Safety and efficacy of pembrolizumab, radiation therapy, and surgery versus radiation therapy and surgery for stage III soft tissue sarcoma of the extremity (SU2C-SARC032): an open-label, randomised clinical trial.
Mowery YM, Ballman KV, Hong AM, Schuetze SM, Wagner AJ, Monga V, Heise RS, Attia S, Choy E, Burgess MA, Bae S, Pryor DI, Van Tine BA, Tinoco G, Chmielowski B, Freeman C, Gronchi A, Meyer CF, Dickson MA, Hartner L, Davis LE, Powers BC, Moding EJ, Weinhold KJ, van de Rijn M, Brigman BE, Riedel RF, Kirsch DG
- DOI
- 10.1016/S0140-6736(24)01812-9
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-20
Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/05894beb-ffba-489c-9f24-347d228174f8 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern ×3−1.5★
- ReportingData & code availability partially met−0.25★
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 2 reported means were read, and their group size is not stated where the values are printed. These checks need the count the mean was averaged over, so none was performed.
- 01Other integrity concern
Trial NCT03307616 was first submitted to ClinicalTrials.gov on 2017-10-05, after the registered study start date of 2017-10-04. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT03307616
reviewer’s wording
This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.
This is a well-conducted randomized phase 2/3 trial with rigorous design, clear reporting of biological variables, ethical approvals, and statistical methods. The main weakness is the vague data sharing statement, which lacks a concrete mechanism for access. Minor reporting gaps include the absence of an explicit reporting guideline and lack of clarity on the safety population denominator.
Both reviewers independently scored all eight dimensions and agreed on all statuses; no divergence. The study is an interventional clinical trial; animal-related criteria were marked not applicable. The statistics verification covered only 2 tests (those with test statistics/CI); the remaining statistics were not machine-verified and should not be assumed correct. The citation check found no retracted or unresolved references.
Numerical inconsistencies
1 finding · worst lowValues that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.
- Internal contradictions in the reported numbersAssessed
Recomputed 2 tests: 2 consistent, 0 inconsistent; 2 via agent-written checks.
- CONSISTENTreported p = .035 · recomputed p = .035Reviewer 1Primary DFS log-rank p-value (one-sided) from mITT analysis
“one-sided stratified log rank p-value = 0·035”
Taken as given: The reported p-value is one-sided.; The test statistic is approximately normal under the null.; The p-value corresponds to a z-score of approximately 1.811.Method: Converted the one-sided p-value to a z-score using the normal CDF.How we recomputed it: 1 - normalCdf(1.811) - CONSISTENTreported p = .035 · recomputed p = .031Reviewer 1DFS HR 90% CI from mITT analysis
“HR 0·61; 90% CI, 0·39 to 0·96”
Taken as given: The HR is a ratio (log=1).; The CI is a 90% confidence interval.; The p-value is two-sided (converted from one-sided).Method: Used the pCI function to derive a two-sided p-value from the HR and 90% CI.How we recomputed it: pCI(0.61, 0.39, 0.96, 1)
- lowinternal contradictionThe number of patients in the safety population (70 experimental, 67 control) differs from the number randomized (71 experimental, 72 control) and the mITT population (64 experimental, 63 control). This is expected due to dropouts, but the paper does not explicitly reconcile these numbers.
Among the 70 patients in the experimental group who received at least one dose of pembrolizumab... Among the 67 patients in the control group who started study treatment...
Resultsreviewer’s wording - lowinternal contradictionThe abstract reports 143 participants randomly assigned, but the mITT analysis includes 127 patients. The difference (16 patients) is not fully explained in the text.
“143 participants were randomly assigned to treatment. A modified intent-to-treat analysis performed with median follow-up of 43 months showed the experimental group (n=64) had significantly longer DFS than the control group (n=63)”
AbstractFind in source
Overstated conclusions
1 finding · worst lowConclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.
- Conclusions only partially backed by the presented evidenceAssessed
5 major claims checked against the paper's own evidence: 2 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The improvement in DFS was predominantly driven by superior DFS in patients with grade 3 disease.The subgroup analysis shows a larger HR for grade 3 (0.57) than grade 2 (0.84), but the interaction was not formally tested and the grade 3 p-value was 0.064, so the claim is partially supported.Evidence: Subgroup analysis: grade 2 HR 0.84 (95% CI 0.26-2.76), grade 3 HR 0.57 (95% CI 0.31-1.03).
“Improvement in the primary endpoint of two-year DFS in the experimental group was predominantly driven by superior DFS in patients with grade 3 disease.”
Discussion ¶2Find in source - partialReviewers 1, 2SU2C-SARC032 establishes pembrolizumab as a new treatment option for patients with high-risk, localized UPS or LPS.The trial shows a DFS benefit, but the claim of establishing a new treatment option may be considered strong given the modest effect and open-label design; however, it is supported by the primary endpoint.Evidence: Primary endpoint DFS improvement.
“SU2C-SARC032 establishes pembrolizumab as a new treatment option for these patients and suggests a path for even greater therapeutic impact by further optimizing immunotherapy.”
Discussion ¶1Find in source - supportedReviewers 1, 2Addition of pembrolizumab to preoperative radiotherapy and surgery significantly improves DFS for patients with stage III UPS and LPS of the extremity.The primary endpoint DFS was significantly improved in the mITT analysis with HR 0.61 and one-sided p=0.035, supporting the claim.Evidence: mITT analysis: HR 0.61 (90% CI 0.39-0.96), one-sided p=0.035.
“Addition of pembrolizumab to preoperative radiotherapy and surgery significantly improves DFS for patients with stage III UPS and LPS of the extremity.”
AbstractFind in source - supportedReviewers 1, 2The two-year DFS increased by 15% with addition of pembrolizumab.The reported two-year DFS rates are 52% (control) and 67% (experimental), a 15% absolute increase, matching the claim.Evidence: Two-year DFS rates: 52% (90% CI 42-64) vs 67% (90% CI 58-78).
“The two-year DFS increased by 15% with addition of pembrolizumab: 52% (90% CI, 42 to 64) and 67% (90% CI, 58 to 78) for control and experimental groups, respectively.”
AbstractFind in source - supportedReviewers 1, 2Grade ≥3 adverse events occurred more frequently in the experimental group (56%) than the control group (31%).The safety analysis reports these exact percentages, supporting the claim.Evidence: Safety analysis: 56% vs 31% grade ≥3 AEs.
“Grade ≥3 adverse events occurred more frequently in the experimental group (56%) than the control group (31%).”
AbstractFind in source
Efficacy claim is anchored to an adequate endpoint and a meaningful effect.
- ADEQUATESurrogate endpointThe primary endpoint is disease-free survival (DFS), a hard clinical outcome, not a surrogate. The trial directly measures disease recurrence and death, which are clinically meaningful events.
“The primary outcome was disease-free survival (DFS), which was assessed by investigators according to clinical exam and imaging review. DFS is defined as the time from randomisation to disease recurrence (determined by the treating oncologist) or death without documented disease recurrence.”
- ADEQUATEEffect sizeThe effect size is reported as a hazard ratio of 0.61 with a 90% CI of 0.39-0.96, and a 15% absolute improvement in two-year DFS (52% to 67%). The authors describe this as 'clinically meaningful' and the trial was powered to detect a 22% absolute difference, so the observed effect is within the expected range.
“The two-year DFS increased by 15% with addition of pembrolizumab: 52% (90% CI, 42 to 64) and 67% (90% CI, 58 to 78) for control and experimental groups, respectively.”
Data authenticity concerns
1 finding · worst mediumAn adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.
- Other integrity concernAssessed
3 integrity concerns flagged (0 high).
- mediumotherTrial NCT03307616 was first submitted to ClinicalTrials.gov on 2017-10-05, after the registered study start date of 2017-10-04. Retrospective registration means the protocol and outcomes were not on the public record before the study ran, which is what prospective registration exists to establish.
NCT03307616
reviewer’s wording
Reporting gaps
1 finding · worst mediumRequired detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.
- Data/code availability incompleteAssessed
The introduction cites SARC028 and other studies showing pembrolizumab activity in UPS and LPS, and discusses the rationale for combining ICB with RT. The hypothesis follows logically from the cited evidence. Limitations of prior research are acknowledged, such as the lack of randomized trials demonstrating a DFS benefit.
“Objective responses to the anti-programmed death-1 (PD-1) monoclonal antibody pembrolizumab occurred in 23% of patients with metastatic undifferentiated pleomorphic sarcoma (UPS) and 10% with pleomorphic or dedifferentiated liposarcoma (LPS) in SARC028.”
“we hypothesized that the addition of pembrolizumab to preoperative RT and surgery for Stage III UPS or LPS would improve disease-free survival (DFS).”
“While these studies suggest some efficacy of anti-PD-1 therapy for UPS and LPS, no prior randomised clinical trials have demonstrated a disease-free survival benefit of adding anti-PD-1 therapy to RT and surgery for resectable STS.”
“Objective responses to the anti-programmed death-1 (PD-1) monoclonal antibody pembrolizumab occurred in 23% of patients with metastatic undifferentiated pleomorphic sarcoma (UPS) and 10% with pleomorphic or dedifferentiated liposarcoma (LPS) in SARC028.”
“we hypothesized that the addition of pembrolizumab to preoperative RT and surgery for Stage III UPS or LPS would improve disease-free survival (DFS).”
“no prior randomised clinical trials have demonstrated a disease-free survival benefit of adding anti-PD-1 therapy to RT and surgery for resectable STS.”
Randomization method is described (centralized permuted block with random block sizes, stratified by tumor grade). Blinding is not applicable as it is an open-label trial, which is stated. Power analysis is provided with a target sample size and effect size. Inclusion/exclusion criteria are described, and the analysis populations (mITT, ITT, safety) are defined. Outlier handling is not explicitly discussed, but the analysis population definitions serve as a proxy. Controls are inherent in the randomized design. Independent replication is not applicable for a single pivotal trial.
“Centralized permuted block randomisation with random block sizes was coordinated by the central clinical trial office at SARC.”
“Patients and physicians were not blinded to group assignment.”
“A sample size of 126 evaluable patients provides 80% power, with a one-sided 0·05 level of significance, to detect a difference in two-year DFS rate of 22% (absolute) assuming a two-year DFS rate of 50%”
“Centralized permuted block randomisation with random block sizes was coordinated by the central clinical trial office at SARC.”
“A sample size of 126 evaluable patients provides 80% power, with a one-sided 0·05 level of significance, to detect a difference in two-year DFS rate of 22% (absolute)”
“Patients and physicians were not blinded to group assignment.”
Sex is reported in Table 1 (e.g., 62% male in control, 64% male in experimental). Age is reported as median and range. Demographics include ethnicity and race. Since both sexes are enrolled, sex_justified is not applicable. Species/strain and housing conditions are not applicable for a human trial.
“Female | 24 (38%) | 23 (36%) | | Male | 39 (62%) | 41 (64%)”
“Median (Range) | 60 (26, 84) | 59 (35, 87)”
“Female | 24 (38%) | 23 (36%) | | Male | 39 (62%) | 41 (64%)”
“Median (Range) | 60 (26, 84) | 59 (35, 87)”
The paper states that the protocol was approved by the institutional review board at each institution, and that the trial was conducted in compliance with GCP and the Declaration of Helsinki. Written informed consent was obtained from all subjects. These statements are adequate.
“All subjects signed written informed consent.”
“The trial was conducted in compliance with Good Clinical Practice (GCP) standards and principles of the Declaration of Helsinki.”
“All subjects signed written informed consent.”
“The trial was conducted in compliance with Good Clinical Practice (GCP) standards and principles of the Declaration of Helsinki.”
Pembrolizumab is identified by name and dose (200 mg IV every three weeks). The manufacturer (Merck Sharp and Dohme) is implied through funding. Statistical software (R version 4·3·0) is identified. Other bench resources are not applicable as this is a clinical trial without wet-lab assays.
“Patients in the experimental group received an intravenous infusion of pembrolizumab (200 mg) every three weeks for three doses”
“R version 4·3·0 was used for statistical analyses.”
“Patients in the experimental group received an intravenous infusion of pembrolizumab (200 mg) every three weeks for three doses”
“R version 4·3·0 was used for statistical analyses.”
The primary analysis uses a stratified log rank test, and Cox models provide HRs with CIs. Exact p-values are reported (e.g., p=0·035). Effect sizes are reported with CIs. Software is identified. Data presentation includes Kaplan-Meier curves and per-group n. Assumptions are handled by design (e.g., exponential distribution for sample size). Mathematical plausibility is not applicable for large-N continuous outcomes.
“The protocol-defined primary statistical analysis plan was to compare DFS between the two treatment groups using a stratified log rank test”
“one-sided stratified log rank p-value = 0·035”
“HR 0·61; 90% CI, 0·39 to 0·96”
“The protocol-defined primary statistical analysis plan was to compare DFS between the two treatment groups using a stratified log rank test”
“one-sided stratified log rank p-value = 0·035”
“HR 0·61; 90% CI, 0·39 to 0·96”
The data sharing statement says deidentified participant data will be made available upon reasonable request to the corresponding author with approval from SARC and a signed data sharing agreement, but it does not specify a platform or conditions beyond that. This is reported_but_inadequate. Repository deposit and accession numbers are not applicable for patient-level data. Code sharing is not applicable as no bespoke code is mentioned.
“Beginning three years after publication, deidentified participant data will be made available upon reasonable request to the corresponding author ( David.Kirsch@uhn.ca ) with approval from SARC and a signed data sharing agreement.”
“Beginning three years after publication, deidentified participant data will be made available upon reasonable request to the corresponding author ( David.Kirsch@uhn.ca ) with approval from SARC and a signed data sharing agreement.”
The trial is registered (NCT03092323). Methods are detailed enough for replication. Limitations are discussed. Conclusions are proportional to the evidence. Funding sources and conflicts of interest are disclosed. A reporting guideline is not explicitly mentioned, but the manuscript follows CONSORT-like structure.
“This study is registered with ClinicalTrials.gov (http://clinicaltrials.gov) ( NCT03092323 (https://clinicaltrials.gov/ct2/show/NCT03092323) ).”
“One limitation of the current study is that it is relatively small, given the rarity of STS.”
“YMM, KVB, KJW, and DGK report grant funding from Stand Up To Cancer (Merck Catalyst Program) to the institution to support this study.”
“This study is registered with ClinicalTrials.gov (http://clinicaltrials.gov) ( NCT03092323 (https://clinicaltrials.gov/ct2/show/NCT03092323) ).”
“One limitation of the current study is that it is relatively small, given the rarity of STS.”
“This study was funded by a SU2C Merck Catalyst grant to DGK and a Merck Investigator Studies Program grant (MSD) to DGK.”
Registered (2 IDs: ClinicalTrials.gov). No reporting guideline cited.
Broken references and links
None foundReferences checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.
Checked — nothing surfaced.
Checked 29 references by DOI: 27 verified — 2 no DOI (shown, not verified).
- NO DOIClinical activity of pembrolizumab (P) in undifferentiated pleomorphic sarcoma (UPS) and dedifferentiated/pleomorphic liposarcoma (LPS): Final results of SARC028 expansion cohortsNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIAdjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: meta-analysis of individual dataNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
1 data/code link checked; 1 live.
- datahttps://clinicaltrials.gov/ct2/show/NCT03092323LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
6 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 6 minor suggestions below.
6 copyedit issues flagged: mostly typo, consistency, other.
- MINORtypoAbstract, Methods“radiotherapy then surgery (control group) or preoperative pembrolizumab with radiotherapy (initiated 1 – 14 days after first dose of pembrolizumab) then surgery and postoperative pembrolizumab (experimental group).”→ Consider rephrasing for clarity: '...or preoperative pembrolizumab with radiotherapy (initiated 1–14 days after the first dose of pembrolizumab), followed by surgery and postoperative pembrolizumab (experimental group).'Minor punctuation and clarity.
- MINORconsistencyResults, Safety“Among the 70 patients in the experimental group who received at least one dose of pembrolizumab, 39 (56%; 95% CI, 44 to 67) experienced at least one grade 3 or 4 AE”→ Ensure consistency in the number of patients in the safety population (70 vs. 71 randomized) and clarify the denominator.The safety population is defined as those who started treatment, which may differ from randomized.
- MINORotherData Sharing“Beginning three years after publication, deidentified participant data will be made available upon reasonable request to the corresponding author ( David.Kirsch@uhn.ca ) with approval from SARC and a signed data sharing agreement.”→ Specify a data access committee or platform to meet modern data sharing standards.Vague data sharing statement.
- MINORtypoAbstract, Findings“log rank one-sided p=0·035”→ Consider hyphenating 'log-rank' for consistency.Minor style issue.
- MINORconsistencyResults, Safety“Among the 70 patients in the experimental group who received at least one dose of pembrolizumab, 39 (56%; 95% CI, 44 to 67) experienced at least one grade 3 or 4 AE”→ Ensure the denominator (70) is consistent with the safety population definition.The safety population is defined as all patients who started treatment; 70 is stated, but the mITT is 64. Clarify the relationship.
- MINORclarityMethods, Statistical Analysis“The study was powered with a one-sided p-value because the control arm treatment was RT and the experimental arm added pembrolizumab to RT.”→ Clarify that the one-sided test was pre-specified and justify the direction.The rationale is given, but could be clearer.
The published work is robust and generally well-reported. An informed reader should weigh the vague data sharing statement and the minor internal inconsistencies in patient numbers (safety population vs. randomized) as areas that could warrant clarification or an erratum. No evidence of statistical errors or integrity concerns that would undermine the main conclusions.
- 1.HIGHdata codeIn the Data Sharing section, specify a concrete data access mechanism (e.g., a named repository like Vivli or YODA) and the conditions and timeframe for access, rather than only 'reasonable request'.The current statement is vague and does not meet modern data sharing standards, which could hinder reproducibility and reader trust.
- 2.HIGHreportingAdd an explicit statement referencing a reporting guideline (e.g., CONSORT) in the Methods or as a checklist submission.The paper follows CONSORT-like structure but does not explicitly mention it, which is a minor transparency gap.
- 3.HIGHreportingReconcile and clarify the patient numbers across the abstract (143 randomized), mITT (127), and safety populations (70 experimental, 67 control) in the Results and Methods.The internal contradiction in patient counts could confuse readers and warrants explicit explanation of the flow from randomization to analysis populations.
- 4.MEDIUMreportingClarify the denominator for the safety population in the Results, Safety section (70 vs. 71 randomized) and ensure consistency with the safety population definition.The copyedit flagged this inconsistency, which could be misinterpreted as an error.
- 5.MEDIUMreportingAdd a CONSORT flow diagram to the supplementary materials to clearly show patient disposition from screening to analysis.This would improve transparency and help reconcile the patient numbers.
- 6.MEDIUMstatisticsIn the Statistical Analysis section, explicitly state that assumptions of the log-rank test and Cox models were checked (e.g., proportional hazards).The reviewers noted that assumptions_verified is reported as adequate but the paper does not explicitly describe checking these assumptions.
- 7.MEDIUMreportingClarify the role of the data monitoring committee or justify its absence, as the paper states there was no independent safety monitoring committee.This is a governance detail that readers may expect in a phase 2/3 trial.
- 8.MEDIUMreportingProvide more detail on the central pathology review process, including how many cases were reviewed and any discrepancies.This would strengthen confidence in the diagnostic accuracy of the trial.
- 9.MEDIUMdata codeConsider sharing analysis code (e.g., R scripts) in a public repository like GitHub or Zenodo to improve reproducibility.The statistical analysis is described but code is not provided, which limits reproducibility.
- 10.LOWcopyeditRephrase the Abstract Methods sentence for clarity: '...or preoperative pembrolizumab with radiotherapy (initiated 1–14 days after the first dose of pembrolizumab), followed by surgery and postoperative pembrolizumab (experimental group).'The original phrasing is slightly awkward and could be clearer.
- 11.LOWcopyeditHyphenate 'log-rank' consistently throughout the manuscript (e.g., in the Abstract Findings).Minor style consistency issue.
- 12.LOWreportingClarify the rationale for the one-sided p-value in the Statistical Analysis section, noting it was pre-specified and the direction justified.The copyedit noted the rationale is given but could be clearer.
The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”
- Reporting — 8 dimensionseach dimension that fully fails−½★
- each dimension partially met−¼★
- Statistics · Integrity · Claimseach serious problem−1★
- each medium problem−½★
- Citationseach retracted or unverifiable reference−¼★
- Copyeditonly when the manuscript needs a full edit−½★
The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.
The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.
Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.
This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.