Alpha¹ by KaimenConfidential

Kaimen Rigor review

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

Heinrich MC, Jones RL, George S, Gelderblom H, Schöffski P, von Mehren M, Zalcberg JR, Kang YK, Razak AA, Trent J, Attia S, Le Cesne A, Siontis BL, Goldstein D, Boye K, Sanchez C, Steeghs N, Rutkowski P, Druta M, Serrano C, Somaiah N, Chi P, Reichmann W, Sprott K, Achour H, Sherman ML, Ruiz-Soto R, Blay JY, Bauer S

DOI: 10.1038/s41591-023-02734-5
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/e7210b81-8722-4e0f-857d-4952e4687d76 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

2.75 / 5

Weak — serious problems found

Observational Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern ×3−1.5★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
StatisticsPrinted percentage does not match its own count (capped) ×2−0.25★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on progression-free survival (PFS), which is a clinical outcome, but the analysis is exploratory and relies on ctDNA mutation subgroups as a surrogate for predicting treatment benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking the specific ctDNA mutation subgroups to clinical outcomes. The claim that ctDNA can identify patients who benefit from ripretinib is based on a biomarker (KIT mutation status) without established surrogacy.
“The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations.”
Find in source
02Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
50% does not match the reported count 12/25
“50.0% versus 33.3%”
Safety, grade 3/4 drug-related TEAEs in…Find in source
03Printed percentage does not match its own count
mediumArithmeticrecomputedFull detail
50% does not match the reported count 12/25
“50.0%”
Safety, hypertension in KIT exon 11 + 1…
04Other integrity concern
mediumAuthenticityreviewer-assessedFull detail
Trial NCT00457743 was first submitted to ClinicalTrials.gov on 2007-04-04, after the registered study start date of 2005-01. 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.
NCT00457743
reviewer’s wording

Findings by category

201ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 103AuthenticityData authenticity concerns 04DisclosureNone found 05AvailabilityNone found 06Copyedit4 minor suggestions

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-reported prespecified exploratory biomarker analysis of a randomized phase 3 trial, with strong scientific premise, clear study design, and transparent reporting. The main weaknesses are minor: lack of explicit reporting guideline adherence, some p-values reported as thresholds, and a few copyedit issues. The retrospective registration of the cited phase 1/2 trial (NCT00457743) is a minor integrity concern but does not affect the current analysis.

Both reviewers classified the study as observational (exploratory biomarker analysis of an RCT), and I adopt that classification. The statistics verification covered only 6 tests (4 consistent, 2 inconsistent but unspecified), so the statistical analysis is not fully verified; the GRIM/GRIMMER checks are not applicable to continuous outcomes. The integrity check flagged retrospective registration of the cited phase 1/2 trial (NCT00457743) as a medium concern, but this does not affect the current paper's validity.

Numerical inconsistencies

2 findings · worst medium

Values 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.

Printed percentage does not match its own countRecomputed
Internal contradictions in the reported numbersAssessed

Recomputed 4 tests: 4 consistent, 0 inconsistent; 4 via agent-written checks. 2 printed percentages that do not match their own count.

Numeric forensics— values impossible for the reported sample size

PERCENT
50% does not match the reported count 12/25
“50.0% versus 33.3%”
Safety, grade 3/4 drug-related TEAEs in…Find in source
PERCENT
50% does not match the reported count 12/25
“50.0%”
Safety, hypertension in KIT exon 11 + 1…

Agent-written checks— recomputed from reported CIs / ratios by code the agent wrote

CONSISTENTreported p < .001 · recomputed p = .001Reviewers 1, 2
PFS HR for KIT exon 11 + 13/14 population (sunitinib vs ripretinib)
“In the KIT exon 11 + 13/14 population, sunitinib demonstrated improved PFS compared with ripretinib (median, 15.0 versus 4.0 months; HR, 3.94; 95% CI, 1.71–9.11; nominal P = 0.0005).”
Find in source
Taken as given: The HR is a ratio (log scale).; The CI is a 95% confidence interval for the HR.; The p-value is two-sided.
Method: Recomputed two-sided p-value from the reported HR and 95% CI using the normal approximation for the log HR.
How we recomputed it: pCI(3.94, 1.71, 9.11, 1)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewers 1, 2
PFS HR for KIT exon 11 + 17/18 population (ripretinib vs sunitinib)
“Conversely, ripretinib demonstrated improved PFS compared with sunitinib in patients with KIT exon 11 + 17/18 mutations (median, 14.2 versus 1.5 months; HR, 0.22; 95% CI, 0.11–0.44; nominal P < 0.0001).”
Find in source
Taken as given: The HR is a ratio (log scale).; The CI is a 95% confidence interval for the HR.; The p-value is two-sided.
Method: Recomputed two-sided p-value from the reported HR and 95% CI using the normal approximation for the log HR.
How we recomputed it: pCI(0.22, 0.11, 0.44, 1)
CONSISTENTreported p = .006 · recomputed p = .009Reviewer 1
OS HR for KIT exon 11 + 17/18 population (ripretinib vs sunitinib)
“Improved OS was observed with ripretinib versus sunitinib in the KIT exon 11 + 17/18 population (median, not reached versus 17.5 months; HR, 0.34; 95% CI, 0.15 to 0.76; nominal P = 0.0061).”
Find in source
Taken as given: The HR is a ratio (log scale).; The CI is a 95% confidence interval for the HR.; The p-value is two-sided.
Method: Recomputed two-sided p-value from the reported HR and 95% CI using the normal approximation for the log HR.
How we recomputed it: pCI(0.34, 0.15, 0.76, 1)
CONSISTENTreported p < .001 · recomputed p = <.001Reviewer 2
ORR difference for KIT exon 11 + 17/18 population
“A higher ORR was observed with ripretinib versus sunitinib in the KIT exon 11 + 17/18 population (44.4% versus 0%; RD, 44.4%; 95% CI, 23.0–62.7; nominal P = 0.0001; Fig. ).”
Find in source
Taken as given: The ORR for ripretinib is 44.4% of 27 patients, giving 12 responders.; The ORR for sunitinib is 0% of 25 patients, giving 0 responders.; The p-value is from a chi-square test for association.
Method: Recomputed Pearson chi-square p-value from the 2x2 table of responders/non-responders.
How we recomputed it: pChi2x2(12, 15, 0, 25)

lowinternal contradiction
The abstract states 'KIT mutations in 213/362 patients (59%)' but the results section states '213/362 (59%) had detectable KIT mutations' - consistent. However, the abstract also states 'Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18)' without specifying counts, which is fine.
“ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%).”
AbstractFind in source

Overstated conclusions

2 findings · worst high

Conclusions 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
Conclusions only partially backed by the presented evidenceAssessed

8 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 1
ctDNA analysis may improve prediction of single-drug therapy efficacy in GIST.
The claim is partially supported by the subgroup findings, but the exploratory nature and small numbers limit the strength of the prediction claim.
Evidence: Differential PFS and OS in two mutually exclusive subgroups based on ctDNA mutation status.
The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies.
Discussionreviewer’s wording
supportedReviewer 1
ctDNA sequencing can identify patients with KIT exon 11 + 17/18 mutations who benefit more from ripretinib than sunitinib.
The claim is supported by the reported PFS and OS results in the KIT exon 11 + 17/18 subgroup, with HRs and CIs favoring ripretinib.
Evidence: PFS HR 0.22 (95% CI 0.11-0.44), OS HR 0.34 (95% CI 0.15-0.76) in the KIT exon 11 + 17/18 population.
“Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months).”
AbstractFind in source
supportedReviewer 1
Patients with KIT exon 11 + 13/14 mutations benefit more from sunitinib than ripretinib.
The claim is supported by the reported PFS result in the KIT exon 11 + 13/14 subgroup, with HR favoring sunitinib.
Evidence: PFS HR 3.94 (95% CI 1.71-9.11) favoring sunitinib.
“Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months).”
AbstractFind in source
supportedReviewer 1
Ripretinib should be further evaluated in patients with KIT exon 11 + 17/18 mutations.
The claim is supported by the observed benefit in this subgroup and the ongoing INSIGHT trial is mentioned.
Evidence: PFS and OS benefit in the KIT exon 11 + 17/18 subgroup; ongoing phase 3 INSIGHT trial.
Based on the current findings, a phase 3, randomized, multicenter, open-label study evaluating ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib who harbor KIT exon 11 + 17 and/or 18 mutations ... is ongoing (INSIGHT; NCT05734105).
Discussionreviewer’s wording
supportedReviewer 2
ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies.
The claim is supported by the differential PFS and ORR results in the two mutational subgroups, though the exploratory nature limits strength.
Evidence: PFS and ORR differences in KIT exon 11 + 13/14 and KIT exon 11 + 17/18 populations.
“The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations.”
AbstractFind in source
supportedReviewer 2
Patients with KIT exon 11 + 13/14 mutations had better PFS with sunitinib versus ripretinib.
The reported HR and CI support this claim.
Evidence: HR 3.94, 95% CI 1.71-9.11, nominal P=0.0005.
“In the KIT exon 11 + 13/14 population, sunitinib demonstrated improved PFS compared with ripretinib (median, 15.0 versus 4.0 months; HR, 3.94; 95% CI, 1.71–9.11; nominal P = 0.0005; Figs. and ).”
ResultsFind in source
supportedReviewer 2
Patients with KIT exon 11 + 17/18 mutations had better PFS with ripretinib versus sunitinib.
The reported HR and CI support this claim.
Evidence: HR 0.22, 95% CI 0.11-0.44, nominal P < 0.0001.
“Conversely, ripretinib demonstrated improved PFS compared with sunitinib in patients with KIT exon 11 + 17/18 mutations (median, 14.2 versus 1.5 months; HR, 0.22; 95% CI, 0.11–0.44; nominal P < 0.0001; Figs. and ).”
ResultsFind in source
supportedReviewer 2
The results support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations.
The claim is supported by the observed benefit and the ongoing INSIGHT trial.
Evidence: PFS and ORR benefit in the KIT exon 11 + 17/18 population; ongoing phase 3 INSIGHT trial.
“Based on the current findings, a phase 3, randomized, multicenter, open-label study evaluating ripretinib versus sunitinib in patients with advanced GIST previously treated with imatinib who harbor KIT exon 11 + 17 and/or 18 mutations (without co-occurring mutations in KIT exons 9, 13 or 14) is ongoing (INSIGHT; NCT05734105 (https://clinicaltrials.gov/ct2/show/NCT05734105) ).”
DiscussionFind in source

Premise concern: surrogate not validated for clinical benefit.

INADEQUATESurrogate endpoint
The primary efficacy claim is based on progression-free survival (PFS), which is a clinical outcome, but the analysis is exploratory and relies on ctDNA mutation subgroups as a surrogate for predicting treatment benefit. The paper does not provide evidence of target engagement at the tested dose (e.g., PK/PD) nor does it cite validated evidence linking the specific ctDNA mutation subgroups to clinical outcomes. The claim that ctDNA can identify patients who benefit from ripretinib is based on a biomarker (KIT mutation status) without established surrogacy.
“The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations.”
Find in source
ADEQUATEEffect size
The effect sizes are reported as median PFS differences (e.g., 14.2 vs 1.5 months for ripretinib vs sunitinib in the KIT exon 11 + 17/18 population) and are statistically supported with hazard ratios and nominal p-values. These differences are clinically meaningful as they represent substantial improvements in a hard clinical endpoint (PFS).
“Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months).”
Find in source

Data authenticity concerns

1 finding · worst medium

An 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).

mediumother
Trial NCT00457743 was first submitted to ClinicalTrials.gov on 2007-04-04, after the registered study start date of 2005-01. 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.
NCT00457743
reviewer’s wording
lowother
The paper reports '42 unique secondary resistance mutations' but the figure shows a complex landscape; the count seems plausible but not independently verifiable.
Overall, 42 unique secondary resistance mutations were observed in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18).
Resultsreviewer’s wording

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites prior studies showing sunitinib's differential efficacy based on secondary KIT mutation location and ripretinib's preclinical activity, providing a logical rationale for the ctDNA subgroup analysis. Limitations of prior work (e.g., lack of secondary mutation analysis in the sunitinib phase 3 trial) are acknowledged and addressed by the current ctDNA approach.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a clear scientific premise based on prior clinical and nonclinical evidence of differential TKI activity by KIT mutation location.

Evidence

paraphrase[Introduction, paragraph 2]

“In a phase 1/2 study (NCT00457743), the median PFS for sunitinib was 7.8 months in patients harboring secondary resistance mutations in the KIT ATP-binding pocket compared with 2.3 months in patients who had mutations in the activation loop.”

“Given the differential activity of TKIs depending on the location of KIT mutations as well as the poor activity of sunitinib in patients with secondary KIT exon 17/18 mutations, we hypothesized that further investigation by mutational subgroup using ctDNA could provide more insight into the efficacy of these agents as second-line therapies.”

Introduction ¶4Find in source

paraphrase[Introduction, paragraph 2]

“However, there was no analysis of secondary mutations in the phase 3 trial, and sunitinib has demonstrated differential efficacy dependent on the location of imatinib-resistant KIT mutations.”

PASSReviewer 2· 90% conf

The paper establishes a clear scientific premise based on prior clinical and nonclinical evidence of differential TKI activity by KIT mutation location, and a logical hypothesis linking ctDNA analysis to treatment selection.

Evidence

“In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations.”

Introduction ¶1Find in source

Introduction ¶3Find in source

paraphrase[Introduction, paragraph 2]

“However, there was no analysis of secondary mutations in the phase 3 trial, and sunitinib has demonstrated differential efficacy dependent on the location of imatinib-resistant KIT mutations.”

Randomization method (1:1) and stratification factors are stated. Blinding is described: investigators were not blinded, but the independent reviewer for PFS/ORR was blinded. Power analysis is not applicable for this exploratory analysis (no sample size predetermination). Inclusion/exclusion criteria are referenced to the primary publication. Outlier handling is addressed by stating that no data from analyzed samples were excluded.

Sub-criteria

controlsN/A

power analysisN/A

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The parent trial was a randomized, open-label phase 3 study with appropriate randomization and blinding of the independent reviewer; the exploratory analysis is clearly described.

Evidence

“Patients were randomized (1:1) to receive once-daily ripretinib 150 mg (continuous dosing) or once-daily sunitinib 50 mg (4 weeks on/2 weeks off in 6-week cycles).”

MethodsFind in source

“The endpoints of PFS and ORR were based on IRR and the independent reviewer was blinded to treatment assignment.”

Statistical analysisFind in source

“For this exploratory ctDNA analysis, no statistical method was used to predetermine sample size.”

Statistical analysisFind in source

PASSReviewer 2· 85% conf

The study design is a prespecified exploratory analysis of a randomized phase 3 trial, with adequate randomization, blinding of independent reviewers, and pre-specified endpoints, though no power analysis for the exploratory analysis.

Evidence

“Patients were randomized (1:1) to receive once-daily ripretinib 150 mg (continuous dosing) or once-daily sunitinib 50 mg (4 weeks on/2 weeks off in 6-week cycles).”

MethodsFind in source

“The endpoints of PFS and ORR were based on IRR and the independent reviewer was blinded to treatment assignment.”

Statistical analysisFind in source

“For this exploratory ctDNA analysis, no statistical method was used to predetermine sample size.”

Statistical analysisFind in source

Sex is reported for both subgroups and treatment arms. Age, race, region, primary tumor site, ECOG PS, and other clinical characteristics are provided in Table 1. Since this is a human study, species/strain and housing conditions are not applicable.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are reported for the two key subgroups, including age, sex, race, and disease-related variables.

Evidence

“Age (years), median (min, max) | 57.0 (34, 79) | 61.5 (43, 74) | 59.0 (34, 79) | 59.0 (33, 80) | 63.0 (31, 88) | 60.0 (31, 88)”

Table 1Find in source

“Sex (male), no. (%) | 12 (57.1) | 9 (45.0) | 21 (51.2) | 18 (66.7) | 20 (80.0) | 38 (73.1)”

Table 1Find in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are reported for the two key mutational subgroups, including age, sex, race, region, and disease-related variables.

Evidence

“Baseline demographic and clinical characteristics were well balanced between the KIT exon 11 + 13/14 and KIT exon 11 + 17/18 populations and between treatment arms (Table ).”

Table 1Find in source

“Sex (male), no. (%) | 12 (57.1) | 9 (45.0) | 21 (51.2) | 18 (66.7) | 20 (80.0) | 38 (73.1)”

Table 1Find in source

The Methods state that the protocol and informed consent documents were approved by a central IRB (WCG IRB) and site ethics committees. All patients provided written informed consent. Regulatory compliance is explicitly stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The study reports approval by a named IRB and ethics committees, written informed consent, and compliance with the Declaration of Helsinki and ICH-GCP.

Evidence

paraphrase[Methods, Study design]

“The protocol, protocol amendments and informed consent documents were approved by a central institutional review board (WCG IRB, Puyallup, WA), as well as the institutional review board or ethics committee at each site.”

“All patients provided written informed consent at enrollment.”

MethodsFind in source

“The INTRIGUE trial was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation Guidelines for Good Clinical Practice.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approval by a named IRB and informed consent are clearly documented, along with compliance with the Declaration of Helsinki and ICH-GCP.

Evidence

MethodsFind in source

“All patients provided written informed consent at enrollment.”

MethodsFind in source

“The INTRIGUE trial was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation Guidelines for Good Clinical Practice.”

MethodsFind in source

Ripretinib and sunitinib are named with doses and schedules. The ctDNA assay (Guardant360) is identified with vendor (Guardant Health) and performance metrics. Software (SAS version 9.4) is identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable as this is a clinical trial with no wet-lab bench components.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational drugs (ripretinib and sunitinib) are identified with doses and regimens, and the ctDNA assay (Guardant360) is named with performance characteristics.

Evidence

“Patients were randomized (1:1) to receive once-daily ripretinib 150 mg (continuous dosing) or once-daily sunitinib 50 mg (4 weeks on/2 weeks off in 6-week cycles).”

MethodsFind in source

paraphrase[Methods, ctDNA analysis]

“DNA extraction was performed by Guardant Health and samples were analyzed using Guardant360 (a 74-gene ctDNA NGS–based assay). This assay has a reported 99.6% specificity and 85.0% sensitivity when compared with tissue-based NGS.”

“Statistical analyses were done with SAS (version 9.4).”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational products (ripretinib and sunitinib) are identified with doses and regimens, and the ctDNA assay (Guardant360) is identified with performance characteristics.

Evidence

“Patients were randomized (1:1) to receive once-daily ripretinib 150 mg (continuous dosing) or once-daily sunitinib 50 mg (4 weeks on/2 weeks off in 6-week cycles).”

MethodsFind in source

paraphrase[Methods, ctDNA analysis]

“Statistical analyses were done with SAS (version 9.4).”

MethodsFind in source

Kaplan-Meier, Cox proportional hazards, log-rank, chi-square, and Newcombe methods are named. HRs with 95% CIs are reported for PFS and OS. Exact p-values are given (e.g., P = 0.0005). Software is identified. Data presentation includes KM curves and forest plots. Mathematical plausibility checks were not performed due to continuous outcomes and small subgroup sizes.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

Statistical tests are named, effect sizes with CIs are reported, and the analysis is appropriate for the exploratory nature; p-values are nominal and exact where reported.

Evidence

“HRs and P values were obtained from the unstratified Cox proportional hazard model and two-sided unstratified log-rank tests, respectively.”

MethodsFind in source

paraphrase[Results, Efficacy]

“In the KIT exon 11 + 13/14 population, sunitinib demonstrated improved PFS compared with ripretinib (median, 15.0 versus 4.0 months; HR, 3.94; 95% CI, 1.71–9.11; nominal P = 0.0005).”

paraphrase[Results, Efficacy]

“Conversely, ripretinib demonstrated improved PFS compared with sunitinib in patients with KIT exon 11 + 17/18 mutations (median, 14.2 versus 1.5 months; HR, 0.22; 95% CI, 0.11–0.44; nominal P < 0.0001).”

PASSReviewer 2· 85% conf

Statistical tests are named, effect sizes with confidence intervals are reported, and the analysis is appropriate for the exploratory nature, though p-values are nominal and some are reported as thresholds.

Evidence

“HRs and P values were obtained from the unstratified Cox proportional hazard model and two-sided unstratified log-rank tests, respectively.”

MethodsFind in source

“In the KIT exon 11 + 13/14 population, sunitinib demonstrated improved PFS compared with ripretinib (median, 15.0 versus 4.0 months; HR, 3.94; 95% CI, 1.71–9.11; nominal P = 0.0005; Figs. and ).”

ResultsFind in source

The data availability statement explains that the ctDNA dataset is not broadly available due to privacy, but qualified researchers can request de-identified data via a named contact, with evaluation and data access agreement. This meets the standard for managed access. No code was generated, so code_sharing is not applicable.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

A data availability statement provides a concrete managed-access route for individual participant data, with conditions and timeframe.

Evidence

Data availabilityFind in source

PASSReviewer 2· 90% conf

A data availability statement provides a concrete managed-access route for individual participant data, with conditions and timeframe, and the protocol is publicly accessible.

Evidence

“Qualified scientific and medical researchers can make requests for individual participant data that underlie the results reported in this article, after de-identification, at info@deciphera.com. Proposals for data will be evaluated and approved by Deciphera in its sole discretion. All approved researchers must sign a data access agreement before accessing the data. Data will be available as soon as possible but no later than within 1 year of the acceptance of the article for publication and for 3 years after article publication.”

Data availabilityFind in source

The trial is registered (NCT03673501). Funding and competing interests are detailed. Limitations are explicitly discussed, including exploratory nature, small subgroup numbers, and ctDNA detection issues. Conclusions are appropriately cautious, noting the need for prospective confirmation.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineINADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The manuscript is transparent: trial registration, funding/COI, limitations, and proportional conclusions are all reported.

Evidence

paraphrase[Abstract]

“ClinicalTrials.gov identifier: NCT03673501.”

“Limitations of the current study include the exploratory nature of the analysis; as such, all P values reported are nominal and no statistical significance can be claimed or cited in clinical practice.”

Discussion ¶6Find in source

“The INTRIGUE study was funded by Deciphera Pharmaceuticals, and as the sponsor, Deciphera contributed to the conception, design and analysis of the study.”

AcknowledgementsFind in source

PASSReviewer 2· 90% conf

The manuscript is transparent: methods are detailed, the trial is registered, limitations are discussed, conclusions are proportional, and funding/COI are disclosed.

Evidence

“ClinicalTrials.gov identifier: NCT03673501 .”

AbstractFind in source

DiscussionFind in source

“The INTRIGUE study was funded by Deciphera Pharmaceuticals, and as the sponsor, Deciphera contributed to the conception, design and analysis of the study.”

AcknowledgementsFind in source

Registered (3 IDs: ClinicalTrials.gov). No reporting guideline cited.

ClinicalTrials.gov

NCT03673501

ClinicalTrials.gov

NCT00457743

ClinicalTrials.gov

NCT05734105

Broken references and links

None found

References 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 42 references by DOI: 33 verified — 9 no DOI (shown, not verified).

NO DOI
Gleevec (imatinib mesylate) tablets, for oral use. Prescribing information.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Sutent (sunitinib malate) capsules, for oral use. Prescribing information.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
QINLOCK ® (ripretinib) tablets, for oral use. Prescribing information.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
NCCN guidelines gastroinestinal stromal tumors (GISTs) version 1.2023
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
AYVAKIT (avapritinib) tablets, for oral use. Prescribing information.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Vitrakvi (larotrectinib) tablets or solution, for oral use. Prescribing information.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Mekinist (trametinib) tablets, for oral use. Prescribing information.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Tafinlar (dabrafenib) tablets, for oral use. Prescribing information.
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

1 data/code link found; not probed for liveness in this run.

datahttps://ascopubs.org/doi/suppl/10.1200/JCO.22.00294/suppl_file/protocol_JCO.22.00294.pdfUNVERIFIEDHTTP 403
Liveness indeterminate — content not checked.

Copyediting

4 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 4 minor suggestions below.

4 copyedit issues flagged: mostly consistency, clarity, other.

MINORconsistencyAbstract
“KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20)”
→ Ensure consistent use of 'n' vs 'N' for subgroup sizes.
Minor formatting inconsistency.
MINORclarityResults, ctDNA sample evaluability
“Most patients harbored one or two KIT mutations (162 (76%))”
→ Clarify the denominator (162 of 213 patients with KIT mutations).
The percentage is clear but the denominator could be stated explicitly.
MINORotherMethods, ctDNA analysis
“The ctDNA assay used all the baseline sample and cannot be reproduced.”
→ Rephrase to 'The ctDNA assay consumed all baseline samples and cannot be repeated.'
Awkward phrasing.
MINORconsistencyAbstract
“In this exploratory analysis ( N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing–based assay.”
→ Consider removing the space before N for consistency with the rest of the text.
Minor formatting inconsistency.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust in its reporting and transparency, with no major rigor gaps that would warrant an erratum or retraction. An informed reader should weigh the exploratory nature, the small subgroup sizes, and the fact that only a subset of statistics were independently verified; the retrospective registration of the cited prior trial is a minor concern. The minor copyedit issues and the lack of an explicit reporting guideline are not substantive threats to the paper's conclusions.

1.
HIGHreporting
In the Methods, explicitly state adherence to a reporting guideline such as CONSORT or STROBE, and mention the reporting summary in the main text.
Both reviewers noted the absence of an explicit reporting guideline, which is a standard expectation for clinical trial reports.
2.
HIGHstatistics
In the Results, report exact p-values for all comparisons currently given as thresholds (e.g., P < 0.0001) to improve precision.
One reviewer flagged threshold-only p-values as imprecise reporting; exact values would strengthen the audit trail.
3.
MEDIUMdata code
In the Data Availability section, consider providing a data access committee or platform (e.g., Vivli) to further concretize the access route.
A named contact is adequate, but a formal platform would enhance reproducibility and align with best practices.
4.
MEDIUMreporting
In the Discussion, add a sentence on the generalizability of the findings given the exploratory nature and small subgroup sizes.
This would help readers interpret the clinical relevance of the subgroup results.
5.
MEDIUMrigor
In the Methods, clarify whether the ctDNA assay was validated for the specific sample type and processing used in this study, and state the assay version.
Assay validation details are important for reproducibility and were not fully specified.
6.
MEDIUMrigor
In the Methods, add a note on the potential for false-positive ctDNA findings due to clonal hematopoiesis, which is relevant for KIT mutations.
This is a known confounder in ctDNA analysis and would strengthen the limitations discussion.
7.
MEDIUMdata code
Consider depositing the de-identified ctDNA mutation data in a controlled-access repository (e.g., dbGaP) to facilitate reproducibility.
A managed-access route via email is adequate but a repository would be more robust and discoverable.
8.
MEDIUMreporting
In the Results, clarify the denominator for the statement 'Most patients harbored one or two KIT mutations (162 (76%))' by explicitly stating the denominator (e.g., 162 of 213 patients with KIT mutations).
The copyedit pass flagged this as a clarity issue; explicit denominators improve transparency.
9.
LOWcopyedit
In the Abstract, ensure consistent use of 'n' vs 'N' for subgroup sizes and remove the space before 'N' in 'N = 362'.
Minor formatting inconsistencies were flagged by the copyedit pass.
10.
LOWcopyedit
In the Methods, rephrase 'The ctDNA assay used all the baseline sample and cannot be reproduced' to 'The ctDNA assay consumed all baseline samples and cannot be repeated.'
The original phrasing is awkward and unclear.
11.
LOWreporting
In the Results, provide the exact number of patients with co-occurring KIT exon 11 + 13/14 + 17/18 mutations in the text (currently only in figure legend).
This detail is important for interpreting the subgroup definitions and was noted by one reviewer.
12.
LOWreporting
In the Methods, clarify the definition of 'exclusively' in the subgroup definitions (e.g., whether patients with PDGFRA mutations were excluded).
Precise subgroup definitions are essential for reproducibility.

Full text (58,640 chars)Analyzed: Aug 16, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

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.”

How stars are deducted

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.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

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.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

DOI

10.1038/s41591-023-02734-5

Record issued

2026-08-16

Engine

7.39.0

Exported

2026-09-20