A phase 3, multicenter, open-label, randomized clinical trial comparing trastuzumab deruxtecan to chemotherapy in patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer has demonstrated promising results. The study, known as DESTINY-Breast06, was funded by AstraZeneca and Daiichi Sankyo and published in the New England Journal of Medicine on December 5, 2024.
The primary objective of this trial was to evaluate the efficacy and safety of trastuzumab deruxtecan compared to physician's choice of chemotherapy (capecitabine, nanoparticle albumin-bound paclitaxel, or paclitaxel) in patients who had received one or more lines of endocrine-based therapy but no previous chemotherapy for metastatic disease.
A total of 866 patients were enrolled across 324 sites and randomized 1:1 to receive either trastuzumab deruxtecan (5.4 mg/kg intravenously every 3 weeks) or chemotherapy. The study population included 713 patients with HER2-low disease (defined as IHC 1+ or IHC 2+ and ISH-negative) and 153 patients with HER2-ultralow disease (defined as IHC 0 with membrane staining).
Key eligibility criteria included hormone receptor-positive metastatic breast cancer, HER2-low or HER2-ultralow expression, and disease progression after receiving at least two previous lines of endocrine-based therapy for metastatic disease. Patients who had received one previous line of endocrine therapy for metastatic disease were also eligible if they had disease recurrence within 24 months after initiation of adjuvant endocrine therapy or disease progression within 6 months after initiation of first-line endocrine therapy plus a CDK4/6 inhibitor.
The primary endpoint was progression-free survival in the HER2-low population as determined by blinded independent central review. Secondary endpoints included progression-free survival in the intention-to-treat population, overall survival, objective response rate, and safety.
Results showed a significant improvement in progression-free survival with trastuzumab deruxtecan compared to chemotherapy. In the HER2-low population, median progression-free survival was 13.2 months with trastuzumab deruxtecan versus 8.1 months with chemotherapy (hazard ratio 0.62; 95% CI, 0.52-0.75; P<0.001). Similar benefits were observed in the intention-to-treat population and the exploratory HER2-ultralow subgroup.
The confirmed objective response rate was also higher with trastuzumab deruxtecan compared to chemotherapy across all populations. In the HER2-low group, the response rates were 56.5% and 32.2%, respectively. The median duration of response was 14.1 months with trastuzumab deruxtecan versus 8.6 months with chemotherapy.
Regarding safety, the incidence of adverse events was similar between the two groups (98.8% with trastuzumab deruxtecan vs. 95.2% with chemotherapy). The most common drug-related adverse events with trastuzumab deruxtecan were nausea, fatigue, and alopecia. Adverse events of grade 3 or higher occurred in 52.8% of patients receiving trastuzumab deruxtecan and 44.4% of those receiving chemotherapy.
Of note, adjudicated drug-related interstitial lung disease or pneumonitis occurred in 11.3% of patients treated with trastuzumab deruxtecan, including three fatal cases. This highlights the importance of careful monitoring and management of this known risk associated with trastuzumab deruxtecan.
The study had several limitations. Overall survival data were immature at the time of this analysis, with only 39.6% maturity in the HER2-low population. Additionally, the trial was not powered to show statistical significance in the HER2-ultralow population. The study also lacked representation of patients with hormone receptor-negative disease, leaving uncertainty about the potential efficacy of trastuzumab deruxtecan as first-line chemotherapy in this subgroup.
The authors concluded that trastuzumab deruxtecan resulted in significantly longer progression-free survival compared to chemotherapy in patients with hormone receptor-positive, HER2-low or HER2-ultralow metastatic breast cancer who had received one or more lines of endocrine-based therapy. No new safety signals were identified, although interstitial lung disease remains an important risk to monitor.
These findings have potentially significant clinical implications. Trastuzumab deruxtecan may represent a new treatment option for patients with HER2-low or HER2-ultralow metastatic breast cancer, providing an effective alternative between endocrine therapy and standard chemotherapy. The study also suggests that patients with HER2-ultralow expression, previously not considered candidates for HER2-directed therapies, may benefit from trastuzumab deruxtecan.
Furthermore, the results challenge the current categorization of HER2 expression in breast cancer. The effectiveness of trastuzumab deruxtecan in tumors with very low levels of HER2 expression suggests that the current IHC 0 category may need to be further subdivided to identify patients who could benefit from this therapy.
In conclusion, the DESTINY-Breast06 trial provides compelling evidence for the efficacy of trastuzumab deruxtecan in hormone receptor-positive, HER2-low and HER2-ultralow metastatic breast cancer. As further data mature and additional studies are conducted, this agent may reshape treatment algorithms for this patient population. However, careful patient selection and vigilant monitoring for potential adverse effects, particularly interstitial lung disease, will be crucial in clinical practice.
References
Bardia A, Hu X, Dent R, et al. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024;391(22):2110-2122. doi:10.1056/NEJMoa2407086
