# DESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer

Source: https://onco.cc/key-papers/paper-destiny-breast03-nejm-2022/  
OnCo record `paper-destiny-breast03-nejm-2022` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A newer antibody-drug conjugate, trastuzumab deruxtecan, kept HER2-positive metastatic breast cancer under control roughly four times longer than the previous standard, T-DM1, and later lengthened survival.

## Summary

Open-label phase 3 trial of 524 patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab and a taxane, randomised 1:1 to trastuzumab deruxtecan (T-DXd, 5.4 mg/kg) or trastuzumab emtansine (T-DM1). Primary endpoint was progression-free survival by blinded independent central review.

At the interim analysis, 12-month PFS was 75.8% vs 34.1% (HR 0.28). The 2023 update reported median PFS 28.8 vs 6.8 months and a significant overall survival benefit (HR 0.64). It moved T-DXd into the second line and is the clearest head-to-head demonstration that ADC design (payload, drug-to-antibody ratio, bystander effect) determines clinical outcome.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: New England Journal of Medicine
- Year: 2022
- DOI: 10.1056/NEJMoa2115022
- Authors: Cortes J, Kim SB, Chung WP, et al.
- Findings: 12-month progression-free survival 75.8% with T-DXd vs 34.1% with T-DM1; HR 0.28 (95% CI 0.22-0.37).; Confirmed objective response 79.7% vs 34.2%.; Updated analysis (Lancet 2023): median PFS 28.8 vs 6.8 months; overall survival HR 0.64.; Drug-related interstitial lung disease/pneumonitis in roughly one in ten T-DXd patients, mostly low grade, with no grade 4-5 events in the primary report.
- What it means: For HER2-positive metastatic breast cancer that has progressed after trastuzumab and a taxane, trastuzumab deruxtecan is now the standard second-line treatment and T-DM1 has moved later in the sequence. The benefit is large enough that ADC design, not just the target, is understood to be what matters. Patients need lung monitoring because of the risk of pneumonitis.
- Caveats: Open-label design, though the primary endpoint was assessed by blinded central review.; Interstitial lung disease requires proactive CT surveillance and dose interruption; fatal cases occurred in other T-DXd trials.; Many patients had not received pertuzumab-based first-line therapy, so the population differs slightly from today's second line.; What to give after T-DXd, and whether a TOP1-payload ADC can follow another, remains unresolved.

## Sources

- NEJM 2022: https://doi.org/10.1056/NEJMoa2115022
- ClinicalTrials.gov NCT03529110: https://clinicaltrials.gov/study/NCT03529110

## Connected records

- ideas: [Payload-class switching as the rule for ADC sequencing](https://onco.cc/ideas/idea-payload-switching/)
- cancers: [HER2-positive breast cancer](https://onco.cc/cancers/breast-her2-positive/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Topoisomerase-I inhibitors (and ADC payloads)](https://onco.cc/technologies/topoisomerase-inhibitors/)
- targets: [HER2](https://onco.cc/targets/her2/)
- drugs: [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/), [Trastuzumab emtansine](https://onco.cc/drugs/trastuzumab-emtansine/)
- companies: [AstraZeneca](https://onco.cc/companies/astrazeneca/), [Daiichi Sankyo](https://onco.cc/companies/daiichi-sankyo/)
- terms: [ADC sequencing](https://onco.cc/terms/adc-sequencing/), [Bystander effect (ADC)](https://onco.cc/terms/bystander-effect/), [Drug-to-antibody ratio (DAR)](https://onco.cc/terms/dar/), [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/), [Overall survival (OS)](https://onco.cc/terms/os/), [Payload (ADC)](https://onco.cc/terms/payload/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/)
- trials: [DESTINY-Breast03](https://onco.cc/trials/destiny-breast03/)
- people: [Binghe Xu](https://onco.cc/people/xu-binghe/), [Giuseppe Curigliano](https://onco.cc/people/giuseppe-curigliano/), [Ian E. Krop](https://onco.cc/people/ian-krop/), [Javier Cortés](https://onco.cc/people/javier-cortes/), [Sara A. Hurvitz](https://onco.cc/people/sara-hurvitz/), [Seock-Ah Im](https://onco.cc/people/im-seock-ah/), [Sung-Bae Kim](https://onco.cc/people/kim-sung-bae/), [Yeon Hee Park](https://onco.cc/people/park-yeon-hee/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/), [Toxicity and quality of life are undervalued](https://onco.cc/bottlenecks/b-toxicity-qol/)
- journals: [New England Journal of Medicine](https://onco.cc/journals/nejm/)

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