Datopotamab-deruxtecan plus durvalumab in early-stage breast cancer: the sequential multiple assignment randomized I-SPY2.2 phase 2 trial.
Shatsky RA, Trivedi MS, Yau C, Nanda R, Rugo HS, Davidian M, Tsiatis B, Wallace AM, Chien AJ, Stringer-Reasor E, Boughey JC, Omene C, Rozenblit M, Kalinsky K, Elias AD, Vaklavas C, Beckwith H, Williams N, Arora M, Nangia C, Roussos Torres ET, Thomas B, Albain KS, Clark AS, Falkson C, Hershman DL, Isaacs C, Thomas A, Tseng J, Sanford A, Yeung K, Boles S, Chen YY, Huppert L, Jahan N, Parker C, Giridhar K, Howard FM, Blackwood MM, Sanft T, Li W, Onishi N, Asare AL, Beineke P, Norwood P, Brown-Swigart L, Hirst GL, Matthews JB, Moore B, Symmans WF, Price E, Heditsian D, LeStage B, Perlmutter J, Pohlmann P, DeMichele A, Yee D, van 't Veer LJ, Hylton NM, Esserman LJ
- DOI
- 10.1038/s41591-024-03267-1
- Record issued
- 2026-08-16
- Engine
- 7.39.0
- Exported
- 2026-09-22
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/35cecbe3-67a2-4af4-b21d-d4152cabaf24 is authoritative.
How this rating was calculated
- CitationsUnresolved reference ×4−1★
- ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
- ClaimsTreatment effect not shown to be clinically meaningful−0.5★
- No reported statistical tests were found to recompute.
- The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 1 reported mean was read, and its group size is not stated where the value is printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.
- Declared data/code links were not checked for liveness or content.
- 01Efficacy rests on an unvalidated surrogate endpoint
The primary endpoint is pathological complete response (pCR), a surrogate for long-term clinical outcomes such as event-free survival. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data) nor cite validated evidence linking pCR to the specific clinical outcome in this context, beyond general statements that pCR is an important prognostic marker.
“pathologic complete response (pCR) is an important prognostic marker for individuals with molecularly high-risk breast cancer, regardless of the treatment they receive”
- 02Treatment effect not shown to be clinically meaningful
The primary positive result is a modeled pCR rate of 41% in a small subtype (n=11) compared to a dynamic control of 16%, but the absolute improvement is modest and the confidence interval is wide (16-66%). No minimal clinically important difference is provided, and the effect is not anchored to a clinically meaningful threshold beyond the trial's graduation criteria.
“the treatment strategy across all blocks graduated in the hormone receptor-negative HER2 − Immune − DNA repair deficiency − subtype with an estimated pathological complete response rate of 41%”
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.
The paper reports a well-conducted adaptive platform trial with strong ethical approvals, detailed methods, and transparent reporting. The main weakness is incomplete reporting of randomization details and blinding, which are minor but notable for a clinical trial.
All three reviewers classified the study as interventional; no disagreement. The evaluation covered the full text, with N/A for animal-related and cell-line criteria. The statistics verification could not recompute any tests due to lack of test statistics/df, so statistical correctness is not independently confirmed.
Numerical inconsistencies
None foundValues 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.
Checked — nothing surfaced.
Overstated conclusions
2 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
6 major claims checked against the paper's own evidence: all adequately supported.
- supportedReviewers 2, 3Dato-DXd did not meet the prespecified threshold for success after block A in any subtype.The paper reports that Dato-DXd did not graduate in any subtype after block A, and the posterior probabilities are all below the 85% threshold.Evidence: Figure 3 shows P(>Th) values all below 0.85 for each subtype.
“While Dato-DXd did not meet the prespecified threshold for success (graduation) after block A in any subtype”
AbstractFind in source - supportedReviewer 2The treatment strategy across all blocks graduated in the HR−HER2−Immune−DRD− subtype with an estimated pCR rate of 41%.The paper reports a modeled pCR rate of 41% with P(>DC)=0.97, exceeding the 85% threshold.Evidence: Figure 4b and Supplementary Table 2 show P(>DC)=0.97 for this subtype.
“the treatment strategy across all blocks graduated in the hormone receptor-negative HER2 − Immune − DNA repair deficiency − subtype with an estimated pathological complete response rate of 41%”
AbstractFind in source - supportedReviewer 2Dato-DXd was particularly active in the HR−HER2−Immune−DRD− signature, warranting further investigation.The paper shows a high pCR rate in this subtype and discusses the potential for further investigation.Evidence: Results show 4/11 patients achieved pCR, and the treatment strategy graduated.
“Dato-DXd was particularly active in the hormone receptor-negative/HER2 − Immune − DNA repair deficiency − signature, warranting further investigation”
AbstractFind in source - supportedReviewers 2, 3Dato-DXd was safe in other subtypes in patients who followed the treatment strategy.The paper reports no new toxicities and low-grade adverse events, and the safety profile is described.Evidence: Safety results show no grade 4/5 events in block A and manageable toxicities.
“and was safe in other subtypes in patients who followed the treatment strategy”
AbstractFind in source - supportedReviewer 3The treatment strategy across all blocks graduated in the HR − HER2 − Immune − DRD − subtype with an estimated pCR rate of 41%.The paper reports a modeled pCR rate of 41% with P(>DC)=0.97, meeting the graduation threshold.Evidence: Figure 4b and Supplementary Table 2 show P(>DC)=0.97.
“the treatment strategy across all blocks graduated in the hormone receptor-negative HER2 − Immune − DNA repair deficiency − subtype with an estimated pathological complete response rate of 41%.”
AbstractFind in source - supportedReviewer 3Dato-DXd was particularly active in the HR − HER2 − Immune − DRD − subtype, warranting further investigation.The paper provides evidence of activity in this subtype, including a high pCR rate and graduation, supporting further investigation.Evidence: Results show 4/11 pCRs and graduation in this subtype.
“These results suggest that Dato-DXd is highly active in this subtype and warrants further investigation.”
DiscussionFind in source
Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.
- INADEQUATESurrogate endpointThe primary endpoint is pathological complete response (pCR), a surrogate for long-term clinical outcomes such as event-free survival. The paper does not demonstrate target engagement at the tested dose (e.g., PK/PD data) nor cite validated evidence linking pCR to the specific clinical outcome in this context, beyond general statements that pCR is an important prognostic marker.
“pathologic complete response (pCR) is an important prognostic marker for individuals with molecularly high-risk breast cancer, regardless of the treatment they receive”
- INADEQUATEEffect sizeThe primary positive result is a modeled pCR rate of 41% in a small subtype (n=11) compared to a dynamic control of 16%, but the absolute improvement is modest and the confidence interval is wide (16-66%). No minimal clinically important difference is provided, and the effect is not anchored to a clinically meaningful threshold beyond the trial's graduation criteria.
“the treatment strategy across all blocks graduated in the hormone receptor-negative HER2 − Immune − DNA repair deficiency − subtype with an estimated pathological complete response rate of 41%”
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
None foundRequired 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.
The introduction cites prior clinical studies (TROPION-PanTumor01, pooled analysis) and the I-SPY2 trial, acknowledging strengths and limitations. The rationale for testing Dato-DXd in early-stage breast cancer is clearly linked to its mechanism and activity in metastatic disease. Limitations of prior work are addressed through the adaptive trial design and dynamic control.
“In the phase 1 TROPION-PanTumor01 study that included patients with metastatic non-small cell lung cancer, hormone receptor (HR) + / human epidermal growth factor receptor 2 (HER2) − breast cancer and TNBC, Dato-DXd showed promising clinical activity with an overall response rate of 31.8% in heavily pretreated patients with TNBC, 26.8% in HR + /HER2 − breast cancer and 40% in patients with TNBC who had not received prior treatment with a topoisomerase inhibitor-based ADC 10 .”
“Using the lessons from I-SPY2, I-SPY2.2 was designed with the goal of further refining the biological targeting of treatments to give each woman the best opportunity to reach pCR, while at the same time reducing exposure to unnecessary treatments to minimize toxicities.”
“In the phase 1 TROPION-PanTumor01 study that included patients with metastatic non-small cell lung cancer, hormone receptor (HR) + / human epidermal growth factor receptor 2 (HER2) − breast cancer and TNBC, Dato-DXd showed promising clinical activity with an overall response rate of 31.8% in heavily pretreated patients with TNBC, 26.8% in HR + /HER2 − breast cancer and 40% in patients with TNBC who had not received prior treatment with a topoisomerase inhibitor-based ADC 10 .”
“Using the lessons from I-SPY2, I-SPY2.2 was designed with the goal of further refining the biological targeting of treatments to give each woman the best opportunity to reach pCR, while at the same time reducing exposure to unnecessary treatments to minimize toxicities.”
Randomization method is described (equal probability to open arms), and the unit is the patient. Blinding is not reported, but this is an open-label trial; the lack of blinding is not explicitly justified, but it is typical for such platform trials. Power analysis is replaced by a preset maximum sample size based on simulations. Inclusion/exclusion criteria are described. Outlier handling is addressed through modified ITT analysis and sensitivity analyses. Controls are provided by the dynamic control. Independent replication is not applicable as this is a single trial.
“I-SPY2.2 is open to women and men aged ≥18 years with anatomic stage II or III breast cancer whose primary tumors are ≥2.5 cm by clinical examination or ≥2.0 cm by imaging.”
“I-SPY2.2 is open to women and men aged ≥18 years with anatomic stage II or III breast cancer whose primary tumors are ≥2.5 cm by clinical examination or ≥2.0 cm by imaging.”
Sex is reported (women and men eligible, but all participants appear to be women based on breast cancer context). Age, race, ethnicity, and health status (ECOG performance status) are reported. Species/strain and housing are not applicable as this is a human trial. Demographics are adequately reported in Table 1.
“The median age at screening was 46 (range 28–78) years.”
“Most patients were White (58.3%), 11.7% were Hispanic/Latino, 10.7% were Black, 8.7% were Asian and 1% were Indigenous American/Alaska Native.”
“Age (years) at screening Mean (s.d.) 47.8 (11.6) Median (min, max) 46.0 (28.0, 78.0)”
“Race Asian 9 (8.7%) Black 11 (10.7%) Indigenous American/Alaska Native 1 (1.0%) White 60 (58.3%) Missing 22 (21.4%)”
“Participants must have an Eastern Cooperative Oncology Group performance status 0 or 1 (ref. 25).”
“Median (min, max) 46.0 (28.0, 78.0)”
“Most patients were White (58.3%), 11.7% were Hispanic/Latino, 10.7% were Black, 8.7% were Asian and 1% were Indigenous American/Alaska Native.”
“Participants must have an Eastern Cooperative Oncology Group performance status 0 or 1 (ref. 25).”
The study was approved by Wake Forest School of Medicine as the central IRB. Informed consent is described (written consent before screening and after randomization). Regulatory compliance is stated with the Declaration of Helsinki. No animal research is involved.
“All participants signed written informed consent before screening and again after randomization; no compensation was provided for participation in the study.”
“The I-SPY2.2 trial complies with all local and national regulations regarding the use of human study participants and was conducted in accordance to the criteria set by the Declaration of Helsinki.”
“The study was approved by Wake Forest School of Medicine, who acted as the central institutional review board (IRB)”
“All participants signed written informed consent before screening and again after randomization; no compensation was provided for participation in the study.”
“The I-SPY2.2 trial complies with all local and national regulations regarding the use of human study participants and was conducted in accordance to the criteria set by the Declaration of Helsinki.”
Dato-DXd is identified as an antibody-drug conjugate with manufacturer (AstraZeneca) and dose (6 mg/kg IV). The drug is adequately described. Statistical software (R and STAN) is identified. Antibodies, cell lines, mycoplasma, and organisms are not applicable as this is a clinical trial without wet-lab assays.
“paclitaxel (T) only (for HR + Immune − DRD − ), paclitaxel (T) plus concurrent carboplatin (C) (for HER2 − Immune − DRD + ), or concurrent pembrolizumab (Pe), paclitaxel and carboplatin (for HR − HER2 − Immune − DRD − , HER2 − Immune + and HER2 − Immune − DRD + ).”
“Participants in the DATO arm received intravenous 6 mg kg −1 Dato-DXd (D) on day 1 of each 3 week cycle for up to four cycles in block A.”
“Efficacy analysis of block A alone was performed using R and STAN via the RSTAN package, which implements the NUTS sampler.”
“Participants in the DATO arm received intravenous 6 mg kg −1 Dato-DXd (D) on day 1 of each 3 week cycle for up to four cycles in block A.”
“Efficacy analysis of block A alone was performed using R and STAN via the RSTAN package, which implements the NUTS sampler.”
The paper uses Bayesian models for efficacy, reporting posterior probabilities and credible intervals. Exact p-values are not reported for the primary analyses, but this is appropriate for Bayesian estimation. Effect sizes are reported with confidence intervals. Statistical software is identified. Data presentation includes CONSORT diagram and figures with distributions. Mathematical plausibility checks are not applicable due to model-derived estimates.
“In this analysis, we estimated the pCR rate of block A (alone) using a Bayesian covariate-adjusted model with MRI imputation based on pCR and MRI data.”
“The modeled pCR rate for the treatment strategy (across all blocks) was 41% (confidence interval (CI) 16–66%).”
“Efficacy analysis of block A alone was performed using R and STAN via the RSTAN package, which implements the NUTS sampler.”
“Efficacy analysis of block A alone was performed using R and STAN via the RSTAN package, which implements the NUTS sampler.”
“The modeled pCR rate for the treatment strategy (across all blocks) was 41% (confidence interval (CI) 16–66%).”
“Figure 2 is the CONSORT diagram, which shows the flow of patients from screening to randomization and demonstrates how many patients proceeded through each block of therapy.”
Data availability statement names a concrete route (I-SPY Data Access and Publications Committee) with a URL. Repository deposit is not applicable for patient-level data. Accession numbers are not applicable. Code sharing is described with a concrete application process.
“De-identified subject level data and/or clinical specimens are made available to members of the research community upon approval of the I-SPY Data Access and Publications Committee.”
The trial is registered (NCT01042379). A CONSORT diagram is provided. Limitations are discussed, including nonadherence and small subtype sizes. Conclusions are proportional, noting the exploratory nature of the findings. Funding and competing interests are disclosed.
“ClinicalTrials.gov registration: NCT01042379.”
“Note that the planned secondary endpoint of event-free survival is not reported in this paper.”
“ClinicalTrials.gov registration: NCT01042379.”
“One major limitation of this trial arm was lack of adherence to trial guidance on escalation or de-escalation strategies recommended as a result of pre-RCB assessments.”
“Research reported in this paper was supported by the NCI of the National Institutes of Health (NIH) under award numbers P01CA210961 and U01CA225427 (L.J.E., N.H.).”
“ClinicalTrials.gov registration: NCT01042379.”
“Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.”
“One major limitation of this trial arm was lack of adherence to trial guidance on escalation or de-escalation strategies recommended as a result of pre-RCB assessments.”
Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.
Broken references and links
1 finding · worst lowReferences 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.
- References not resolvable to a published paperRecomputed
Checked 31 references by DOI: 23 verified — 4 DOI unresolved, 4 no DOI (shown, not verified).
- UNRESOLVED10.1001/jamaoncol.2020.0075Effect of pembrolizumab plus neoadjuvant chemotherapy on pathologic complete response in women with early-stage breast cancerCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1200/jco.23.02609Datopotamab deruxtecan in advanced or metastatic HR+/HER2− and triple-negative breast cancer: results from the phase I TROPION-PanTumor01 studyCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1177/1740774514526376Introduction to dynamic treatment strategies and sequential multiple assignment randomizationCited DOI does not resolve to any Crossref record.
- UNRESOLVED10.1038/s41523-020-00208-6Predicting breast cancer response to neoadjuvant treatment using multi-feature MRI: results from the I-SPY 2 TRIALCited DOI does not resolve to any Crossref record.
- NO DOIMRI models by response predictive subtype for predicting pathologic complete responseNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIfunctional tumor volume at 3 and 6 week MRI as an indicator of patients with inferior outcome after neoadjuvant chemotherapyNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOIProspective performance of an MRI algorithm for early re-direction of breast cancer neoadjuvant treatmentNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
- NO DOICommon terminology criteria for adverse events (CTCAE) protocol developmentNo DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
Copyediting
4 minorWording, 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, typo, clarity.
- MINORconsistencyAbstract“hormone receptor-negative HER2 − Immune − DNA repair deficiency − subtype”→ Use consistent formatting for subtype names, e.g., 'HR−HER2−Immune−DRD−'.Subtype naming is inconsistent between abstract and results.
- MINORtypoResults, Efficacy of treatment strategy“P (>DC) of 0.97 within this subtype”→ Consider adding a space: 'P (>DC)'.Minor formatting issue.
- MINORconsistencyAbstract“hormone receptor-negative HER2 − Immune − DNA repair deficiency − subtype”→ Ensure consistent use of hyphens and spacing in subtype names.Subtype naming is inconsistent in spacing.
- MINORclarityResults, Efficacy of treatment strategy“In the HR − HER2 − Immune − DRD − subtype, a small subtype, 4 of 11 patients (36%) achieved a pCR.”→ Rephrase to avoid redundancy: 'In the small HR − HER2 − Immune − DRD − subtype, 4 of 11 patients (36%) achieved a pCR.'Redundant phrasing.
The published work is robust overall, but readers should weigh the incomplete reporting of randomization and blinding, and the lack of independent statistical verification. No erratum is warranted, but a correction to add randomization details and a blinding rationale would strengthen the record.
- 1.HIGHreportingIn the Methods, add a statement describing the randomization method in detail, including whether allocation was concealed, stratification factors, and block sizes.The current description only states equal probability to open arms, which is insufficient for replication and assessment of bias.
- 2.HIGHreportingIn the Methods, explicitly state that the trial was open-label and provide a rationale for not blinding, and discuss potential bias.Blinding is not mentioned anywhere, and an open-label design without justification is a reporting gap that readers should weigh.
- 3.HIGHreportingIn the Results, explicitly state that the secondary endpoint of event-free survival is not reported and provide a reason or reference to future publications.The paper notes EFS is not reported but does not explain why, which is a transparency gap.
- 4.HIGHotherVerify the four references flagged as not found in any registry (pembrolizumab JAMA Oncol, TROPION-PanTumor01 JCO, dynamic treatment strategies, MRI prediction npj Breast Cancer) and correct or replace them if they are erroneous.References that cannot be located in Crossref/OpenAlex may be fabricated or have incorrect DOIs, which is an integrity concern.
- 5.MEDIUMreportingIn the Methods, provide more detail on the dynamic control construction, including how weights are calculated and sensitivity to candidate comparators.The dynamic control is central to the analysis, and more detail would improve reproducibility.
- 6.MEDIUMdata codeIn the Data Availability section, clarify the timeline for public access to the full dataset, as the current statement says 'within 6 months of publication' but does not specify a date.A concrete timeline would help readers know when data will be available.
- 7.MEDIUMreportingIn the Results, provide the exact pCR rates with 95% CIs for the block A analysis in the text, not only in figures.Currently the rates are only shown in figures, which is less accessible and less precise.
- 8.MEDIUMreportingIn the Methods, report the a priori power/sample-size calculation for the block A efficacy analysis, including assumed effect size, alpha, and power.The preset maximum sample size is mentioned but the operating characteristics are not fully specified.
- 9.MEDIUMreportingIn Table 1, consider adding menopausal status and BMI, as these are prognostic in breast cancer.These variables are not reported, and their absence limits the ability to assess confounding.
- 10.LOWcopyeditIn the Abstract, standardize the formatting of subtype names (e.g., 'HR−HER2−Immune−DRD−') for consistency.Subtype naming is inconsistent between abstract and results, which could confuse readers.
- 11.LOWcopyeditIn the Results, add a space in 'P (>DC)' for consistency.Minor formatting issue.
- 12.LOWcopyeditIn the Results, rephrase 'In the HR − HER2 − Immune − DRD − subtype, a small subtype, 4 of 11 patients (36%) achieved a pCR.' to avoid redundancy.Redundant phrasing reduces clarity.
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.