DESTINY-Breast06: trastuzumab deruxtecan before any chemotherapy in hormone-receptor-positive, HER2-low or ultralow breast cancer
Given as the first chemotherapy-type treatment after hormone therapy stopped working, trastuzumab deruxtecan delayed progression by about five months compared with standard chemotherapy, including in tumours with barely detectable HER2.
Open-label phase 3 trial of 866 patients with hormone-receptor-positive metastatic breast cancer that was HER2-low (IHC 1+ or 2+/ISH-negative) or HER2-ultralow (IHC 0 with faint membrane staining), who had progressed on endocrine therapy but had not received chemotherapy for metastatic disease. Patients were randomised to trastuzumab deruxtecan or physician's choice chemotherapy (capecitabine, paclitaxel or nab-paclitaxel). Primary endpoint was PFS in the HER2-low group.
Median PFS was 13.2 vs 8.1 months (HR 0.62) in HER2-low patients, with a similar effect in the ultralow subgroup. It moved T-DXd one line earlier and pushed the HER2 threshold down to almost any detectable staining.
- HER2-low: median PFS 13.2 vs 8.1 months, HR 0.62 (95% CI 0.51-0.74).
- HER2-ultralow (about 150 patients): median PFS 13.2 vs 8.3 months, HR 0.78, consistent with the HER2-low result.
- Objective response rate roughly 57% vs 31% in the HER2-low group.
- Overall survival was immature at the primary analysis and not significantly different.
- Interstitial lung disease in about 11% of T-DXd patients, with a small number of fatal cases.
Patients with hormone-receptor-positive metastatic breast cancer that has stopped responding to endocrine therapy can be offered trastuzumab deruxtecan as their first chemotherapy-type treatment if the tumour shows any HER2 staining, rather than waiting until after conventional chemotherapy. Whether to use it before or after chemotherapy is now a choice, since overall survival was not shown to differ and the drug carries a risk of lung inflammation.
- No overall survival benefit was demonstrated at the primary analysis, so the case for using it earlier rests on PFS and response.
- HER2-ultralow scoring is even less reproducible than HER2-low, and the ultralow subgroup was small and exploratory.
- Comparator chemotherapy was single-agent and the trial was open-label.
- Cost and pneumonitis risk are much higher than for capecitabine, which many patients tolerate well for a long time.
Pages like this
not linked directly; found by shared links- Key paperDESTINY-Breast04: trastuzumab deruxtecan works in HER2-low breast cancer, creating a new treatable group
Shares Joohyuk Sohn, Seock-Ah Im, Immunohistochemistry (IHC), Interstitial lung disease (ILD) / pneumonitis.
- Key paperTROPION-Breast01: datopotamab deruxtecan versus chemotherapy in pretreated hormone-receptor-positive breast cancer, and why a PFS win did not translate to survival
Shares Carlos Barrios, Seock-Ah Im, Immunohistochemistry (IHC), Daiichi Sankyo.
- IdeaCalibrated reference slides so every lab scores HER2-low the same way
Shares DESTINY-Breast06, Immunohistochemistry (IHC), HER2-low and HER2-ultralow, Histopathology & immunohistochemistry.
- Key paperDESTINY-Breast03: trastuzumab deruxtecan beats T-DM1 as second-line treatment of HER2-positive metastatic breast cancer
Shares Giuseppe Curigliano, Seock-Ah Im, Interstitial lung disease (ILD) / pneumonitis, Daiichi Sankyo.
- PairingHER2-low scoring → T-DXd
Shares DESTINY-Breast06, HER2-low and HER2-ultralow, Histopathology & immunohistochemistry, Trastuzumab deruxtecan.
- IdeaRandomised trials to test whether biomarker-negative patients really do not benefit
Shares DESTINY-Breast06, HER2-low and HER2-ultralow, Trastuzumab deruxtecan, Biomarkers are not validated or standardised.
- IdeaAI quantification of HER2-low and HER2-ultralow
Shares Immunohistochemistry (IHC), HER2-low and HER2-ultralow, Histopathology & immunohistochemistry, Trastuzumab deruxtecan.
- IdeaRe-test the metastasis, not the old primary, before every change of treatment
Shares Immunohistochemistry (IHC), HER2-low and HER2-ultralow, Histopathology & immunohistochemistry, HR-positive / HER2-negative breast cancer.