Tivozanib plus nivolumab versus tivozanib monotherapy in patients with renal cell carcinoma following an immune checkpoint inhibitor: results of the phase 3 TiNivo-2 Study.
Choueiri TK, Albiges L, Barthélémy P, Iacovelli R, Emambux S, Molina-Cerrillo J, Garmezy B, Barata P, Basu A, Bourlon MT, Moon H, Ratta R, McKay RR, Chehrazi-Raffle A, Hammers H, Heng DYC, Braendle E, Beckermann KE, McGregor BA, Motzer RJ
- DOI
- 10.1016/S0140-6736(24)01758-6
- 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/ee4f5f28-0e77-4f18-86da-31516ecc71e4 is authoritative.
How this rating was calculated
- IntegrityIntegrity concern−0.5★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- 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.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary endpoint is progression-free survival (PFS), a surrogate for overall survival. The paper does not demonstrate target engagement at the tested dose (no PK/PD data) and does not cite validated evidence linking PFS to overall survival in this specific post-ICI RCC setting. The efficacy claim is based on PFS, which is a surrogate.
“Primary endpoint was PFS by independent radiology review.”
- 02Treatment effect not shown to be clinically meaningful
The primary analysis shows no benefit of the combination (HR 1.10, p=0.49). The claim of tivozanib monotherapy efficacy is based on a median PFS of 7.4 months, but no anchor to a minimal clinically important difference or comparison to a clinically meaningful threshold is provided. The effect size is not explicitly anchored as clinically meaningful.
“mPFS was 5·7 months (95%CI, 4·04–7·43) with tivozanib–nivolumab and 7·4 months (5·55–9·23) with tivozanib (HR, 1·10; 95%CI, 0·84–1·43; p=0·49).”
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 phase 3 randomized trial with rigorous design, clear reporting of ethics, demographics, and statistical methods. The main weakness is the vague data sharing statement, and minor omissions include lack of statistical software identification and explicit reporting guideline adherence. The copyedit pass found only minor typographical and consistency issues.
Both reviewers independently scored all eight dimensions and agreed on every status; no divergence required reconciliation. The statistics verification recomputed only 2 tests (those with test statistics/CI), so the broader statistical correctness is not fully verified. 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 = .490 · recomputed p = .483Reviewers 1, 2Primary PFS hazard ratio p-value
“The stratified hazard ratio was 1·10 (95% CI, 0·84–1·43; p=0·49)”
Taken as given: The hazard ratio is 1.10 with 95% CI 0.84-1.43.; The CI is two-sided at 95%.; The p-value is two-sided.Method: Recomputed p-value from the hazard ratio and its 95% confidence interval using the normal approximation for the log hazard ratio.How we recomputed it: pCI(1.10, 0.84, 1.43, 1) - CONSISTENTreported p = .920 · recomputed p = .941Reviewers 1, 2Investigator-assessed PFS hazard ratio p-value
“Similar results were seen with investigator-assessed PFS: 5·7 months (95% CI, 4·14–7·43) with tivozanib–nivolumab and 7·4 months (95% CI, 5·52–9·23) with tivozanib monotherapy (stratified HR, 1.01; 95% CI, 0·78–1·32; p=0·92).”
Taken as given: The hazard ratio is 1.01 with 95% CI 0.78-1.32.; The CI is two-sided at 95%.; The p-value is two-sided.Method: Recomputed p-value from the hazard ratio and its 95% confidence interval using the normal approximation for the log hazard ratio.How we recomputed it: pCI(1.01, 0.78, 1.32, 1)
- lowinternal contradictionThe abstract states 'Serious adverse events occurred in 54/168 patients (32%) receiving tivozanib–nivolumab and 64/171 patients (37%) receiving tivozanib.' but the results section says 'Serious AEs occurred in 54 of 168 patients (32%) who received tivozanib–nivolumab and in 64 of 171 patients (37%) who received tivozanib monotherapy.' This is consistent, but the abstract uses 'tivozanib' without 'monotherapy' which could be ambiguous.
“Serious adverse events occurred in 54/168 patients (32%) receiving tivozanib–nivolumab and 64/171 patients (37%) receiving tivozanib.”
AbstractFind in source
Overstated conclusions
3 findings · worst highConclusions 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.
- Efficacy rests on an unvalidated surrogate endpointAssessed
- Treatment effect not shown to be clinically meaningfulAssessed
- Conclusions only partially backed by the presented evidenceAssessed
4 major claims checked against the paper's own evidence: 1 only partially supported (evidence backs part of the claim; gaps or caveats remain); the rest adequately supported.
- partialReviewer 1The reduced dose of tivozanib in the combination arm may have impacted efficacy.The paper notes this as a limitation, but it is speculative and not directly tested.Evidence: Discussion of limitations, noting the reduced dose may have impacted efficacy.
“The reduced dose of tivozanib used to manage the potential increased toxicity in the combination arm. This choice may have impacted the efficacy reflected by the numerically lower median PFS in the combination arm.”
Discussion ¶5Find in source - supportedReviewers 1, 2The addition of nivolumab to tivozanib does not improve progression-free survival in patients with advanced RCC following an ICI.The primary endpoint analysis shows no significant difference in PFS between arms, supporting the claim.Evidence: Primary PFS analysis: HR 1.10, 95% CI 0.84-1.43, p=0.49.
“mPFS was 5·7 months (95%CI, 4·04–7·43) with tivozanib–nivolumab and 7·4 months (5·55–9·23) with tivozanib (HR, 1·10; 95%CI, 0·84–1·43; p=0·49).”
AbstractFind in source - supportedReviewers 1, 2ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma.The study's negative result for the combination arm, along with the prior CONTACT-03 trial, supports this conclusion.Evidence: Primary PFS analysis and discussion of CONTACT-03.
“These data further support that ICI rechallenge should be discouraged in patients with advanced renal cell carcinoma.”
AbstractFind in source - supportedReviewers 1, 2Tivozanib monotherapy has efficacy in the post-ICI setting.The monotherapy arm showed a median PFS of 7.4 months, which is clinically meaningful, supporting the claim.Evidence: Median PFS of 7.4 months in the tivozanib monotherapy arm.
“Furthermore, these data suggest that tivozanib monotherapy has efficacy in the post-ICI setting.”
AbstractFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary endpoint is progression-free survival (PFS), a surrogate for overall survival. The paper does not demonstrate target engagement at the tested dose (no PK/PD data) and does not cite validated evidence linking PFS to overall survival in this specific post-ICI RCC setting. The efficacy claim is based on PFS, which is a surrogate.
“Primary endpoint was PFS by independent radiology review.”
- INADEQUATEEffect sizeThe primary analysis shows no benefit of the combination (HR 1.10, p=0.49). The claim of tivozanib monotherapy efficacy is based on a median PFS of 7.4 months, but no anchor to a minimal clinically important difference or comparison to a clinically meaningful threshold is provided. The effect size is not explicitly anchored as clinically meaningful.
“mPFS was 5·7 months (95%CI, 4·04–7·43) with tivozanib–nivolumab and 7·4 months (5·55–9·23) with tivozanib (HR, 1·10; 95%CI, 0·84–1·43; p=0·49).”
Data authenticity concerns
None foundAn 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.
Checked — nothing surfaced.
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 TIVO-3 and CONTACT-03, acknowledging their strengths and limitations, and builds a rationale for testing tivozanib with or without nivolumab in the post-ICI setting. The hypothesis follows logically from the cited evidence, and the paper addresses gaps in prior research, such as differences between anti-PD-1 and anti-PD-L1 rechallenge.
“To further explore retreatment with ICI we conducted a study comparing tivozanib with or without nivolumab in patients with mRCC who have progressed following 1 or 2 lines of therapy in the post-ICI setting.”
“The TIVO-3 study was the first phase 3 study to prospectively define a study population with prior ICI (26% of patients) and demonstrated an improvement in progression-free survival (PFS) with tivozanib compared with sorafenib (median PFS, 7·3 months vs 5·1 months, respectively; HR, 0·55; p=0·028) in the subgroup that received prior ICI.”
“The negative outcome of CONTACT-03 left several questions unanswered, such as potential differences between anti–PD-1 and anti–PD-L1 therapies in the rechallenge setting, whether outcomes of ICI rechallenge would be impacted if a non-ICI were used before subsequent ICI treatment, and whether VEGFR TKI dosing and TKI selectivity would impact tolerability or efficacy of combination therapy.”
Randomization method (complete permutated block design) and unit (patient) are described. Blinding is not applicable as the trial is open-label, but the rationale is stated. Power analysis is reported with sample size and hazard ratio assumptions. Inclusion/exclusion criteria are detailed. Outlier handling is addressed through ITT and safety populations. Controls are inherent in the comparator arm. Independent replication is not applicable for a single pivotal trial.
“Randomisation was performed using a randomisation trial supply management system. Once the strata were identified, patients were randomly assigned to a treatment arm within the strata using a complete permutated block design in an unblinded fashion (open label).”
“The planned sample size of 326 patients with 191 events was intended to detect an improvement of 4 months or 50% and a hazard ratio of 0.67 with respect to the primary endpoint of PFS per IRR”
“Eligible patients were ≥18 years of age, with measurable disease per Response Evaluation Criteria in Solid Tumours (RECIST) version 1·1, Eastern Cooperative Oncology Group performance status 0 or 1, life expectancy ≥3 months, and adequate recovery from AEs related to prior therapy”
“Randomisation was performed using a randomisation trial supply management system. Once the strata were identified, patients were randomly assigned to a treatment arm within the strata using a complete permutated block design in an unblinded fashion (open label).”
“The planned sample size of 326 patients with 191 events was intended to detect an improvement of 4 months or 50% and a hazard ratio of 0.67 with respect to the primary endpoint of PFS per IRR”
Sex, age, and race are reported in Table 1. Age and health status (ECOG) are reported. Demographics are comprehensive. Species/strain and housing are not applicable for a human trial. Sex justification is not applicable as both sexes are enrolled.
“Age (years) Mean (range) | 63·3 (37–87) | 62·2 (33–82) | | Sex, n (%) Male Female | 125 (73) 46 (27) | 134 (78) 38 (22)”
“Race, n (%) White Asian Black or African American Not reported, other, or missing | 112 (65) 1 (<1) 2 (1) 56 (33) | 107 (62) 0 8 (5) 57 (33)”
“Sex, n (%) Male Female | 125 (73) 46 (27) | 134 (78) 38 (22) |”
“Race, n (%) White Asian Black or African American Not reported, other, or missing | 112 (65) 1 (<1) 2 (1) 56 (33) | 107 (62) 0 8 (5) 57 (33) |”
The study protocol was approved by independent review boards or ethics committees at each site. Written informed consent was obtained from all patients. Regulatory compliance with ICH-GCP and Declaration of Helsinki is stated.
“the study protocol and all amendments were approved by independent review boards or ethics committees at each study site.”
“All patients provided written informed consent prior to any screening or study procedures.”
“each investigative facility agreed to follow all applicable local regulatory requirements and to perform the study in accordance with the Good Clinical Practice Guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the Declaration of Helsinki.”
“the study protocol and all amendments were approved by independent review boards or ethics committees at each study site.”
“All patients provided written informed consent prior to any screening or study procedures.”
“each investigative facility agreed to follow all applicable local regulatory requirements and to perform the study in accordance with the Good Clinical Practice Guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use and the Declaration of Helsinki.”
Tivozanib and nivolumab are named with manufacturers (Aveo and BMS) and dosing regimens. No bench reagents or cell lines are used, so those criteria are not applicable. Software tools are not described in detail, but the statistical software is not specified; however, this is not a key resource for a clinical trial.
“Tivozanib was provided by the study sponsor (Aveo Pharmaceuticals, Inc.; Boston, MA, USA), and nivolumab was provided by Bristol Myers Squibb (Princeton, NJ, USA).”
“patients in arm A received tivozanib at an oral dose of 0·89 mg QD for 21 consecutive days followed by a 7-day rest period; nivolumab was administered on day 1 of each cycle at an intravenous (IV) dose of 480 mg.”
“Tivozanib was provided by the study sponsor (Aveo Pharmaceuticals, Inc.; Boston, MA, USA), and nivolumab was provided by Bristol Myers Squibb (Princeton, NJ, USA).”
“patients in arm A received tivozanib at an oral dose of 0·89 mg QD for 21 consecutive days followed by a 7-day rest period; nivolumab was administered on day 1 of each cycle at an intravenous (IV) dose of 480 mg.”
Tests are named (stratified log-rank, Cochran-Mantel-Haenszel). Assumptions are handled by design (stratified analysis). Exact p-values are reported (e.g., p=0.49). Effect sizes with CIs are reported. Statistical software is not identified, but this is a minor omission. Data presentation includes Kaplan-Meier curves and forest plots. Mathematical plausibility checks are not applicable for large-N continuous outcomes.
“Treatment arms were compared using a stratified log-rank test with a two-sided 5% significance level.”
“The stratified hazard ratio was 1·10 (95% CI, 0·84–1·43; p=0·49)”
“mPFS was 5·7 months (95%CI, 4·04–7·43) with tivozanib–nivolumab and 7·4 months (5·55–9·23) with tivozanib (HR, 1·10; 95%CI, 0·84–1·43; p=0·49).”
“Treatment arms were compared using a stratified log-rank test with a two-sided 5% significance level.”
“The stratified hazard ratio was 1·10 (95% CI, 0·84–1·43; p=0·49)”
The data sharing statement says 'qualified researchers may request access to individual patient-level clinical data through a data request platform' but does not name the platform or provide conditions. 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.
“For eligible studies, qualified researchers may request access to individual patient-level clinical data through a data request platform.”
“For eligible studies, qualified researchers may request access to individual patient-level clinical data through a data request platform.”
The trial is registered (NCT04987203). Limitations are explicitly discussed, including open-label design and reduced tivozanib dose. Conclusions are proportional to the evidence, noting the primary endpoint was not met. Funding and COI statements are provided. Reporting guideline (CONSORT) is not explicitly mentioned, but the paper follows standard reporting.
“The trial is registered with ClinicalTrials.gov (https://clinicaltrials.gov/) : NCT04987203 (https://clinicaltrials.gov/ct2/show/NCT04987203) .”
“Funding Aveo Pharmaceuticals, Inc.”
“The trial is registered with ClinicalTrials.gov (https://clinicaltrials.gov/) : NCT04987203 (https://clinicaltrials.gov/ct2/show/NCT04987203) .”
“There are, however, several limitations of the study to be recognized: (1) The reduced dose of tivozanib used to manage the potential increased toxicity in the combination arm. This choice may have impacted the efficacy reflected by the numerically lower median PFS in the combination arm. (2) The open-label study design is in principle more vulnerable to patient bias and placebo effects due to lack of blinding for both patients and investigators.”
Registered (1 ID: 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 21 references by DOI: 19 verified — 2 no DOI (shown, not verified).
- NO DOIFotivda (tivozanib) capsules: highlights of prescibing informationNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIFotivda: EPARNo 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/NCT04987203LIVEHTTP 200Resolves, but the content could not be matched to the paper.
Copyediting
5 minorWording, consistency and formatting errors that need correcting before submission.
No major wording or formatting errors. 5 minor suggestions below.
5 copyedit issues flagged: mostly consistency, typo, clarity.
- MINORconsistencyAbstract, Findings“Serious adverse events occurred in 54/168 patients (32%) receiving tivozanib–nivolumab and 64/171 patients (37%) receiving tivozanib.”→ Ensure consistent use of 'tivozanib monotherapy' instead of 'tivozanib' for clarity.The abstract uses 'tivozanib' while the rest of the paper uses 'tivozanib monotherapy'.
- MINORtypoDiscussion, paragraph 5“the potential benefit of ICI rechallenge remains unknow for this histology”→ Change 'unknow' to 'unknown'.Typographical error.
- MINORclarityResults, paragraph 4“The outcome of the mPFS for the group of patients after a non-ICI as their most recent line of therapy, could be due to the fact that those patients were predominately in the third line setting and potentially due to emerging resistance mechanisms.”→ Rephrase for clarity: 'The mPFS outcome in the non-ICI most recent therapy group may be due to these patients being predominantly in the third-line setting and potentially due to emerging resistance mechanisms.'Awkward phrasing.
- MINORconsistencyResults, paragraph 3“In a predefined analysis per strata in patients who had received ICI as part of their most recent therapy (predominantly 2L), median PFS was 7·4 months (95% CI, 5·55–9·56) with tivozanib–nivolumab and 9·2 months (95% CI, 7·43–9·99) with tivozanib monotherapy (HR 1·0 [0·80–1·52]; ).”→ Remove the extra semicolon before the closing parenthesis.Punctuation error.
- MINORconsistencyResults, paragraph 3“In a predefined analysis per strata in patients who had received ICI as part of their most recent therapy (predominantly 2L), median PFS was 7·4 months (95% CI, 5·55–9·56) with tivozanib–nivolumab and 9·2 months (95% CI, 7·43–9·99) with tivozanib monotherapy (HR 1·0 [0·80–1·52]; ).”→ Remove the stray semicolon before the closing parenthesis.Punctuation error.
The published work is robust and transparent, with only minor reporting gaps (vague data sharing, unnamed software, no explicit CONSORT statement) and minor copyedit issues. An informed reader should weigh the open-label design and reduced tivozanib dose as limitations, but these are disclosed. No erratum is warranted for the identified issues, though the data sharing statement could be clarified in a future update.
- 1.HIGHdata codeIn the Data sharing statement, specify the data request platform (e.g., Vivli, YODA) and the conditions for access (e.g., proposal review, timeframe).The current statement is vague and does not meet the standard for data availability, which is a common reviewer concern.
- 2.HIGHstatisticsIn the Methods, Statistical analysis, identify the statistical software and version used (e.g., SAS 9.4, R 4.0).Naming the software improves reproducibility and is expected in clinical trial reporting.
- 3.MEDIUMreportingIn the Methods or end of manuscript, state adherence to CONSORT reporting guidelines and provide the checklist as supplementary material.Explicitly following a reporting guideline enhances transparency and is often required by journals.
- 4.MEDIUMreportingIn the Methods, clarify the blinding maintenance plan details, even though the trial is open-label, to address potential bias concerns.Clarifying how bias was minimized in an open-label trial strengthens the design description.
- 5.MEDIUMreportingIn the Results, consider reporting the number of patients with missing data for key endpoints to enhance transparency.Missing data handling is a key aspect of trial reporting and is currently not detailed.
- 6.MEDIUMreportingIn the Discussion, expand on the potential impact of the reduced tivozanib dose on efficacy, as it is a key limitation.The reduced dose may have affected the primary endpoint, and a fuller discussion would help readers interpret the results.
- 7.MEDIUMdata codeIn the Data sharing statement, mention if the study protocol and statistical analysis plan are available publicly.Providing access to the protocol and SAP increases transparency and reproducibility.
- 8.MEDIUMreportingIn the Methods, provide more detail on the independent radiology review process, including how discordance was adjudicated.Details on the independent review process are important for assessing endpoint reliability.
- 9.MEDIUMreportingIn the Results, include a CONSORT flow diagram to show patient disposition clearly.A flow diagram is a standard element of trial reporting and improves clarity.
- 10.MEDIUMreportingIn the Discussion, avoid cross-study comparisons without emphasizing the limitations more strongly, as they are prone to bias.Cross-trial comparisons are inherently biased and should be interpreted cautiously.
- 11.LOWcopyeditIn the Abstract, Findings, change 'tivozanib' to 'tivozanib monotherapy' for consistency with the rest of the paper.Consistent terminology avoids ambiguity about the comparator arm.
- 12.LOWcopyeditIn the Discussion, paragraph 5, change 'unknow' to 'unknown'.Corrects a typographical error.
- 13.LOWcopyeditIn the Results, paragraph 4, rephrase the sentence about mPFS in the non-ICI group for clarity.The current phrasing is awkward and could be misinterpreted.
- 14.LOWcopyeditIn the Results, paragraph 3, remove the stray semicolon before the closing parenthesis in the HR reporting.Fixes a punctuation error.
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.