Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC) (MK-7690-046): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC) (MK-7690-046) (NCT03631407), a randomized phase 2 study. The primary outcome is Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1).

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group phase 2 trial of vicriviroc combined with pembrolizumab in participants with advanced or metastatic MSS colorectal cancer. Random allocation means participants were assigned to one of the two dose groups, while open-label means the registry lists no masking. The groups differed in the daily vicriviroc dose: 150 mg in one arm and 250 mg in the other. Both arms used pembrolizumab 200 mg on Day 1 of each 21-day cycle, and treatment could continue for up to 35 cycles.

The registry reports enrollment of 41 participants and a completed trial. The listed start date is 2018-09-24, and the primary completion date is 2021-06-08. The primary endpoint analysis population is described separately: participants had to have received at least 1 dose of study treatment and have a baseline scan with measurable disease per investigator assessment. The result for each arm lists 20 participants. The reason for the difference between the reported enrollment and endpoint analysis counts is not reported in the registry record.

The primary endpoint was objective response rate (ORR) according to RECIST 1.1, assessed by the investigator. The registry also lists ORR using iRECIST, progression-free survival using RECIST 1.1 and iRECIST, overall survival, and pharmacokinetic measures for vicriviroc. The available record describes both the trial structure and the endpoint definitions, but does not report a detailed sample-size justification, an interim-analysis plan, or a complete statistical analysis plan. Details of concealment procedures, stratification, and protocol deviations are not reported in the registry record.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis population consisted of all participants who received at least 1 dose of study treatment, and had a baseline scan with measurable disease per investigator's assessment per RECIST 1.1.

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.

6. Primary Endpoint

The registry lists the primary outcome as Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1), measured over Up to ~32 months.

The primary endpoint, objective response rate, is the percentage of participants who experienced a complete response or a partial response. Under the registry’s RECIST 1.1 definition, a complete response means disappearance of all target lesions, while a partial response requires at least a 30% decrease in the sum of the diameters of target lesions. The investigator assessed response, and the stated timeframe was up to ~32 months.

ORR is a binary outcome at the participant level: each participant either met the response definition or did not. It gives a direct summary of the proportion with a documented tumor response under the specified assessment criteria. It does not describe how long a response lasted, how long participants lived without progression, or overall survival; those are separate outcomes listed in the registry.

The primary analysis used the population that received at least 1 dose of study treatment and had measurable disease on a baseline scan, according to investigator assessment. That restriction matters when interpreting the estimates: they apply to the defined response-evaluable group, not automatically to every person enrolled. The endpoint is a measure of observed response frequency in each arm, not by itself a comparison with an untreated group or a basis for attributing any response to one component of the combination.

7. Results Posted in the Registry

• Vicriviroc QD at Dose Level 2 (250 mg) + Pembrolizumab (200 mg): 5.0% (1/20) versus 5.0% (1/20) on control; risk difference 0.0 percentage points (95% CI -13.5 to 13.5), risk ratio 1.00 (0.07–14.90); unadjusted two-proportion z-test p = 1.000.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors 1.1 for Immune-based Therapeutics (iRECIST)

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Vicriviroc QD at Dose Level 2 (250 mg) + Pembrolizumab (200 mg): 5.0% (1/20) versus 5.0% (1/20) on control; risk difference 0.0 percentage points (95% CI -13.5 to 13.5), risk ratio 1.00 (0.07–14.90); unadjusted two-proportion z-test p = 1.000.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Vicriviroc QD at Dose Level 2 (250 mg) + Pembrolizumab (200 mg) and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists secondary outcomes spanning response by iRECIST, progression-free survival by RECIST 1.1 and iRECIST, overall survival, and vicriviroc pharmacokinetic measures. The structured results include an iRECIST ORR estimate of 5.0% in each arm, with 20 participants per arm and a 95% confidence interval from 0.1% to 24.9% in each. This pattern is descriptively aligned with the primary RECIST 1.1 result: the reported response proportions match across the dose groups under both response criteria.

The registry record does not report numerical results for the listed progression-free survival, overall survival, or pharmacokinetic outcomes in the information available for these results. Their presence as outcomes does not establish what those analyses found. The registry also does not report a detailed interpretation of how the response assessments under RECIST 1.1 and iRECIST were reconciled or whether assessment differences affected conclusions.

Secondary outcomes can help describe other aspects of a trial, but they do not automatically strengthen the primary result. Each outcome may use a different definition, follow-up period, analysis population, or statistical method. Multiple outcome analyses also create more opportunities for apparently notable results to occur by chance when no adjustment or prespecified hierarchy is applied. Whether such adjustments or a testing hierarchy were planned is not reported in the registry record.

The secondary response result should therefore be understood as another descriptive estimate with the same basic limitation: sparse response events and broad uncertainty. It is not independent confirmation in the sense of evidence from a separate trial, because it comes from the same participants and study. The listed time-to-event and pharmacokinetic outcomes could address distinct questions, but their numerical findings and analysis details are not reported in the registry record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Objective Response Rate (ORR) Based on Modified Response Evaluation Criteria in Solid Tumors 1.1 for Immune-based Therapeutics (iRECIST)
• Progression-Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST 1.1)
• PFS Based on Modified Response Evaluation Criteria in Solid Tumors 1.1 for Immune-based Therapeutics (iRECIST)
• Overall Survival (OS)
• Plasma Area Under the Concentration Time-Curve From 0 to 8 Hours (AUC 0-8hrs) of Vicriviroc
• Maximum Observed Plasma Concentration (Cmax) of Vicriviroc
• Trough Plasma Concentration (Ctrough) of Vicriviroc

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary: each participant either had a complete or partial response under RECIST 1.1 or did not. For a binary outcome, an arm-specific percentage is the observed proportion meeting the definition in that arm. The registry reports an ORR of 5.0% for each arm, with 20 participants in each analysis group and one response in each. The percentage describes the observed sample; uncertainty remains about the response proportion that would be seen in a wider population.

What does a confidence interval express?

A confidence interval is a way to show the statistical uncertainty around an estimate. In general, a narrower interval indicates greater precision, while a wider interval indicates less precision. A 95% confidence interval is generated by a procedure that, over repeated comparable sampling under its assumptions, would cover the underlying quantity at the stated rate. It does not mean there is a 95% probability that the fixed underlying value lies within this particular interval.

The registry states that the primary ORR was estimated and analyzed using the Clopper-Pearson interval. This is an exact binomial interval method commonly used for a proportion, particularly when event counts are small. The reported 95% intervals are 0.1% to 24.9% in both arms. Their width conveys that the observed response proportion is not estimated precisely. The interval does not account for every possible source of uncertainty, such as differences in assessment practices or departures from the analysis population definition.

How should the comparison be read?

The record reports a risk difference for the comparison of the 250 mg arm with the 150 mg arm. A risk difference expresses the difference between the two proportions on an additive scale. Its reported estimate is 0.0. The confidence interval extends both below and above zero, so values consistent with the data include differences in either direction. The interval is not narrow enough to establish that any underlying difference is negligible, and the registry record does not give a prespecified equivalence or non-inferiority margin.

The reported p-value is unadjusted and equals 1.0. In general, a p-value measures how compatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, nor does it measure the size or clinical importance of a difference. A high p-value does not prove that two treatments are identical. The specific details of the comparison test beyond the reported unadjusted result are not reported in the registry record.

What does randomization contribute?

Random allocation is intended to reduce systematic differences between groups at the point of assignment. It supports a comparative interpretation of outcomes, but does not guarantee that groups will be balanced on every characteristic, especially in a small trial. The registry identifies the allocation as randomized and the model as parallel. Details about the randomization sequence, allocation concealment, or stratification are not reported in the registry record. Since masking is listed as none, investigators and participants were not described as blinded to assigned group; further details about who knew treatment assignment are not reported.

Both arms received pembrolizumab, and the assigned vicriviroc dose differed. Consequently, the randomized comparison concerns the two combination regimens. It does not isolate the effect of either drug, and it does not compare the combinations with pembrolizumab alone, vicriviroc alone, or a placebo arm. The record lists no such additional group.

Why do small event counts matter?

When only a small number of participants meet a binary endpoint, each individual outcome has a substantial influence on the observed proportion. General statistical reasoning therefore expects greater uncertainty than would usually occur with many observations, all else equal. In this trial, the registry reports one response in each arm. The matching point estimates should be interpreted alongside the broad confidence intervals rather than as evidence of precise equality.

Over-dispersion is a general concept in which observed variation exceeds what a simple statistical model expects. It can matter for some count and clustered-data analyses, but the primary endpoint is reported as a binary proportion with a Clopper-Pearson interval. The registry record does not report an over-dispersion adjustment for this endpoint, and the posted data do not justify adding one to the analysis.

What can planning calculations establish?

General sample-size calculations describe planning scenarios under stated assumptions; they are not observed power. The record describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It also states that the effect to detect is a stated fraction of the observed effect. The record does not report the trial’s own sample-size justification, and planning illustrations cannot be used to claim that the trial had a particular probability of detecting an effect after the results were observed.

The registry’s description of the analysis method is limited. Information about the test specification, missing-data procedures, protocol-defined analysis sets beyond the stated primary population, multiplicity control, interim analyses, and adjustment for covariates is not reported in the registry record. Those omissions make it harder to assess how closely the posted results follow the planned analysis.

11. Confidence Intervals and Precision

Precision is limited for the primary response estimates. Both arms have a point estimate of 5.0%, with a 95% confidence interval from 0.1% to 24.9%. The intervals are identical as reported, and each arm’s analysis includes 20 participants. One response was recorded in each arm. With so few events, the point estimates alone should not be treated as stable or exact estimates of the response proportions in a broader population.

The interval endpoints span a wide range of possible response proportions. The lower endpoint is close to zero, while the upper endpoint is substantially higher than the point estimate. In general, this width signals that the data are compatible with a range of underlying response rates. The interval method reported for the endpoint is Clopper-Pearson, which is designed for binomial proportions and can be useful when event counts are small. Its use does not remove the basic uncertainty created by limited observations.

The estimated risk difference is 0.0, while its confidence interval extends in both directions around zero. That pattern does not demonstrate no difference; it indicates that the observed sample cannot tightly locate the difference between the arm-level response rates. The unadjusted p-value of 1.0 likewise should not be read as proof of equivalence. No equivalence margin or non-inferiority criterion is reported in the registry record.

These intervals quantify sampling uncertainty under the statistical method, but do not encompass all limitations. They do not resolve uncertainty about missing or excluded participants, the representativeness of the analysis population, the effect of open-label assessment, or the applicability of the results beyond this trial. Those issues require information not reported in the registry record.

12. Multiplicity, Missing Data and Analysis Populations

The registry identifies a primary endpoint and lists several secondary outcomes, including response under a second set of criteria, two progression-free survival measures, overall survival, and pharmacokinetic measures. Testing or estimating many outcomes raises a general multiplicity concern: when many comparisons are considered, some results may appear notable by chance. A prespecified hierarchy or statistical adjustment can help define how evidence across outcomes should be interpreted. Whether either approach was used is not reported in the registry record.

The posted primary comparison is described as unadjusted. The record does not state whether the primary hypothesis was the only formally tested comparison, whether secondary analyses were exploratory, or whether any family-wise error or false-discovery procedure was planned. It also does not report interim analyses or a stopping rule. These details matter when interpreting p-values across multiple outcomes, but their absence does not change the descriptive arm-specific response estimates.

The primary analysis population is defined as participants who received at least 1 dose and had measurable disease on a baseline scan according to investigator assessment. This definition clarifies who contributes to the endpoint estimate, but the record does not explain how participants who lacked a qualifying scan, did not receive treatment, or had other unavailable assessments were handled. Specific missing-data methods, censoring rules for time-to-event outcomes, and sensitivity analyses are not reported in the registry record.

Enrollment is reported as 41, while the primary endpoint results list 20 participants in each arm. The record does not explain how participants moved from enrollment to the endpoint analysis population, or whether any participants were excluded from that analysis and why. This limits the ability to assess possible selection effects and to reproduce the analysis population from the registry information alone.

The endpoint description gives the response definition, assessment method, analysis population, timeframe, and interval method. A fuller statistical analysis plan, including covariate adjustment, treatment of protocol deviations, and handling of missing outcomes, is not reported in the registry record. These omissions should be kept distinct from the results themselves: they limit methodological assessment but do not permit assumptions about what the investigators did.

13. 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: abdominal pain (10.0%), blood bilirubin increased (10.0%), atrial fibrillation (5.0%), hyperthyroidism (5.0%), visual field defect (5.0%).

The safety summaries list serious adverse events among 12 of 20 participants in the 150 mg arm and 10 of 20 in the 250 mg arm. Other adverse events are listed for 14 of 20 and 19 of 20 participants, respectively. The registry also reports 19 deaths in the lower-dose arm and 17 in the higher-dose arm. These are counts in the safety groups; the record does not provide a causal attribution for the deaths or establish that they were due to study treatment.

The listed serious adverse event terms include abdominal pain and blood bilirubin increased, each reported at 10.0%, and atrial fibrillation, hyperthyroidism, visual field defect, and dysphagia, each reported at 5.0%. These terms and percentages describe reported events. They should not be interpreted as proof that a particular treatment caused an event, nor do they provide details about severity, timing, duration, recurrence, or relatedness beyond the registry’s serious-event classification.

Counts from small safety groups can be informative descriptions, but are imprecise and may not capture uncommon events. The registry record does not provide enough detail to compare event duration, exposure-adjusted rates, or treatment attribution. The safety figures therefore describe what was recorded in these groups without establishing a causal difference between dose levels.

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

The result means that, in the defined primary analysis population, the investigator-assessed ORR was 5.0% in each vicriviroc plus pembrolizumab arm. The response assessment used RECIST 1.1, and each arm included 20 participants with one response. The 95% confidence intervals are broad, from 0.1% to 24.9% in both arms, so the estimates are imprecise. The reported risk difference is 0.0, and the unadjusted p-value is 1.0.

These findings do not prove that the two dose regimens have identical response rates. A zero observed difference can occur even when the underlying rates differ, particularly when few outcomes are observed. The confidence interval for the comparison extends in both directions around zero, and the record reports no equivalence or non-inferiority margin. The result therefore does not establish that either dose is equivalent to the other.

The trial compares two combination regimens, not vicriviroc against no vicriviroc or pembrolizumab against no pembrolizumab. Any response observed cannot be attributed separately to one component using this design. Nor does the response endpoint establish response duration, progression-free survival, or overall survival. Although those outcomes are listed in the registry, their numerical results are not reported in the record information.

The result also does not establish how the regimens would perform outside the trial population. The primary analysis included participants with measurable baseline disease who received at least 1 dose, and the endpoint results list 20 participants per arm. The record does not explain the relation between these analysis counts and total enrollment of 41. Generalization is limited by the small analysis groups and by the information not reported about participant characteristics and assessment procedures.

In general, statistical evidence should be considered together with the design, endpoint definition, precision, and missing methodological details. The posted data support a cautious description of the observed response proportions and uncertainty. They do not support a definitive claim that one dose is superior or that the two combinations have the same effect. No treatment recommendation follows from these registry results.

15. Why This Trial Matters Statistically

This trial is statistically informative as an example of how a randomized comparison can still yield uncertain estimates when the endpoint is rare and the analyzed groups are small. Each arm had 20 participants and one response. The matching 5.0% point estimates are easy to compare, but the broad confidence intervals show why the point estimates alone should not carry the interpretation.

The design also illustrates the distinction between comparing regimens and isolating treatment components. Randomization supports a comparison of the two vicriviroc dose levels within the pembrolizumab combination. Because both arms received pembrolizumab and the record lists no single-agent or untreated group, the comparison cannot separate the contribution of each drug.

The endpoint definition and analysis population are central to interpreting the result. The response rate concerns participants with measurable baseline disease who received at least 1 dose, rather than necessarily everyone enrolled. The registry reports enrollment of 41 and endpoint results for 20 participants in each arm, but does not explain that relationship. This makes transparent reporting of participant flow and analysis-set decisions particularly important.

Finally, the registry lists multiple secondary outcomes while reporting limited numerical results and limited information about multiplicity, missing data, and the analysis plan. This highlights why outcome listings, estimates, uncertainty, and prespecified statistical procedures each contribute different information. A statistically careful reading keeps the primary result descriptive, recognizes its imprecision, and avoids treating unreported analyses as evidence for or against a conclusion.

16. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary result rests on 20 participants per arm and one response in each arm. The broad 95% confidence intervals indicate substantial uncertainty. The record reports enrollment of 41, but does not explain the analysis counts, participant flow, or reasons any enrolled participants may not have contributed to the primary endpoint.

The trial is open-label, and response was assessed by the investigator. The registry does not report whether independent review was used, how assessments were adjudicated, or what procedures were applied to reduce assessment bias. Allocation is identified as randomized, but sequence generation, concealment, stratification, and other implementation details are not reported in the registry record.

The primary comparison includes two active combination regimens with different vicriviroc doses. No arm in the record isolates either drug’s contribution, and no placebo or single-agent comparator is listed. Thus, the design does not answer whether either component alone accounts for observed responses.

The registry lists secondary outcomes but does not provide numerical results for several listed outcomes in the available record information. Details of follow-up, censoring, missing-data handling, multiplicity control, interim analyses, and a complete statistical analysis plan are not reported. These gaps limit assessment of the full set of analyses and the robustness of conclusions beyond the primary descriptive result.

The endpoint is response under RECIST 1.1, with a stated timeframe of up to ~32 months. The registry record does not give further detail about the timing of each assessment or the distribution of follow-up. The available information therefore supports interpretation of the reported response proportions, but not a detailed evaluation of response duration or the time course of outcomes.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Safety and Efficacy of Vicriviroc (MK-7690) in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic Microsatellite Stable (MSS) Colorectal Cancer (CRC) (MK-7690-046) — NCT03631407.
• Registry record last updated 2024-11-21; status last verified 2024-11.
• Results first posted 2022-06-07.
• 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.

20. Record Summary

NCT03631407 is a completed randomized, open-label, parallel-group phase 2 trial sponsored by Merck Sharp & Dohme LLC. It enrolled 41 participants with advanced or metastatic MSS colorectal cancer. The listed start date is 2018-09-24, and the primary completion date is 2021-06-08.

The trial compared vicriviroc 150 mg or 250 mg daily, each combined with pembrolizumab 200 mg on Day 1 of 21-day cycles. The primary endpoint was investigator-assessed ORR using RECIST 1.1. Each arm’s reported ORR was 5.0%, based on 20 participants and one response, with a 95% confidence interval from 0.1% to 24.9%. The reported risk difference was 0.0, with an unadjusted p-value of 1.0.

The registry lists additional response, survival, and pharmacokinetic outcomes. Numerical results for several of these outcomes, as well as details of missing-data handling, multiplicity procedures, and the complete statistical analysis plan, are not reported in the registry record.