Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma: (NCT02348008), a non-randomized phase 1, phase 2 study. The primary outcome is Overall Response Rate.

2. Clinical Question

3. Trial Design

This is a completed, open-label, multi-institutional study with phase Ib and phase II components. The brief description identifies a single-arm dose-escalation phase Ib cohort followed by a phase II cohort of MK-3475 combined with bevacizumab. The registry record lists enrollment of 61. The study started in 2015-03 and has a primary completion date of 2019-12-05.

In phase Ib, the study uses dose escalation. The phase II description says that the maximum safe dose of MK-3475 in combination with bevacizumab, as determined in the phase Ib cohort, is given on day 1 of each 21-day cycle. The phase Ib description includes dosing details for the first cohort, but the record truncates the description of the next cohort. Further dosing details are therefore not reported in the registry record.

Allocation is non-randomized, masking is none, and the model is single group. The record explicitly says there is no randomization or blinding. These features matter when interpreting response and safety findings: the study is not designed to estimate a randomized treatment contrast, and open-label assessment can be susceptible to knowledge of treatment. The endpoint refers to RECIST 1.1 response criteria, but details of independent review or other assessment safeguards are not reported in the registry record.

The registry lists progression-free survival, overall survival, clinical benefit rate, and adverse-event characterization as secondary outcomes. It lists 6 outcome measures and no analyses. The record states that results for Arm A, the phase Ib cohort, are reported as a single group, with no per-group analyses planned or performed. The protocol’s sample-size justification, interim-analysis plan, and detailed statistical analysis plan 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:

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: No per-group analysis was completed in the dose escalation cohort because the Phase IB dose-finding study found no dose-limiting toxicities and the primary objective (determine MTD) was satisfied. The baseline demographics as presented have been presented in several abstracts and published in the Journal of Clinical Oncology.

6. Primary Endpoint

The registry lists the primary outcome as Overall Response Rate, measured over Every 6 weeks while on treatment (estimated 10 months).

Overall response rate is the percentage of participants whose best qualifying response is complete or partial response. Under the registry’s RECIST 1.1 definitions, complete response means disappearance of all target lesions. Partial response requires at least a 30% decrease in the sum of the longest diameters of target lesions, using the baseline sum as reference. The endpoint is assessed every 6 weeks while participants are on treatment, over an estimated timeframe of 10 months.

A response-rate endpoint gives a direct summary of tumor response under the specified criteria. It reduces each participant’s assessment to whether a complete or partial response occurred, then expresses the count as a proportion of the relevant participant group. Its interpretation depends on which participants are included, how response assessments are handled, and how missing assessments are treated. Those analysis details are not reported in the registry record.

The endpoint description also defines progressive disease and stable disease. Progressive disease includes at least a 20% increase in the sum of target-lesion longest diameters from the smallest sum recorded since treatment started, or the appearance of one or more new lesions. Stable disease is neither sufficient shrinkage for partial response nor sufficient increase for progressive disease, using the stated reference. These categories clarify how response status is distinguished, but they are not counted as responses in the primary endpoint definition.

The registry record does not report the observed overall response rate, the number of complete or partial responses, or the 95% confidence interval. The endpoint definition alone therefore does not establish the magnitude or precision of the study’s response findings.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a response proportion describe?

Overall response rate is a binary-outcome summary. Each participant is classified according to whether a complete or partial response occurred under RECIST 1.1, and the result is expressed as a percentage of participants in the analysis group. A proportion is easy to interpret, but its meaning depends on the definition of response and the denominator. The registry defines complete and partial response, but the primary response count and denominator used for the reported analysis are not reported in the registry record.

Binary outcomes discard some detail: they distinguish response from no response, while stable disease and progressive disease are not included in the primary response numerator. This does not make the endpoint invalid; it means the result answers a particular question rather than describing every possible change in disease status. The registry lists clinical benefit rate as a secondary outcome, but its precise definition and result are not reported in the registry record.

How should a confidence interval be read?

A confidence interval communicates uncertainty around an estimate. For a response proportion, it indicates the range of values reasonably compatible with the observed data under the interval’s statistical assumptions. A wider interval indicates less precision, while a narrower interval indicates greater precision. The registry identifies the primary endpoint’s dispersion measure as a 95% confidence interval, but does not report the interval itself or the method used to calculate it.

A confidence interval is not a guarantee that the true value lies within its limits, and it does not correct for bias in study design or outcome assessment. In a single-group, open-label study, a precise estimate would still be a description of the observed group, not a randomized estimate of the treatment’s comparative effect. Precision and causal interpretation are distinct issues.

Why does the single-group design matter?

Random allocation helps make groups comparable, on average, by distributing measured and unmeasured characteristics across treatment assignments. This study is non-randomized and single-group, so it has no concurrent control arm for that purpose. Changes in observed outcomes may reflect treatment, participant characteristics, disease course, assessment decisions, or other factors. A within-study response proportion cannot separate those explanations by itself.

Open-label status means masking is absent. Knowledge of treatment can influence some aspects of clinical care and outcome assessment. The endpoint uses RECIST 1.1 criteria, which provides defined response categories, but the registry does not report whether review was independent or centrally assessed. Such assessment details are not reported in the registry record.

What is known about the analysis populations?

The registry says that results for Arm A, the phase Ib cohort, are reported as a single group and that no per-group analyses were planned or performed. It does not give the primary endpoint analysis population, explain whether all enrolled participants were included in that analysis, or describe how participants without evaluable response assessments were handled. Enrollment of 61 should not automatically be treated as the denominator for every outcome.

For a binary endpoint, missing outcome data can affect both the numerator and denominator, depending on the analysis rule. Excluding participants without assessments, treating them as non-responders, or using another approach can yield different interpretations. The method used is not reported in the registry record. The record also does not describe the handling of withdrawals, treatment discontinuation, or assessment timing deviations.

What do the planning illustrations represent?

Planning illustrations based on an observed effect are not the trial’s original design justification and are not observed power. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect set as a stated fraction of the observed effect. For time-to-event outcomes, the illustration concerns the total number of events; for other outcomes, it concerns participants per arm.

Those assumptions describe a hypothetical planning exercise, not the actual single-group trial design. The record does not report the trial’s own sample-size justification, the effect size assumed when planning the trial, or any protocol-based power calculation. An illustration based on an observed effect is conditional on that observed effect and should not be read as evidence that the study had a particular probability of detecting a true effect.

What can be inferred from the analysis listing?

The registry lists 6 outcome measures and no analyses. That means the available record does not supply analysis-specific estimates or test results for interpretation. The absence of a listed analysis is not evidence that no analysis was conducted outside the registry; it means the analysis details are not reported in the registry record. The statistical plan, including any model choices, covariate adjustment, interim analyses, or multiplicity procedures, is not reported in the registry record.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("Arm A - Phase 1b Dose Escalation Cohort", "Arm B - Phase II Investigational Treatment")
n      <- c(13, 48)
events <- c(5, 29)
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  Arm A - Phase 1b Dose Escalation Cohort  13  5  38.5  13.9  68.4  17.7  64.5  17.7  64.9
ARM  Arm B - Phase II Investigational Treatment  48  29  60.4  45.3  74.2  46.3  73.0  46.2  73.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists overall response rate as the primary outcome and names progression-free survival, overall survival, clinical benefit rate, and adverse-event characterization as secondary outcomes. It also reports 6 outcome measures. When a study evaluates multiple outcomes, multiple statistical tests or estimates can raise the chance of a chance-positive finding if results are selected or interpreted without a prespecified approach. Methods such as defining a testing hierarchy or adjusting significance thresholds can address particular multiplicity concerns, but the registry does not report a multiplicity strategy. It is therefore not possible to tell whether or how the study controlled for multiple comparisons.

Missing-data handling is also important for the primary response proportion. Participants may lack an evaluable assessment, but the record does not report whether this occurred or how it was handled. The response-analysis denominator, rules for participants who discontinued treatment, and any imputation or non-responder convention are not reported in the registry record. These choices can affect the interpretation of a proportion and its confidence interval.

The registry states that Arm A phase Ib results are reported as a single group, with no per-group analyses planned or performed. It does not describe the analysis population for the primary endpoint, or whether the phase II cohort and phase Ib cohort were combined for any outcome. The record lists no analyses, and the detailed statistical analysis plan is not reported in the registry record. It would be inappropriate to infer an intention-to-treat, per-protocol, or other analysis population from the enrollment count alone.

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: adrenal insufficiency (8.2%), pneumonitis (4.9%), acute kidney injury (3.3%), dyspnea (3.3%), gastrointestinal disorders (3.3%).

The registry’s All Subjects group reports 61 participants at risk for serious adverse events and 32 affected. For other adverse events, it reports 61 at risk and 60 affected. The registry also reports 28 deaths. These counts describe the group-level safety summary and should not be interpreted as a randomized comparison or as rates adjusted for treatment exposure.

The listed serious adverse-event terms and percentages are adrenal insufficiency, 8.2%; pneumonitis, 4.9%; acute kidney injury, 3.3%; dyspnea, 3.3%; gastrointestinal disorders, 3.3%; and hypercalcemia, 3.3%. These are the top serious terms reported in the registry record. The record does not provide further details on event timing, duration, severity grading, recurrence, or attribution. It also does not state whether participants could be counted under more than one term.

The death count is reported without cause or treatment attribution in the available record. It should not be assumed that every death was related to treatment, nor that the count establishes a comparative safety effect. The figures are descriptive summaries; the registry record does not report enough detail to interpret individual events or compare safety with another group.

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

The study addresses a defined clinical research question: the activity of MK-3475 with bevacizumab in first-line therapy for treatment-naïve metastatic clear cell renal cell carcinoma, using RECIST 1.1 complete or partial response as the primary endpoint. The registry gives the endpoint definition and assessment timeframe, and identifies the phase Ib dose-escalation component followed by phase II treatment at the maximum safe combination dose determined in phase Ib.

The registry record does not report the primary response estimate, response count, or confidence interval. Thus, it does not allow a reader to judge the observed response proportion or how precisely it was estimated. Listing an outcome as primary does not supply its result. Likewise, the registry’s listing of progression-free survival, overall survival, and clinical benefit rate does not establish their findings.

The single-group, non-randomized, open-label design means the study does not provide a direct randomized comparison. Even if an outcome estimate were available, it would describe the study group and would not, on its own, establish what would have happened under an alternative treatment or no study treatment. This distinction is particularly important when interpreting response and safety summaries.

The safety counts and serious-event terms provide descriptive information for the All Subjects group. They do not establish causation, comparative risk, or the timing and clinical course of individual events. The registry’s 28 deaths are not accompanied by attribution details in the available record.

The statistical meaning is therefore bounded by the information reported: the trial structure and endpoint definitions are available, and selected aggregate safety summaries are listed, but key efficacy estimates and several analysis details are not reported in the registry record. The record supports describing how the study was organized and what it intended to measure; it does not support a numerical conclusion about the primary response result or a comparative treatment effect.

14. Why This Trial Matters Statistically

The statistical importance of this trial lies partly in the distinction between a clearly defined endpoint and a reported endpoint result. Overall response rate is specified as the primary outcome, with complete and partial response defined by RECIST 1.1. Yet the estimate and its confidence interval are not reported in the registry record. Statistical interpretation requires both an outcome definition and the observed data used to estimate it.

The study also illustrates why design features shape the questions that results can answer. A single-group, non-randomized study can describe outcomes in its participants, but does not produce a like-for-like randomized contrast. Open-label conduct and the absence of a control group are relevant context when considering how outcomes were assessed and what alternative explanations remain possible.

The phase Ib dose-escalation component and phase II cohort serve different roles in the study structure. The phase II description relies on the maximum safe combination dose determined during phase Ib. The record says that phase Ib results are presented as a single group without per-group analyses. These details matter when considering whether outcomes from the study components can be interpreted together; the registry does not explain a combined analysis approach.

Finally, the registry’s safety summaries demonstrate the difference between counts and a full safety analysis. Counts of participants affected and listed event terms are informative descriptions, but without timing, exposure, attribution, or comparative data they do not answer every question about risk. The protocol’s statistical plan, sample-size justification, missing-data methods, and multiplicity approach are not reported in the registry record. Recognizing these gaps is part of a sound statistical reading, rather than a reason to infer methods that are not documented.

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 efficacy is that the registry record does not report the primary overall response-rate result, the response count, or the 95% confidence interval. It also does not report the results for the listed secondary outcomes. The endpoint definitions and outcome names alone cannot establish what was observed.

The trial is non-randomized, single-group, and open-label, with no concurrent control comparison. This limits causal interpretation and prevents a direct randomized estimate of relative benefit or harm. The record does not report whether response assessments were independently reviewed. The endpoint refers to RECIST 1.1, but that criterion alone does not resolve possible assessment differences.

Important analytic details are absent. The primary endpoint analysis population, denominator, missing-assessment rules, handling of treatment discontinuation, and approach to incomplete follow-up are not reported in the registry record. The detailed statistical analysis plan, multiplicity procedures, interim-analysis plan, and the trial’s own sample-size justification are also not reported.

The phase Ib dose-escalation description is incomplete in the registry record: the description of the second cohort is truncated. The record identifies a phase II cohort using the maximum safe combination dose determined in phase Ib, but does not provide all operational details needed to reconstruct dose escalation or treatment exposure. The safety summary does not report event timing, exposure-adjusted rates, event attribution, or the causes of the reported deaths. These gaps limit interpretation of both the efficacy and safety information.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma: — NCT02348008.
• Registry record last updated 2022-09-14; status last verified 2022-08.
• Results first posted 2020-07-31.
• 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

NCT02348008 is a completed, open-label, multi-institutional phase Ib and phase II study of MK-3475 combined with bevacizumab for clear cell renal carcinoma. It is non-randomized and single-group, with enrollment of 61. The primary endpoint is overall response rate by RECIST 1.1, assessed every 6 weeks while on treatment, with an estimated timeframe of 10 months.

The registry record lists progression-free survival, overall survival, clinical benefit rate, and adverse-event characterization as secondary outcomes. It reports aggregate safety counts for All Subjects, including 32 affected by serious adverse events and 28 deaths. It does not report the primary response estimate, confidence interval, detailed statistical analysis plan, or several key analysis and missing-data procedures.