Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

Shanu Modi; William Jacot; Toshinari Yamashita; Joohyuk Sohn; María Vidal

doi:10.1056/nejmoa2203690

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer

Shanu Modi, William Jacot, Toshinari Yamashita, Joohyuk Sohn, María Vidal, Eriko Tokunaga, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Yee Soo Chae, Keun Seok Lee, Naoki Niikura, Yeon Hee Park, Binghe Xu, Xiaojia Wang...

Massachusetts Medical Society (2022) • Volume 387, Issue 1, Pages 9-20

Empirical-ClinicalRCTPDF AvailableGrade EligiblePre-registered (both)⚠️ Moderate Risk Flags

Overall Assessment

Strong Methodological Quality

Assessment created by PaperScores Medical AI v0.1.0 on Dec 14, 2025

B-

73/100

Key Takeaways

•T-DXd improved PFS vs physician’s-choice chemo in HR+ cohort: 10.1 vs 5.4 mo; HR 0.51.
•OS benefit observed: 23.9 vs 17.5 mo in HR+; HR 0.64.
•Benefit consistent across all patients, including HR− subgroup.
•Safety manageable; ILD/pneumonitis in 12.1% (grade 5: 0.8%).
•Open-label, sponsor-designed; central blinded PFS review and ITT analyses.

Conclusion

Robust superiority RCT showing T-DXd improves PFS and OS over standard chemo in HER2-low metastatic breast cancer with acceptable, monitorable risks.

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Quality Dimensions

Bias & Integrity

COI handling, outcome switching, selective reporting

C+65

Methods Rigour

Protocol clarity, sampling, controls

A-86

External Validity

Generalisability, setting, population

B-70

Transparency & Reproducibility

Data/code/materials availability, preregistration

D40

Significance & Novelty

Contribution vs prior art; context if known

A90

Statistical Validity

Models, assumptions, multiplicity, CI priority

A-85

Integrity & Transparency

Integrity checks

P-hacking risk?

?

None suspected

Signs of selective hypothesis testing or analysis choices that could inflate false positive rates.

Outcome switching?

?

None suspected

Evidence that primary outcomes were changed during or after the study, potentially distorting results.

Conflict of interest?

?

Review recommended

Authors have financial or other relationships that could bias research findings.

Data integrity issues?

?

None suspected

Concerns about the accuracy, completeness, or authenticity of the reported data.

Open science signals

Research data

?

Upon request

Raw data used in the analyses is publicly available or accessible upon request.

Analysis code

?

Not applicable

Code or scripts used to analyze the data are shared for reproducibility.

Study materials

?

Restricted

Protocols, questionnaires, and other materials are publicly available.

Premise

Primary Research Question

Does trastuzumab deruxtecan improve PFS and OS versus physician’s-choice chemotherapy in HER2-low metastatic breast cancer?

Hypothesis

T-DXd is superior to standard chemotherapy for PFS and OS.

Hypothesis is Falsifiable

✓Yes

Superiority RCT with time-to-event endpoints and HRs.

PICO Framework

Population✓Yes

HER2-low (IHC 1+ or 2+/ISH−) metastatic breast cancer; HR+ and HR− strata.

Intervention✓Yes

T-DXd 5.4 mg/kg IV q3w.

Comparison✓Yes

Physician’s-choice standard single-agent chemo (capecitabine, eribulin, etc.).

Outcome✓Yes

Primary PFS (central review); key OS; objective response and safety.

Literature Positioning

Literature Review Balanced

Well covered

Clear background on HER2-low landscape and prior ADC data.

Evidence: p. 10, 17–18

Research Gap Clearly Stated

Well covered

Few effective options for HER2-low; prior HER2 therapies ineffective.

Evidence: p. 10

Stated Contribution Clear

Well covered

Shows PFS and OS benefit of T-DXd vs chemo in HER2-low MBC.

Evidence: p. 9, 12–14

Study Provenance

Peer reviewed venueFunding disclosedConflict disclosure provided5 affiliations listed

Authors & Affiliations

Multinational academic and cancer centres (e.g., MSKCC, Institut Curie, Seoul Natl Univ, etc.).

Funding Statement

Funded by Daiichi Sankyo and AstraZeneca.

Conflicts of Interest

Disclosures provided; editorial/writing assistance funded by Daiichi Sankyo.

Peer Review

✓NEJM 2022;387:9–20.

Evidence: p. 9

Methodological Assessment

Randomized Controlled TrialCONSORTRCT

16 applicable checklist items.

Yes 12 · Unclear 4

Study Design & Protocol

✓

Power Analysis Reported

90% power; ~318 PFS events planned; HR=0.68 assumed.

Evidence: p. 11

?

Randomisation Adequate

Randomised 2:1 with stratification; method of sequence generation not detailed.

Evidence: p. 10–11

?

Allocation Concealment

Allocation concealment not described.

Evidence: p. 10–11

✓

Blinding

Open-label, but PFS assessed by blinded independent central review.

Evidence: p. 11

?

Blinding Adequate

Outcome assessors blinded; participants/investigators not; adequacy partly limited.

Evidence: p. 11

✓

Intervention Replicable

Dose 5.4 mg/kg q3w; comparator regimens per label/NCCN listed.

Evidence: p. 11

✓

Outcomes Pre-specified

Primary PFS HR+; key PFS all, OS HR+ and all; prespecified hierarchy.

Evidence: p. 11

✓

Pre-registration Evidence

Registered NCT03734029; protocol and SAP at NEJM.

Evidence: p. 9, 11

Analysis & Reporting

✓

Analysis Set Appropriate (ITT/mITT)

Efficacy analysed in ITT set.

Evidence: p. 11

?

Missing Data Handled Appropriately

Handling of missing/censoring described minimally; no imputation details.

Evidence: p. 11

✓

Baseline Balance Acceptable

Baseline characteristics similar across arms (Table 1).

Evidence: Table 1, p. 13

✓

Adherence Adequate

IV dosing; exposure, dose reductions, and durations reported.

Evidence: p. 15

✓

Participant Flow Reported (CONSORT)

Screening/randomisation flow referenced (Fig. S1).

Evidence: p. 12

✓

Harms Reported Adequately

Comprehensive AEs; ILD adjudication; grades and deaths reported.

Evidence: p. 15–16

✓

Cluster/Strata Accounted

Stratified randomisation and analyses used.

Evidence: p. 10–12

✓

Interim Analyses Handled

Group sequential testing and interim boundaries described.

Evidence: p. 11, 13

Modules without applicable checklist items (9)

These designs were fully marked as not applicable but remain available for reference.

Abstract

In this trial involving patients with HER2-low metastatic breast cancer, trastuzumab deruxtecan resulted in significantly longer progression-free and overall survival than the physician's choice of chemotherapy. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast04 ClinicalTrials.gov number, NCT03734029.).

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Study Overview

Study Design

RCT

Primary classification used to evaluate this research.

Population

Adults with HER2-low (IHC 1+ or 2+/ISH−) unresectable/metastatic breast cancer after 1–2 prior chemotherapy lines; HR+ and HR− strata.

Brief summary of who or what was studied.

Sample Size

557

Number of participants included in the study analyses.

Study Arms

2 arms

Total number of intervention or comparison groups.

Pre-registration

Registry entry and protocol

Indicates whether the protocol or trial was registered before data collection.

Randomisation

Stratified randomisation

How participants were allocated to groups: None (no randomisation), Simple (random order), Blocked (groups balanced in blocks), Stratified (balanced within subgroups), Adaptive (allocation adjusted based on previous enrollments).

Blinding

None

Who was unaware of group assignments: None (everyone knew), Single blind (participants didn't know their group), Double blind (participants and researchers didn't know), Triple blind (also outcome assessors didn't know).

Analysis Set

ITT (all randomised participants)

Which participants were included in analysis: ITT (all randomized, regardless of adherence), mITT (modified ITT, excluding some for valid reasons), Per protocol (only those who completed as planned), As treated (grouped by actual treatment received), Other (alternative approach).

Follow-up

Median survival follow-up 18.4 months

Duration of observation or follow-up for outcomes.

Primary Outcome

Primary outcome was pre-specified in the protocol or registry.

Effect Size

HR: HR 0.51 (95% CI 0.40–0.64) for PFS (HR+ cohort)

Reviewer Notes

Randomised, open-label, stratified phase 3 superiority trial vs physician’s-choice chemotherapy; blinded central PFS assessment.

Publication Details

DOI

10.1056/nejmoa2203690

Published

June 5, 2022

Citations

2171 citations

FWCI

324.15

External Resources

DOI Link OpenAlex

Disclaimer: This assessment is generated by AI and should not be the sole basis for clinical or research decisions. Always review the original paper and consult with domain experts.

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