or locally advanced NSCLC. Cohort 2 comprised metastatic melanoma progressing during anti-PD-1/PD-L1 treatment. Cohort 3 addressed metastatic or locally advanced NSCLC progressing during anti-PD-1/PD-L1 treatment and was divided into groups A and B according to prior best response or duration of stable disease. The adverse-event listings identify the corresponding NSCLC and melanoma groups, including Cohort 3A and Cohort 3B.

Because allocation was non-randomized and masking was absent, differences across dose levels or cohorts may reflect their different eligibility and disease-history profiles as well as treatment. No concurrent randomized control is listed. The registry record does not report a statistical analysis plan, sample-size justification, interim-analysis plan, or detailed enrollment by cohort. The posted study structure supports describing each group, but not treating between-group contrasts as randomized 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.

Before assignment: For the phase 2 cohorts 1,2,3A,3B, a total of 133 participants were enrolled in 4 cohorts to receive APX005M at 0.3 mg/kg (RP2D) plus nivolumab at 360 mg IV. Three subjects who were treated at the RP2D in the Phase 1b dose-escalation portion of the study were included in Phase 2 of the relevant disease-specific cohort. The study enrollment was completed as planned and all primary and secondary outcome measures and adverse events were collected even though the study was ended by the sponsor.

Only the first 6 of 7 groups are shown.

Phase 1b

Reasons for not completing this period:

Phase 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants in the safety population who received at least 1 dose of study drug in the escalation cohorts (APX005M 0.03 mg/kg + nivolumab; APX005M 0.1 mg/kg + nivolumab; APX005M 0.3 mg/kg + nivolumab)

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: Phase 1b: immunotherapy naïve metastatic or locally advanced NSCLC (inNSCLC) or unresectable or metastatic melanoma (MM) Phase 2: Cohort 1/inNSCLC, Cohort 2/unresec or MM that progressed during treatment with anti-PD-1/PD-L1, Cohort 3/PD1-NSCLC metastatic or locally advanced NSCLC not amenable to curative treatment that progressed during prior treatment with anti-PD-1/PD-L1. Cohort 3A: best response of PD or with SD \<16 wks, Cohort 3B includes PD1-NSCLC with tumor response or with SD ≥ 16 wks.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Phase 2 Evaluate the Objective Response Rate (ORR) by RECIST 1.1 and iRECIST in Each Cohort / Group, measured over From start of the treatment (Day 1) until disease progression, withdrawal of consent, death, initiation of any anticancer therapy, lost to follow-up, or termination by the Sponsor, whichever comes first (for Phase 2: maximum up to 27 months).

The primary endpoint is the objective response rate (ORR), expressed as the percentage of participants in each Phase 2 cohort or group whose best overall response is complete response (CR) or partial response (PR). The registry describes assessment by imaging and gives RECIST 1.1 criteria: CR involves disappearance of target and non-target lesions; PR involves a decrease greater than 30% in the sum of the longest diameters of target lesions, without progression in non-target lesions or new lesions. The endpoint title names both RECIST 1.1 and iRECIST, while the detailed definition posted in the record explains RECIST 1.1. Further operational details for iRECIST are not reported in the registry record.

ORR is a binary participant-level outcome: each assessed participant is classified as having or not having an objective response under the chosen criteria. The resulting proportion summarizes the frequency of observed tumor shrinkage meeting the response definition. It does not, by itself, describe how long a response lasts, whether disease control is sustained, or how outcomes compare with an untreated or randomized control group. The record separately lists duration of response, median progression-free survival, and the 6-month progression-free survival rate among secondary outcomes.

The stated assessment period begins on Day 1 and continues until one of the listed stopping events, with a Phase 2 maximum of up to 27 months. The registry record does not give the cohort response percentages or their confidence intervals, so the magnitude and precision of the primary endpoint cannot be assessed from these registry entries.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a proportion: the number of assessed participants meeting the response definition relative to the relevant assessed group. The registry defines response as CR or PR and reports the outcome unit as percentage of participants. As a general statistical concept, a proportion is a compact summary of a binary outcome. Its interpretation depends on a clear definition of who was assessed, how response was evaluated, and which participants form the denominator. Those analysis details are not reported in the registry record.

What does the confidence interval describe?

The endpoint specifies a 90% confidence interval. In general, a confidence interval expresses the uncertainty associated with an estimate under the statistical method used. It is not a guarantee that the true value lies within the particular interval, and it does not replace the point estimate. A relatively broad interval indicates less precision than a narrow one. The registry record does not provide the interval bounds or identify the interval calculation method, so the precision of any cohort response estimate cannot be evaluated.

For a binary outcome, the precision of a proportion is affected by the number of participants with evaluable outcomes and by the observed response frequency. A percentage alone, without its denominator and interval, can conceal substantial uncertainty. Here, the registry lists an aggregate enrollment of 140, but does not give the number assessed for the primary endpoint in each cohort or group. The enrollment figure should therefore not be substituted for a cohort-specific analysis denominator.

Why does the response definition matter?

Response classification depends on imaging assessments and prespecified criteria. The registry’s RECIST 1.1 description distinguishes complete response from partial response and sets a threshold for reduction in target-lesion measurements while also considering non-target lesions and new lesions. Applying a consistent definition helps make response counts interpretable within a study. The endpoint title also names iRECIST, but detailed iRECIST criteria, confirmation procedures, assessment schedules, and adjudication arrangements are not reported in the registry record. The effect of those details on classification cannot be assessed.

The primary endpoint is based on best overall response over the stated assessment period. This captures whether a participant met the response definition at any qualifying assessment in that period, but it does not convey response duration. A response may be brief or sustained; duration of response is separately listed as a secondary outcome. The record also lists progression-free survival outcomes, which address a different aspect of disease course. The primary response endpoint and those time-to-event outcomes should not be treated as interchangeable.

What can a non-randomized design establish?

Random allocation is used in general to support comparability of treatment groups by balancing, on average, known and unknown prognostic factors. This study is registered as non-randomized and has no masking. Its dose-escalation groups and disease-specific expansion cohorts were assembled under different eligibility conditions. Therefore, a contrast between cohorts is descriptive and may be confounded by differences in cancer type, prior therapy, or clinical status. The registry record does not report an adjusted comparative analysis that could address such differences, and it lists no randomized control arm.

Open-label status means treatment assignment was not masked in the registry description. For an imaging-defined endpoint, assessment procedures and review practices can matter. The record does not report whether response was assessed by independent reviewers, whether scans were centrally reviewed, or how disagreements were handled. These omissions do not demonstrate that assessments were biased; they mean the available information cannot establish how those potential sources of variation were managed.

What is not available about the analysis?

The registry lists 0 analyses. It does not report a statistical analysis plan, a missing-data strategy, definitions of analysis populations, or a multiplicity procedure for assessing responses across cohorts and response criteria. Those omissions leave unanswered whether the primary analysis was prespecified in detail, how participants without an evaluable assessment were handled, and how interpretation across multiple groups was intended to be controlled.

Planning illustrations based on an observed effect are not observed trial results. The registry gives general assumptions for such illustrations, including a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect defined as a fraction of the observed effect. However, no calculated sample-size illustration values are included in the registry record. In general, sample-size planning describes design scenarios; it does not show that the study had a particular probability of detecting an effect after the study has been conducted. No observed-power claim can be drawn from the available information.

Over-dispersion is a general concern when variation in outcome counts exceeds what a simple model assumes. It can make model-based uncertainty too small if the extra variability is ignored. The endpoint is a participant-level binary response proportion, and the registry record does not identify a count model or report a model-based analysis. There is therefore no basis to claim that over-dispersion was present or that a particular correction was used. More broadly, statistical explanations of possible methods should not be mistaken for methods actually documented for this study.

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 (Arm)/inNSCLC (Phase 2)", "Cohort 2(Arm)/PD1-MM (Phase 2)", "Cohort 3A(Arm)/PD1-NSCLC (Phase 2)", "Cohort 3B(Arm)/PD1-NSCLC (Phase 2)")
n      <- c(48, 33, 12, 25)
events <- c(8, 5, 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 (Arm)/inNSCLC (Phase 2)  48  8  16.7  7.5  30.2  8.7  29.6  8.8  29.7
ARM  Cohort 2(Arm)/PD1-MM (Phase 2)  33  5  15.2  5.1  31.9  6.7  30.9  6.8  31.1
ARM  Cohort 3A(Arm)/PD1-NSCLC (Phase 2)  12  0  0.0  0.0  26.5  0.0  24.2  0.2  24.7
ARM  Cohort 3B(Arm)/PD1-NSCLC (Phase 2)  25  0  0.0  0.0  13.7  0.0  13.3  0.1  13.2

11. Multiplicity, Missing Data and Analysis Populations

The primary endpoint is assessed across multiple Phase 2 cohorts or groups, and its title refers to RECIST 1.1 and iRECIST. The registry record does not report whether these assessments were treated as separate hypotheses, whether a primary cohort or response criterion was prioritized, or whether any adjustment for multiple comparisons was planned. Without that information, it is not possible to determine how the risk of false-positive findings across multiple assessments was handled. This limitation is especially relevant if readers later compare response estimates across groups or criteria; the registry entries do not provide a stated inferential framework for such comparisons.

The record does not report the analysis populations for the primary endpoint. It also does not state how missing scans, withdrawals, deaths before response assessment, or unevaluable outcomes were handled in ORR calculations. These are important because the estimated percentage depends on which participants are included in the denominator and how an absent assessment is classified. No missing-data assumptions or sensitivity analyses are reported in the registry record.

The endpoint description gives a maximum Phase 2 period of up to 27 months and lists several events that can end follow-up, including progression, withdrawal of consent, death, initiation of other anticancer therapy, loss to follow-up, or sponsor termination. It does not specify how follow-up ending for these reasons affected the primary response analysis. The registry lists secondary outcomes, but their analysis populations and missing-data methods are not reported. With no analysis records listed, multiplicity handling, missingness assumptions, and population definitions remain unclear.

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: pyrexia (33.3%), pneumonia (33.3%), sepsis (33.3%), optic ischaemic neuropathy (33.3%), acute kidney injury (33.3%).

The serious adverse-event listings report, for each group, the number at risk and the number affected by serious events, along with deaths. These are group-specific counts. The registry also lists selected serious-event terms and percentages, including pyrexia, pneumonia, sepsis, optic ischaemic neuropathy, acute kidney injury, and cardiac arrest. The percentages are reproduced as recorded; the registry entries do not provide enough detail to independently establish their precise event-level denominators or whether terms can overlap within a participant.

Counts should be read in the context of the group definitions and their sizes. The escalation arms are small groups as listed, while the Phase 2 cohorts have different populations and eligibility histories. Some Phase 2 group descriptions explicitly include data from participants in the 0.3 mg/kg dose-escalation group. These features mean that apparent differences in counts or percentages are not randomized safety comparisons. They should not be interpreted as showing that one dose or cohort is safer than another.

The listed deaths are reported as a count in each group; the registry information does not establish their cause or relationship to study treatment. Nor does the adverse-event summary alone establish event timing, duration, severity grading beyond the serious-event classification, or individual clinical circumstances. The figures describe what the record lists and should not be treated as a complete causal assessment of safety.

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

The registry record describes a study designed to examine APX005M with nivolumab in adults with NSCLC or metastatic melanoma. It specifies a Phase 1 dose-escalation aim and Phase 2 expansion cohorts, along with an ORR endpoint based on complete or partial response. Those details establish what the study set out to assess and how the primary endpoint was defined in the record.

They do not provide the cohort-level response percentages or 90% confidence intervals. Accordingly, the available information cannot establish the observed frequency of response in any cohort or the precision of that frequency. Listing an endpoint is not the same as reporting its result. Likewise, the listed secondary outcome names do not supply numerical evidence about duration of response or progression-free survival.

The design does not support a randomized comparison between the combination and a control treatment. Non-randomized cohorts with distinct cancers and prior-treatment histories cannot be treated as if they were comparable by design. Even if outcome estimates were available, differences across those cohorts would be descriptive unless supported by an appropriate comparative analysis and its assumptions. Such an analysis is not reported in the registry record.

The adverse-event counts are informative as recorded safety summaries, but do not by themselves establish causation, comparative safety, or the clinical context of each event. The registry does not report all the information needed to assess event timing, participant-level overlap, or the relationship of deaths to treatment.

In short, the registry entries characterize the trial’s structure, registered objective, and selected safety listings, but not its primary efficacy results. They cannot support a conclusion that the combination does or does not produce a treatment benefit, nor can they determine how its effects compare with another treatment. These are limits of the information recorded, not conclusions about results that are absent from the record.

14. Why This Trial Matters Statistically

This study is statistically notable for the way it combines dose escalation with disease-specific expansion cohorts. That structure can generate information about dosing and describe outcomes in selected populations, but it does not provide the balance created by random allocation. Interpretation therefore depends heavily on keeping dose-escalation descriptions, cohort-specific summaries, and causal comparisons distinct.

The primary endpoint is a familiar clinical-trial measure, ORR, defined through imaging-based response criteria. Its meaning depends on consistent assessment and transparent reporting of response counts, denominators, and uncertainty. The registry identifies a 90% confidence interval but does not include the estimates needed to judge precision. This illustrates why endpoint definitions and results must be read together: a clear definition alone cannot show the magnitude or reliability of an observed response rate.

The multiple Phase 2 groups also make analysis planning important. Cohorts differ by cancer type and treatment history, while the endpoint title names two response frameworks. Without a reported multiplicity strategy, analysis populations, and missing-data rules, readers cannot determine how the study intended to interpret results across those assessments. The registry records 0 analyses, so these statistical details are not available in the listed record.

The safety listings provide a separate reminder that event counts need context. Serious-event summaries can describe events within groups, but non-randomized group differences do not isolate treatment effects. A statistically careful reading distinguishes the descriptive information that is recorded from conclusions that would require comparative design, complete outcome reporting, and a stated analysis approach.

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.

Several trial-specific limitations constrain interpretation. The study is open-label and non-randomized, with no control arm listed. Its dose-escalation arms and expansion cohorts serve different purposes and include populations with different cancers and prior treatment histories. Consequently, cross-group comparisons cannot be interpreted as randomized estimates of treatment effects.

The registry reports aggregate enrollment of 140 but does not report the number assessed for the primary endpoint in each cohort, cohort-specific ORR counts, or the corresponding 90% confidence intervals. It is therefore not possible to assess response magnitude, precision, or how many participants contributed to each endpoint estimate. The record’s primary population description for Cohort 3 is incomplete, ending with “not amenable to curative treat”; the full eligibility wording is not reported in the registry record.

Outcome ascertainment details are also limited. The endpoint title names RECIST 1.1 and iRECIST, but the detailed definition describes RECIST 1.1. The record does not report the iRECIST implementation, independent review procedures, assessment schedule, or handling of unevaluable imaging. Missing-data rules, analysis populations, and a statistical analysis plan are not reported.

The registry lists serious adverse events and deaths by group, but does not report event timing, treatment relatedness, or enough information to verify all event-level denominators. Some group descriptions include data from dose-escalation participants, further limiting simple comparisons. Finally, although the record lists secondary outcomes, their numerical results are not included in the registry record. These reporting gaps limit both efficacy and safety interpretation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: CD40 Agonistic Antibody APX005M (Sotigalimab) in Combination With Nivolumab — NCT03123783.
• Registry record last updated 2023-12-26; status last verified 2023-12.
• Results first posted 2023-12-05.
• 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

The registry record identifies NCT03123783 as a completed Phase 1-2, open-label, non-randomized, sequential study of APX005M with nivolumab in NSCLC and metastatic melanoma. The Phase 1b portion used dose escalation; Phase 2 used expansion cohorts defined by cancer type and treatment history. The recorded enrollment is 140, and the primary completion date is 2020-11-16.

The Phase 2 primary outcome is ORR by RECIST 1.1 and iRECIST, reported as a percentage with a 90% confidence interval. The detailed definition describes complete and partial response under RECIST 1.1. Cohort-level response results and confidence intervals are not reported in the registry record. Secondary outcomes include safety, duration of response, median progression-free survival, and the 6-month progression-free survival rate, but numerical results for these outcomes are not included in the registry record used for this account.

Serious adverse-event counts and selected event terms are listed by group. The non-randomized design and differing cohort populations prevent like-for-like causal comparisons. The registry lists 0 analyses and does not report the statistical plan, analysis populations, missing-data methods, or multiplicity handling.