This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Pembrolizumab With or Without Axitinib for Clear Cell Kidney Cancer in Patients Undergoing Surgery (NCT04370509), a non-randomized phase 2 study. The primary outcome is Proportion of Participants With >= 2-fold Increase in the Number of Tumor-infiltrating Immune Cells (TIICs).
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT04370509 |
| Phase | Phase 2 |
| Condition | Metastatic Clear Cell Renal Cell Carcinoma, Recurrent Clear Cell Renal Cell Carcinoma, Stage III Renal Cell Cancer AJCC v8 |
| Allocation | Non-Randomized |
| Design model | Parallel |
| Masking | None (open label) |
| Enrollment | 6 |
| Arms in the primary outcome | n/a |
| Lead sponsor | University of California, San Francisco |
| Results posted | Yes |
2. Clinical Question
Population
The study concerned people with locally advanced or metastatic clear cell renal cell carcinoma who were undergoing surgery. The registry lists metastatic and recurrent clear cell renal cell carcinoma, stage III and stage IV renal cell cancer, and clear cell renal cell carcinoma among the conditions. The registry record does not report detailed eligibility criteria or characteristics of the enrolled participants.
Intervention
The study examined perioperative pembrolizumab-based treatment. Cohort A received pembrolizumab before cytoreductive nephrectomy or metastasectomy. Cohort B was described as receiving pembrolizumab with axitinib, a VEGF tyrosine kinase inhibitor. The registry describes pembrolizumab as an antibody that blocks PD-1 and axitinib as a drug that blocks tyrosine kinases.
Comparator
The registry describes two non-randomized cohorts, not randomized treatment groups. The study was not a like-for-like control comparison. Its brief summary mentions usual treatment as surgery followed by chemotherapy and/or radiation therapy, but a separate concurrent control cohort is not reported in the registry record.
Primary question
The planned primary question was whether the proportion of participants whose tumor specimens showed at least a 2-fold increase in tumor-infiltrating immune cells from before to after pembrolizumab-based treatment could be determined. The registry says this analysis could not be completed because laboratory experiments were not funded after the collaborating sponsor terminated the study prematurely. Therefore, the primary endpoint does not provide an estimate of the treatment-associated change.
3. Trial Design
This was a phase II, parallel, non-randomized study with no masking. The registry records an enrollment of 6 and lists the study status as terminated. The start date was 2021-02-09, and the primary completion date was 2025-02-28. These dates do not change the registry's statement that the study was terminated.
The planned treatment was given before cytoreductive nephrectomy or metastasectomy. Cohort A was pembrolizumab monotherapy: the description specifies 200mg intravenously on day 1 of each 21-day cycle, for up to 3 cycles. Surgery was described as occurring within 14-21 days after treatment. The description for Cohort B specifies pembrolizumab with axitinib, including axitinib 5mg by mouth twice daily on days 1-42 of each cycle; the registry's arm description is incomplete, so further scheduling detail is not reported in the registry record.
Because allocation was non-randomized, the cohorts should not be interpreted as balanced treatment groups created by chance. Differences between them could reflect who entered each cohort or other factors, not just the treatment received. The registry explicitly cautions that the arms are not a like-for-like control comparison. A usual-care control group is not reported in the registry record. The planned study question was therefore about perioperative pembrolizumab-based treatment and tissue immune changes, rather than a randomized estimate of comparative benefit.
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: The study was closed to enrollment by the sponsor before enrollment in Cohort B was made available to participants. Therefore, no participants could be enrolled in Cohort B.
Overall Study
| Stage | Cohort A (Pembrolizumab Monotherapy) | Cohort B (Pembrolizumab + VEGF-TKI) |
|---|---|---|
| STARTED | 6 | 0 |
| Completed Cytoreductive Nephrectomy (CN) or Metastasectomy (MET) | 5 | 0 |
| Received 1 Year of Pembrolizumab | 4 | 0 |
| COMPLETED | 4 | 0 |
| NOT COMPLETED | 2 | 0 |
Reasons for not completing this period:
| Reason | Cohort A (Pembrolizumab Monotherapy) | Cohort B (Pembrolizumab + VEGF-TKI) |
|---|---|---|
| Adverse Event | 1 | 0 |
| Did not receive post-op Pembrolizumab | 1 | 0 |
Analysis population for the primary outcome, as defined in the registry: The analysis for this endpoint could not be completed due to insufficient funds for the laboratory experiments to determine the number of tumor-infiltrating immune cells (TIICs), when the collaborating sponsor (Merck Sharp and Dohme) terminated the study prematurely. Therefore, no plans currently exist to fund analysis of this endpoint in the future.
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: The study was closed by the sponsor to further enrollment before Cohort B was open for accrual.
| Characteristic | Unit | Cohort A (Pembrolizumab Monotherapy) | Cohort B (Pembrolizumab + VEGF-TKI) | Total |
|---|---|---|---|---|
| Participants analysed | 6 | 0 | 6 | |
| Age, Customized: 40-49 years old | Participants | 1 | 0 | 1 |
| Age, Customized: 50-59 years old | Participants | 1 | 0 | 1 |
| Age, Customized: 60-69 years old | Participants | 1 | 0 | 1 |
| Age, Customized: 70-79 years old | Participants | 3 | 0 | 3 |
| Sex: Female, Male: Female | Participants | 2 | 0 | 2 |
| Sex: Female, Male: Male | Participants | 4 | 0 | 4 |
| Ethnicity (NIH/OMB): Hispanic or Latino | Participants | 2 | 0 | 2 |
| Ethnicity (NIH/OMB): Not Hispanic or Latino | Participants | 2 | 0 | 2 |
| Ethnicity (NIH/OMB): Unknown or Not Reported | Participants | 2 | 0 | 2 |
| Race (NIH/OMB): American Indian or Alaska Native | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Asian | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): Native Hawaiian or Other Pacific Islander | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): Black or African American | Participants | 0 | 0 | 0 |
| Race (NIH/OMB): White | Participants | 3 | 0 | 3 |
| Race (NIH/OMB): More than one race | Participants | 1 | 0 | 1 |
| Race (NIH/OMB): Unknown or Not Reported | Participants | 1 | 0 | 1 |
| Region of Enrollment: United States | participants | 6 | — | 6 |
6. Primary Endpoint
The registry lists the primary outcome as Proportion of Participants With >= 2-fold Increase in the Number of Tumor-infiltrating Immune Cells (TIICs), measured over Baseline to cytoreductive nephrectomy (CN)/metastasectomy (MET), up to 1 year.
| Element | Registry entry |
|---|---|
| Result type | N/A |
| Measure of spread | not applicable |
| Unit | not stated |
| Endpoint classification | not reduced to a single comparison |
The primary endpoint was the proportion of participants with at least a 2-fold increase in the number of tumor-infiltrating immune cells (TIICs) in tumor specimens from before to after pembrolizumab-based treatment. The specified timeframe ran from baseline to cytoreductive nephrectomy or metastasectomy, up to 1 year. The endpoint description says that TIICs were to be analyzed in pre- and post-treatment tumor specimens.
In general, a proportion endpoint expresses how many participants meet a defined response criterion relative to the relevant analysis group. Here, the criterion was a change in a tissue-based immune-cell measure, not a measure of tumor shrinkage, survival, or quality of life. In general, measuring immune cells in paired specimens can be used to investigate whether treatment is accompanied by a biological change in the tumor environment. Such a change, by itself, would not establish a clinical benefit.
The registry states that the endpoint analysis could not be completed because there were insufficient funds for the laboratory experiments needed to determine TIIC numbers after the collaborating sponsor terminated the study prematurely. No endpoint estimate or uncertainty interval is reported in the registry record. Consequently, the primary endpoint describes the intended measurement, not a result from the study.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The central statistical result is the absence of a completed primary endpoint analysis. The planned outcome was the proportion of participants with at least a 2-fold increase in tumor-infiltrating immune cells, but the laboratory measurements needed to calculate that proportion were not completed. The registry attributes this to insufficient funds for the experiments after the collaborating sponsor terminated the study prematurely. There is therefore no reported estimate for this primary question to interpret.
The registry records enrollment of 6, but that number alone does not establish how many participants contributed usable data to any particular endpoint. Participant flow by cohort, treatment received, surgery completed, specimen availability, and endpoint eligibility is not reported in the registry record. The registry also records no analyses. Estimates for objective response, disease-free survival, progression-free survival, and median survival are not reported in the registry record, despite those outcomes being listed as secondary outcomes.
The trial was non-randomized and unmasked. Even if outcome estimates were available, a comparison between its cohorts would not have the protection against confounding that random allocation can provide. Differences in prognosis, clinical circumstances, or other characteristics could be associated with cohort assignment and outcomes. The registry specifically says the arms are not a like-for-like control comparison. No causal claim about the relative effects of pembrolizumab alone and pembrolizumab with axitinib follows from the design description.
Safety information is reported for Cohort A. The registry lists 6 participants at risk for serious adverse events, with 4 affected, and 6 at risk for other adverse events, with 6 affected; deaths are recorded as 0. It also lists serious-event terms with percentages. These are descriptive safety records, not a comparative safety estimate: a corresponding Cohort B safety summary is not reported in the registry record. Event figures in a small study are imprecise descriptions of the recorded participants and do not, on their own, establish how often an event would occur in a broader population.
In general, an estimate should be read together with its uncertainty and the population from which it was calculated. Here, no primary endpoint estimate, confidence interval, or efficacy analysis is reported in the registry record. The study's termination and incomplete laboratory work limit what can be learned from its planned biological endpoint. The posted information supports describing the design, the incomplete endpoint work, and the recorded Cohort A safety data; it does not support a treatment-effect conclusion.
9. Statistical Methods Explained
Several design and analysis concepts help clarify what the registry record can and cannot establish. The study is described as phase II, parallel, non-randomized, and unmasked. Those labels describe the intended study structure; they do not substitute for completed outcome analyses.
What does non-randomized allocation mean?
In general, random allocation uses chance to assign participants to treatment groups. This can reduce systematic differences between groups, including differences that investigators may not have measured. In a non-randomized study, assignment does not have that protection. People in different cohorts may differ in clinical characteristics or circumstances that are also related to outcomes. If outcome estimates are compared, those differences can make it difficult to distinguish treatment associations from other explanations. The registry itself states that these arms are not a like-for-like control comparison.
Parallel describes groups receiving their assigned study approaches during the same overall study, rather than the same participant receiving each approach in sequence. It does not imply randomization or comparability. Unmasked means masking is listed as none; the registry does not report a blinded treatment or outcome-assessment process. The registry record does not report further details about allocation procedures or adjustments to account for potential differences between cohorts.
What would the primary proportion represent?
The planned endpoint classifies participants according to whether the number of TIICs in tumor specimens increased by at least 2-fold from before to after treatment. In general, a proportion is a summary of how many individuals meet a defined criterion among those included in an analysis. To interpret it, readers need to know how many participants had the necessary specimens, how the cells were measured, and which participants were included in the denominator. The registry describes the specimen comparison but does not report those analysis details or a calculated proportion. It says the laboratory work could not be completed, so the endpoint cannot be interpreted as an observed treatment response.
In general, confidence intervals describe the range of values reasonably compatible with an estimate under the statistical model. They communicate uncertainty that a point estimate alone cannot show. No confidence interval for the primary endpoint is reported in the registry record. No primary endpoint result is reported at all, so there is no estimate whose precision can be assessed.
Why do missing specimens and incomplete analyses matter?
General statistical principle: an analysis of available specimens may not represent everyone enrolled if specimen availability is related to health status, surgery, treatment, or other factors. Missing outcome measurements can therefore affect both the denominator and the interpretation. The registry states that the TIIC laboratory experiments were not completed, but it does not report participant-level specimen availability, reasons for missing measurements beyond the stated funding issue, or a plan for handling missing endpoint data. These details are not reported in the registry record.
The registry lists secondary outcomes including objective response rate, disease-free survival, progression-free survival, median survival measures, and treatment-related adverse events. Listing an outcome is not the same as reporting an estimate. The registry records no analyses, and the outcome estimates and their statistical uncertainty are not reported in the registry record. Analysis populations, endpoint-specific denominators, censoring rules, and any adjustments are also not reported in the registry record.
What does multiplicity mean in general?
When a study evaluates multiple outcomes or several time points, the chance of finding at least one apparently notable result can increase if each is assessed separately. Multiplicity methods can address that issue, but the appropriate approach depends on the planned hypotheses and analysis strategy. A multiplicity plan is not reported in the registry record. Because no analyses are recorded, there are no reported hypothesis tests to assess for multiplicity.
The registry-associated planning assumptions describe illustrations based on a stated fraction of an observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. Time-to-event illustrations are described in terms of total events, while other illustrations are described in participants per arm. These are planning assumptions, not observed trial results or evidence of achieved power. The registry record does not report a sample-size justification for the actual study, and the posted information does not provide outcome estimates on which to base a trial-specific planning interpretation.
In general, a planning calculation estimates the sample size needed under chosen assumptions; it does not show that a study with a particular enrollment had a given probability of detecting an effect. Such a probability is not an observed result. No interim-analysis plan or detailed statistical analysis plan is reported in the registry record. The available record therefore supports a limited methods interpretation: the trial was non-randomized, the primary biological endpoint was not analyzed, and detailed analysis procedures for the listed outcomes are not reported.
10. Multiplicity, Missing Data and Analysis Populations
The registry lists several secondary outcomes: objective response rate; disease-free survival at 1 year and 2 years for a defined resection and response group; median disease-free survival for that group; progression-free survival at 1 year and 2 years for participants with residual disease after surgery; median progression-free survival for that group; and treatment-related adverse events. Multiple endpoints and time points can create multiplicity concerns. In general, when many statistical tests are conducted, interpreting any one result as confirmatory requires attention to the planned testing strategy. A multiplicity adjustment or hierarchy is not reported in the registry record.
The registry records no analyses. It does not report estimates for the listed secondary outcomes, their confidence intervals, or hypothesis tests. Analysis populations, endpoint-specific denominators, and methods for handling censored time-to-event observations are not reported in the registry record. These omissions prevent assessment of how the listed outcomes would have been analyzed or how uncertainty would have been presented.
For the primary TIIC endpoint, the registry explicitly says the laboratory experiments needed to determine cell numbers could not be completed because of insufficient funds after premature study termination. The registry does not report how many participants had usable paired specimens or how missing measurements would have been handled. In general, missing outcome data can affect interpretation when availability is related to participant characteristics or outcomes. No missing-data strategy is reported in the registry record. No interim-analysis plan or analysis population definition is reported in the registry record either.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Cohort A (Pembrolizumab Monotherapy) | 4 | 6 | 66.7% |
Deaths
| Arm | Deaths (participants affected of at risk) |
|---|---|
| Cohort A (Pembrolizumab Monotherapy) | 0 of 6 |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 0% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Cohort A (Pembrolizumab Monotherapy) | 6 of 6 |
Most frequent serious adverse event terms
| Event term | Organ system | Cohort A (Pembrolizumab Monotherapy) |
|---|---|---|
| Colitis | Gastrointestinal disorders | 1 of 6 |
| Hematuria | Renal and urinary disorders | 1 of 6 |
| Anemia | Blood and lymphatic system disorders | 1 of 6 |
| Cholecystitis | Hepatobiliary disorders | 1 of 6 |
| Myositis | Musculoskeletal and connective tissue disorders | 1 of 6 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Cohort A (Pembrolizumab Monotherapy) |
|---|---|---|
| Arthralgia | Musculoskeletal and connective tissue disorders | 3 of 6 |
| Pain in extremity | Musculoskeletal and connective tissue disorders | 3 of 6 |
| Creatinine increased | Investigations | 3 of 6 |
| Cough | Respiratory, thoracic and mediastinal disorders | 3 of 6 |
| Joint range of motion decreased | Musculoskeletal and connective tissue disorders | 2 of 6 |
| Diarrhea | Gastrointestinal disorders | 2 of 6 |
| Edema limbs | General disorders | 2 of 6 |
| Fatigue | General disorders | 2 of 6 |
| Hyponatremia | Metabolism and nutrition disorders | 2 of 6 |
| Paresthesia | Nervous system disorders | 2 of 6 |
Serious events with the highest arm-level rate: colitis (16.7%), hematuria (16.7%), anemia (16.7%), cholecystitis (16.7%), myositis (16.7%).
The registry's safety figures are for Cohort A, Pembrolizumab Monotherapy. It records 6 participants at risk for serious adverse events and 4 affected. For other adverse events, it records 6 at risk and 6 affected. Deaths are recorded as 0. The listed serious-event terms are colitis, hematuria, anemia, cholecystitis, and myositis, each reported as 16.7%.
These figures are descriptive counts and percentages in the registry record. They do not establish that each listed term occurred in a separate participant, and the figures should not be added together to infer a total number of affected participants. The registry does not give further detail in the posted information about event timing, severity grading, duration, or attribution beyond the categories and terms shown. A corresponding Cohort B summary is not reported in the registry record, so these data do not support a between-cohort safety comparison.
In general, adverse-event proportions from a small study can be unstable and depend on how events were collected and classified. The record describes observed safety entries for Cohort A; it does not establish the frequency of these events in a broader population or a comparative risk attributable to a treatment.
12. What the Result Does, and Does Not, Mean
The study was intended to examine pembrolizumab-based treatment before surgery for locally advanced or metastatic clear cell kidney cancer. Its primary endpoint focused on whether tumor-infiltrating immune cells increased in pre- and post-treatment specimens. That endpoint could not be analyzed because the required laboratory experiments were not completed after the collaborating sponsor terminated the study prematurely. No primary endpoint estimate is reported in the registry record.
The registry lists secondary clinical outcomes, including response and survival measures, but does not report their estimates or analyses. Thus, the posted information does not establish what happened to response, disease-free survival, or progression-free survival among participants. It also does not provide a completed comparison of pembrolizumab alone with pembrolizumab plus axitinib.
The design is important to interpretation. Cohort allocation was non-randomized, there was no masking, and the registry cautions that the arms are not a like-for-like control comparison. In general, non-randomized group differences may reflect participant characteristics or clinical decisions as well as treatment. The record therefore cannot support a causal comparison between the cohorts, even if descriptive differences were available.
The Cohort A safety figures report serious and other adverse events and deaths for the recorded participants. They are not a comparative assessment, and a matching Cohort B summary is not reported in the registry record. The listed event terms and percentages should be read as descriptive registry information rather than as a complete characterization of safety.
Overall, the registry record documents a planned perioperative study and some safety reporting, but the primary biological endpoint and listed efficacy outcomes do not yield reported results. This does not show that treatment did or did not change tumor immune cells, response, or survival. It means those conclusions cannot be drawn from the outcome information reported in the registry record.
13. Why This Trial Matters Statistically
This study illustrates why a clearly described endpoint and a completed analysis are both necessary for statistical interpretation. The primary question concerned a measurable biological change in tumor specimens, but the laboratory work needed to calculate that endpoint was not completed. Without the measurements, there is no proportion to estimate and no uncertainty around that proportion to evaluate. The endpoint's clinical and statistical rationale cannot replace the missing result.
The non-randomized design also matters. A comparison of cohorts can look informative while still being confounded by differences in who received each treatment approach. The registry's explicit warning that the arms are not a like-for-like control comparison is central to interpretation. It prevents treating the study as a randomized comparison of pembrolizumab alone against pembrolizumab with axitinib.
The record also demonstrates the difference between outcomes being planned and outcomes being reported. It lists response and survival measures, but the registry records no analyses. A long outcome list does not supply evidence about those outcomes, and it does not resolve questions about analysis populations, missing data, or statistical uncertainty.
Finally, the safety information is limited to Cohort A in the posted record. Reporting event counts and terms is useful descriptive information, but it cannot answer comparative safety questions without corresponding data and an appropriate design. The statistical value of the record is therefore mainly in clarifying the intended question, the study's limitations, and the extent of the reported safety information, rather than in estimating treatment effects.
14. 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 study was terminated, and the registry states that laboratory experiments needed for the primary TIIC endpoint were not completed because of insufficient funds after the collaborating sponsor terminated the study prematurely. As a result, the primary endpoint has no reported estimate. The registry also records no analyses, and it does not report estimates for the listed secondary outcomes.
Enrollment was 6, but the registry record does not provide participant flow by cohort or endpoint, detailed participant characteristics, or endpoint-specific denominators. Although Cohort A safety figures are reported, a corresponding Cohort B safety summary is not reported in the registry record. The available safety information is therefore not a complete comparative summary across cohorts.
The non-randomized, unmasked design limits causal interpretation. The registry itself states that the arms are not a like-for-like control comparison. A usual-care control cohort is not reported in the registry record. Treatment assignment procedures, adjustment methods, and detailed eligibility criteria are not reported in the registry record.
The record does not report a multiplicity strategy, a missing-data plan, analysis populations, or an interim-analysis plan. It also does not report endpoint-specific methods for time-to-event analyses or uncertainty estimates. The description of Cohort B is incomplete, which limits interpretation of its planned regimen details. These limitations mean that neither the planned biological endpoint nor comparative efficacy can be evaluated from the posted results.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Pembrolizumab With or Without Axitinib for Clear Cell Kidney Cancer in Patients Undergoing Surgery — NCT04370509.
- Registry record last updated 2025-11-19; status last verified 2025-10.
- Results first posted 2025-11-05.
- 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.
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18. Record Summary
NCT04370509 was a phase II, parallel, non-randomized, unmasked study of pembrolizumab with or without axitinib before cytoreductive nephrectomy or metastasectomy for clear cell kidney cancer. The registry records enrollment of 6 and status as terminated. The primary endpoint was the proportion with at least a 2-fold increase in tumor-infiltrating immune cells from baseline to surgery, up to 1 year. The registry says the required laboratory experiments were not completed after premature termination, so the endpoint could not be analyzed.
The registry lists response, disease-free survival, progression-free survival, and treatment-related adverse events as secondary outcomes, but records no analyses. Cohort A safety figures are reported; a comparative safety assessment is not. The non-randomized cohorts are not a like-for-like control comparison, and the posted information does not support conclusions about comparative treatment effects.