A Study of MK-6598 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-6598-001): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of MK-6598 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-6598-001) (NCT05594043), a non-randomized phase 1 study. The primary outcome is Number of Participants With a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) Version 5.0.

2. Clinical Question

3. Trial Design

This was a Phase 1, open-label, multicenter study of MK-6598 as monotherapy and with pembrolizumab in participants with advanced solid tumors. The registry record describes a non-randomized allocation and a sequential model. Enrollment was 39, and the study status is completed. The recorded study start was 2022-12-21 and the primary completion date was 2025-05-21.

Participants received daily MK-6598 at doses from 50-500 mg in the monotherapy groups, or from 50-250 mg in the combination groups. Combination treatment also included pembrolizumab 200 mg once every 21-day cycle. Treatment could last up to 35 cycles, described as up to approximately 24 months. Participants in monotherapy could be allowed to switch to combination treatment at the investigator's discretion and after consultation with the Sponsor. The registry lists separate switch-over groups, so those participants should not be treated as if they had been assigned to combination treatment from the outset.

The stated study purpose was to assess safety and efficacy and establish a preliminary recommended Phase 2 dose. The registry also lists pharmacokinetic and tumor phenylpyruvate concentration outcomes. The design is appropriate to read as an early-phase, dose-assessment study, not as a randomized comparison of treatment strategies. The registry record does not report the dose-escalation rules, the decision process for selecting a dose, or the rationale for the enrollment target. It also does not report whether interim analyses were planned.

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 7 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received at least 1 dose of study intervention and either completed Cycle 1 or experienced a DLT during Cycle 1

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 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) Version 5.0, measured over Up to approximately 21 days.

The primary endpoint was the number of participants with a dose-limiting toxicity, or DLT, during approximately 21 days. A DLT was defined using specified adverse-event severity grades and treatment interruptions, with criteria graded under National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. The definition included several types of severe hematologic and nonhematologic toxicity, as well as treatment-related events such as a delay in starting Cycle 2, discontinuation during Cycle 1, or missing more than 25% of MK-6598 doses during Cycle 1.

This is a binary participant-level endpoint: each eligible participant is classified according to whether a DLT occurred within the stated assessment period. In general, early-phase studies use DLT monitoring to describe short-term tolerability at tested doses and inform dose selection. This endpoint is not a complete measure of all later toxicity, and an absence of a DLT during the assessment window would not mean that no adverse events occurred at other times.

The specified analysis population included participants who received at least 1 dose and either completed Cycle 1 or experienced a DLT during Cycle 1. The registry record does not report the observed DLT count, the number analyzed, or an estimate of uncertainty for this primary endpoint. It therefore supplies the endpoint definition and analysis-population rule, but not the primary result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a participant count: whether a participant in the defined analysis population had a DLT during the assessment period. This differs from an outcome measured repeatedly over time or on a continuous scale. For a binary outcome, a typical summary is the number with the event alongside the number assessed. The registry record identifies the outcome type and the analysis-population rule, but does not report the primary count or its denominator. No event frequency can therefore be described for the primary endpoint.

What does the DLT window mean?

The endpoint covers approximately 21 days, corresponding to Cycle 1 in the record's definition. A fixed assessment window makes clear which events qualify for this early dose-assessment outcome. It also limits what the result would represent: events outside the window, or other aspects of tolerability not included in the DLT definition, are not captured by this endpoint. The record's DLT criteria include adverse-event severity, duration, clinically significant consequences, treatment interruption, and discontinuation. The criteria therefore define more than a simple count of any adverse event.

How should counts across dose groups be read?

In general, an event count is most informative alongside the number of participants assessed and a clear definition of who was eligible for analysis. Counts can be difficult to compare when group sizes differ. In this study, the design was non-randomized and sequential, and the registry cautions that arms are not like-for-like controls. A numerical difference between groups would not, by itself, estimate a causal effect of dose or combination treatment. Treatment assignment, dose, timing, and switch-over all matter to interpretation.

For serious adverse events, the registry lists counts at risk and counts affected by group. These are descriptive safety data, not randomized comparisons. The separate deaths field is likewise a group-level count. The registry record does not state in the registry record whether deaths were treatment-related, nor does a group count alone determine cause. Serious-event term percentages are listed, but their denominator and calculation basis are not reported in the registry record.

What can uncertainty measures tell readers?

In general, a confidence interval describes the range of values reasonably compatible with the observed data under the statistical method used. An interval is wider when data provide less precision and narrower when they provide more precision. A p-value, when used, measures how compatible the data are with a specified null model; it does not measure the probability that a treatment works or that the null hypothesis is true. The registry record does not report a confidence interval or p-value for the primary endpoint, so neither the uncertainty nor the statistical testing for that outcome can be evaluated.

The record notes 8 outcome measures and 7 analyses, but does not report the mapping between those analyses and outcomes in the registry record. It does not report the statistical methods for the primary endpoint, including whether estimates were adjusted or whether any formal comparisons were planned. The simple participant count is identifiable as the endpoint format, but the inferential analysis cannot be reconstructed from the record details.

What is the role of the planning illustration?

In general, sample-size planning asks how much information a future study might need to detect a specified effect under stated assumptions. The planning illustration described for this record uses a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the target effect is a stated fraction of the observed effect. Such calculations are planning illustrations, not evidence that the study had a particular probability of detecting an effect, and not a measure of the trial's observed power. The record does not report that these assumptions were the trial's own design assumptions or its sample-size justification.

The illustration is especially limited in relation to this study's design: treatment groups were not randomized, the registry cautions against treating arms as comparable controls, and the primary endpoint result is not reported in the record details. Without a clearly defined comparative estimate and its uncertainty, a planning calculation based on an observed effect should not be read as validating a treatment contrast. Its interpretation depends on the effect definition and assumptions stated with that calculation.

General statistical principles also caution against treating a small early-phase group as a definitive estimate of uncommon or delayed safety outcomes. A short DLT window can support assessment of early toxicities defined by protocol, while other safety outcomes may have different timing and definitions. The registry lists pharmacokinetic outcomes, tumor phenylpyruvate concentration, and other outcomes, but their observed results and analysis details are 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("50 mg MK-6598", "125 mg MK-6598", "250 mg MK-6598", "500 mg MK-6598", "50 mg MK-6598 + Pembrolizumab", "125 mg MK-6598 + Pembrolizumab")
n      <- c(3, 4, 3, 8, 6, 4)
events <- c(0, 0, 0, 0, 1, 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  50 mg MK-6598  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  125 mg MK-6598  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  250 mg MK-6598  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  500 mg MK-6598  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6
ARM  50 mg MK-6598 + Pembrolizumab  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  125 mg MK-6598 + Pembrolizumab  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 8 outcome measures and 7 analyses. The registry entries available do not explain how these analyses map to the outcomes, which outcome analyses were primary or secondary beyond the listed primary DLT measure, or whether any formal hypothesis tests were conducted. A multiplicity strategy for handling multiple outcomes or comparisons is not reported in the registry record.

In general, when a study tests multiple outcomes or contrasts, the chance of at least one apparently unusual result can increase unless the analysis plan accounts for multiplicity. Whether and how that issue applies depends on the planned inferential analyses. Here, the study is described as a non-randomized, sequential Phase 1 study; the registry record does not provide a statistical analysis plan or specify confirmatory hypotheses. No conclusion about multiplicity adjustment can be made.

The primary endpoint population is defined as participants who received at least 1 dose and either completed Cycle 1 or experienced a DLT during Cycle 1. That rule describes who was intended to be counted for the DLT endpoint. The record details do not report how many participants met the rule, how many had missing endpoint information, or how missing data were handled. Reasons for missingness and any sensitivity analyses are not reported in the registry record.

Other analysis populations, including populations used for pharmacokinetic or efficacy analyses, are not described in the registry record. The record does not state whether analyses were based on all enrolled participants, treated participants, or other defined groups for those outcomes. Because the primary outcome count and denominator are not reported, the result cannot be independently interpreted as a complete-case count or as an analysis using a particular missing-data method.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (50.0%), abdominal pain (40.0%), intestinal perforation (28.6%), enterocolitis infectious (25.0%), upper respiratory tract infection (25.0%).

The serious adverse event figures are descriptive counts by listed group. For example, the record reports 1 participant affected among 4 at risk in the 50 mg MK-6598 group, and 3 affected among 9 at risk in the 500 mg MK-6598 group. In the combination groups, it reports 4 affected among 7 at risk at 50 mg MK-6598 plus pembrolizumab, 4 among 6 at 125 mg, and 4 among 6 at 250 mg. The switch-over groups are listed separately: 0 affected among 3 at 50 mg and 2 among 5 at 125 mg.

These counts should not be treated as randomized comparisons. The registry describes sequential, non-randomized treatment groups, and the switch-over groups are distinct from groups that began combination treatment. The record also lists deaths by group, but does not establish that they were caused by treatment. The top serious-event terms include pneumonia at 50.0%, abdominal pain at 40.0%, intestinal perforation at 28.6%, enterocolitis infectious and upper respiratory tract infection at 25.0%, and tumour haemorrhage at 20.0%. The denominator for these term percentages is not reported in the registry record. Serious events and deaths warrant careful descriptive reading, not causal attribution from these figures alone.

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

The registry record establishes that this was a Phase 1 study of MK-6598 alone and with pembrolizumab in adults with advanced or metastatic solid tumors. It specifies dose ranges, treatment schedules, a DLT definition, and an analysis population for the primary endpoint. It also provides group-level serious adverse event counts. These details describe the study's scope and how its early safety outcome was defined.

The record details do not report the primary endpoint result. There is no observed DLT count or analysis denominator, and no reported estimate of uncertainty. Consequently, readers cannot determine from these registry entries how many participants experienced a DLT, how the event frequency varied by dose, or how precisely any frequency was estimated. The absence of a reported count is not evidence that no DLTs occurred.

The serious adverse event counts show that events were reported in the listed treatment groups. They do not, on their own, establish a treatment effect or allow a valid causal comparison among doses or regimens. Non-randomized sequential allocation and the possibility of switching from monotherapy to combination treatment make the groups unsuitable as like-for-like controls. The death counts likewise do not establish treatment attribution.

The registry states that the study aimed to assess efficacy and safety and establish a preliminary recommended Phase 2 dose. The registry entries available do not report efficacy outcomes or the dose selected. They also do not report the protocol's dose-selection rules, sample-size justification, interim analyses, or complete statistical analysis plan. The record therefore supports a description of the design and its stated questions, but not a conclusion about efficacy, comparative benefit, a recommended dose, or the precision of the primary endpoint.

In general, a Phase 1 dose-assessment study can inform later research by characterizing tolerability under specified conditions. Its findings should be read in light of the tested groups, short DLT observation window, endpoint definition, and limitations in reported results. The registry record alone does not answer whether a regimen is effective or establish that one dose is safer than another.

14. Why This Trial Matters Statistically

This study raises several statistical issues that are important in early-phase clinical research. The primary endpoint is a defined short-window DLT count, which makes the endpoint directly relevant to dose assessment but only represents events meeting the criteria during the stated period. The criteria combine toxicity grade, duration, clinical consequences, and treatment disruption, so interpretation depends on both the event definition and the population assessed.

The non-randomized, sequential design is central to reading the groups. A dose cohort is not automatically a control for another cohort, and a switch-over group is not equivalent to a group that started combination therapy. This matters because a simple contrast of group counts could conflate treatment differences with differences in timing, cohort composition, or the decision to switch. The registry itself warns against treating the arms as like-for-like controls.

Reporting the analysis denominator, event count, and uncertainty would be essential for understanding how informative the primary endpoint is. Those primary results are not reported in the registry entries. This gap prevents assessment of both the observed DLT frequency and its precision. It also illustrates why a complete outcome record matters: endpoint definitions and trial aims cannot substitute for outcome estimates.

The record also includes serious adverse event counts and term percentages, but these are descriptive and do not resolve questions of causation or comparative risk. For later development, the relationship among dose, early DLTs, other safety outcomes, pharmacokinetics, and any efficacy findings would be relevant. The registry entries do not report the results needed to assess those relationships or the process used to select a preliminary recommended Phase 2 dose.

Statistically, the trial is therefore informative as a design and endpoint description, while its posted outcome information in the registry record is insufficient for a quantitative interpretation of the primary question. That distinction helps separate what the study set out to assess from what can be concluded from the 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 main limitation for interpreting the primary endpoint is that the registry entries do not report its observed count, denominator, estimate, or uncertainty interval. Although the primary endpoint and its analysis population are defined, the result itself cannot be assessed. The registry record also does not report the number of participants who completed Cycle 1 or experienced a DLT during Cycle 1.

The study was non-randomized and sequential, and the registry cautions that its arms are not like-for-like controls. Doses and treatment combinations differed, and participants receiving monotherapy could be allowed to switch to combination treatment. The registry entries do not describe the selection process for switching or provide an adjustment strategy for differences between groups. Group contrasts should therefore not be interpreted as causal comparisons.

The DLT assessment window was approximately 21 days. By definition, that endpoint does not represent all later adverse events or every aspect of safety. The serious adverse event data are listed by group, but the record details do not provide event timing, causal attribution, or the denominator underlying the percentages for the top serious-event terms. Death counts are reported without information establishing whether deaths were treatment-related.

The registry entries do not report efficacy results, the selected preliminary recommended Phase 2 dose, the dose-escalation or dose-selection rules, sample-size justification, interim analyses, multiplicity handling, or missing-data methods. Statistical details for the listed secondary outcomes are also not reported. These omissions limit assessment of the study's estimates, precision, and analysis decisions; they should not be filled in by assuming standard practices.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study of MK-6598 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Advanced Solid Tumors (MK-6598-001) — NCT05594043.
• Registry record last updated 2026-07-15; status last verified 2026-06.
• Results first posted 2026-07-15.
• 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

NCT05594043 is a completed Phase 1, open-label, multicenter, non-randomized, sequential study of MK-6598 as monotherapy and with pembrolizumab in participants with advanced or metastatic solid tumors. Enrollment was 39. The recorded start date was 2022-12-21, and the primary completion date was 2025-05-21.

The primary outcome was the number of participants with a DLT during approximately 21 days, using National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0. The record details define the endpoint and its analysis population but do not report the primary outcome count or denominator. Serious adverse event counts and deaths are listed by group; they are descriptive and do not establish treatment causation or comparative effects.

The registry describes the study aim as assessing efficacy and safety and establishing a preliminary recommended Phase 2 dose. Efficacy results, dose-selection results, and key statistical analysis details are not reported in the registry record.