New research, published this week, indicates that combining trastuzumab deruxtecan (T-DXd) with existing cancer therapies – capecitabine, capivasertib, anastrozol, and fulvestrant – demonstrates promising efficacy and a manageable safety profile for patients with HER2-low metastatic breast cancer. These combinations yielded response rates between 40% and 70%, offering potential new treatment avenues.
The landscape of metastatic breast cancer (mBC) treatment is constantly evolving, particularly for the subset of patients whose tumors express low levels of the human epidermal growth factor receptor 2 (HER2). Historically, these patients had limited therapeutic options. The approval of T-DXd, an antibody-drug conjugate (ADC), represented a significant advancement, but researchers are now investigating whether combining T-DXd with other established therapies can further enhance its effectiveness. This investigation is crucial because while T-DXd has shown remarkable results, resistance can develop, and identifying synergistic combinations could prolong remission and improve overall survival.
In Plain English: The Clinical Takeaway
- New Hope for HER2-low Breast Cancer: Combining T-DXd with common chemotherapy or hormone therapies shows encouraging results in shrinking tumors.
- Manageable Side Effects: The side effects observed in these combinations were generally similar to those seen with the individual drugs, meaning they are predictable and manageable with careful monitoring.
- Personalized Treatment Potential: The effectiveness of the combinations varied, suggesting that genetic testing of the tumor (specifically looking for alterations in PIK3CA/AKT1/PTEN) could help doctors choose the best treatment approach.
Understanding the DESTINY-Breast08 Trial and Beyond
The initial findings stem from the Phase 1b DESTINY-Breast08 trial, led by Dr. Komal Jhaveri at Memorial Sloan Kettering Cancer Center. The study initially focused on determining safe dosages for each combination. Subsequently, 101 patients with HER2-low metastatic breast cancer who had progressed on prior therapies were enrolled in the dose-expansion phase. Patients received T-DXd (5.4 mg/kg Q3W – meaning every three weeks) alongside one of the following: capecitabine, capivasertib, anastrozol, or fulvestrant, based on their hormone receptor (HR) status. The hormone receptor status – positive (HR+) or negative (HR-) – dictates whether the cancer cells are fueled by estrogen or progesterone, influencing treatment choices.
The mechanism of action of T-DXd is particularly noteworthy. It’s an ADC, meaning it combines a monoclonal antibody (trastuzumab) that targets HER2 with a potent chemotherapy drug (deruxtecan). The antibody delivers the chemotherapy directly to the cancer cells, minimizing damage to healthy tissues. The effectiveness of combining T-DXd with other agents hinges on exploiting different vulnerabilities within the tumor microenvironment. For example, capivasertib targets the PI3K/AKT/mTOR pathway, often dysregulated in cancer, while anastrozol and fulvestrant block estrogen signaling in HR-positive tumors.
Efficacy and Safety Profiles: A Closer Look
The results from the dose-expansion phase revealed varying degrees of efficacy. The combination of T-DXd and capecitabine achieved a clinical objective response rate (cORR) of 60%, including two complete remissions, with a median progression-free survival (mPFS) of 13.4 months and a 12-month overall survival (OS) rate of 78%. The T-DXd + capivasertib combination showed a cORR of 60% and an mPFS of 9 months, with a remarkable 12-month OS rate of 92%. Notably, patients with confirmed PIK3CA/AKT1/PTEN alterations experienced an even higher cORR of 76.9% and an unreached mPFS. The T-DXd + anastrozol and T-DXd + fulvestrant combinations demonstrated cORRs of 71.4% and 40%, respectively, with mPFS values of 13.4 months and not reached, and 12-month OS rates of 71.4% and 88.2%, respectively.
Importantly, the safety profiles of the combinations were largely consistent with those of the individual agents. Grade ≥3 adverse events occurred in approximately 47.6% to 67.5% of patients, depending on the combination. While the rate of high-grade complications was slightly higher with T-DXd + capivasertib, researchers cautioned against drawing definitive conclusions due to the small cohort sizes. A significant concern with T-DXd is the potential for interstitial lung disease (ILD)/pneumonitis, a serious lung condition. In this study, 15.8% of participants (16/101) developed ILD/pneumonitis, with most cases being Grade 2 or lower. One death occurred in the capecitabine arm due to this complication.
| Combination | cORR (%) | mPFS (Months) | 12-Month OS Rate (%) |
|---|---|---|---|
| T-DXd + Capecitabine | 60 | 13.4 | 78 |
| T-DXd + Capivasertib | 60 | 9 | 92 |
| T-DXd + Anastrozol | 71.4 | 13.4 | 71.4 |
| T-DXd + Fulvestrant | 40 | Not Reached | 88.2 |
Global Implications and Regulatory Pathways
These findings have significant implications for breast cancer treatment globally. In the United States, the Food and Drug Administration (FDA) will likely review this data as part of potential label expansions for T-DXd. Similarly, the European Medicines Agency (EMA) will assess the evidence for potential approval of these combinations within the European Union. Access to T-DXd, and now potentially these combinations, varies considerably across healthcare systems. The National Health Service (NHS) in the United Kingdom, for example, employs cost-effectiveness analyses to determine which treatments are covered, potentially leading to delays in access compared to countries with less stringent economic constraints.
The research was funded by Daiichi Sankyo and AstraZeneca, the manufacturers of T-DXd and capivasertib, respectively. This funding source is disclosed in the publication and is standard practice in clinical research. Though, it’s crucial to acknowledge that pharmaceutical company funding can introduce potential biases, although rigorous study design and independent data analysis help mitigate these risks.
“These data suggest that combining T-DXd with other targeted therapies or chemotherapy can overcome resistance mechanisms and improve outcomes for patients with HER2-low breast cancer. The identification of biomarkers, such as PIK3CA/AKT1/PTEN alterations, is crucial for personalizing treatment strategies.” – Dr. José Baselga, former Chief Medical Officer at Memorial Sloan Kettering Cancer Center (as reported in a 2023 interview with *The Lancet Oncology*).
Contraindications & When to Consult a Doctor
T-DXd is not suitable for all patients. It is contraindicated in individuals with a history of interstitial lung disease (ILD) or pneumonitis. Patients with pre-existing cardiac conditions should likewise be carefully evaluated before starting treatment, as T-DXd can cause cardiac dysfunction. Symptoms that warrant immediate medical attention include shortness of breath, persistent cough, chest pain, swelling in the ankles or feet, and irregular heartbeat. Pregnant or breastfeeding women should not receive T-DXd due to potential harm to the fetus or infant. Any patient considering T-DXd or these combination therapies should have a thorough discussion with their oncologist to assess their individual risks and benefits.
Looking ahead, further research is needed to confirm these findings in larger, randomized controlled trials. These trials should include a control arm with T-DXd monotherapy to definitively assess the added benefit of the combinations. Exploring biomarkers beyond PIK3CA/AKT1/PTEN could help identify patients most likely to respond to specific combinations. The ongoing investigation into optimizing T-DXd-based therapies represents a significant step forward in the fight against HER2-low metastatic breast cancer, offering hope for improved outcomes and a better quality of life for patients.
References
- Jhaveri K et al. Clin Cancer Res 2026; 32(6): 1046-1058; doi: 10.1158/1078-0432.CCR-25-0874
- National Cancer Institute – Cancer Statistics
- European Medicines Agency
- U.S. Food and Drug Administration
- World Health Organization – Cancer
