Highlighting the Evolving Landscape of HER2-Low Breast Cancer
The management of metastatic breast cancer (mBC) has undergone a paradigm shift with the identification of the HER2-low subgroup—defined as an immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization (ISH). Historically, these patients were treated as HER2-negative, missing the targeted potential of anti-HER2 therapies. Trastuzumab deruxtecan (T-DXd), a next-generation antibody-drug conjugate (ADC), changed this landscape by demonstrating significant survival benefits in the DESTINY-Breast04 trial. However, the next frontier in clinical research focuses on whether T-DXd can be safely and effectively combined with other therapeutic agents to overcome resistance and enhance clinical outcomes.
The DESTINY-Breast08 phase 1b study was designed to address this question by evaluating T-DXd in combination with a variety of agents, including chemotherapy, immunotherapy, AKT inhibitors, and endocrine therapies, specifically for patients with HER2-low mBC. The results offer a critical early look at the safety signals and preliminary efficacy of these novel regimens.
Study Design: A Modular Approach to Dose Finding
DESTINY-Breast08 (NCT04556773) was a multicenter, open-label, phase 1b study consisting of two parts: dose-finding and dose-expansion. The study utilized a modular design to assess T-DXd (5.4 mg/kg) in combination with several partners:
Module 1: T-DXd + Capecitabine
Investigating the synergy between the topoisomerase I inhibitor payload of T-DXd and the antimetabolite capecitabine.
Module 2: T-DXd + Durvalumab + Paclitaxel
Exploring the triplet combination of an ADC, a checkpoint inhibitor, and a taxane. Note: This module was discontinued early for strategic reasons.
Module 3: T-DXd + Capivasertib
Targeting the PI3K/AKT/mTOR pathway, which is frequently dysregulated in hormone receptor-positive (HR+) breast cancer and may contribute to ADC resistance.
Module 4 and 5: T-DXd + Endocrine Therapy
Combining T-DXd with anastrozole (aromatase inhibitor) or fulvestrant (selective estrogen receptor degrader) to target HR+/HER2-low disease through dual pathways.
The primary objectives were to establish the recommended phase 2 dose (RP2D) and characterize the safety and tolerability profile. Secondary endpoints included the objective response rate (ORR) as assessed by investigators.
Key Results: Safety and Recommended Dosing
In the dose-finding phase, 37 patients were enrolled across modules. The study successfully identified RP2Ds for T-DXd in combination with capecitabine, capivasertib, anastrozole, and fulvestrant. The dose-expansion phase subsequently enrolled 101 patients to further characterize these combinations.
Safety Profiles Across Combinations
The safety results were largely consistent with the known profiles of the individual agents. However, the cumulative toxicity of combining potent agents requires careful clinical monitoring. Grade 3 or higher adverse events (AEs) were reported as follows:
- T-DXd + Capecitabine: 55.0% (11/20 patients)
- T-DXd + Capivasertib: 67.5% (27/40 patients)
- T-DXd + Anastrozole: 47.6% (10/21 patients)
- T-DXd + Fulvestrant: 55.0% (11/20 patients)
Common toxicities included gastrointestinal symptoms (nausea, diarrhea), hematologic suppression (neutropenia, anemia), and fatigue. The capivasertib combination showed a higher frequency of Grade 3+ AEs, likely reflecting the overlapping toxicity of AKT inhibition and ADC therapy.
Preliminary Clinical Activity: Robust Response Rates
Despite being a phase 1b study, the preliminary efficacy data across the HER2-low population were encouraging, suggesting that T-DXd remains highly active even when paired with other systemic therapies.
High Response Rates in Endocrine Combinations
The T-DXd plus anastrozole module demonstrated the highest ORR at 71.4%, followed by the capecitabine and capivasertib modules, both showing an ORR of 60.0%. The T-DXd plus fulvestrant module reported an ORR of 40.0%. These results are particularly relevant for patients with HR+/HER2-low disease who have progressed on prior endocrine therapy and CDK4/6 inhibitors.
The Critical Issue of Interstitial Lung Disease (ILD)
A primary safety concern with T-DXd remains drug-related interstitial lung disease (ILD) or pneumonitis. In DESTINY-Breast08, adjudicated ILD events were observed in several modules:
- T-DXd + Capecitabine: 3 events (2 Grade 2; 1 Grade 5).
- T-DXd + Capivasertib: 8 events (all Grade 1 or 2).
- T-DXd + Fulvestrant: 5 events (all Grade 2).
The occurrence of a Grade 5 (fatal) event in the capecitabine module underscores the necessity for rigorous pulmonary monitoring and early intervention with corticosteroids at the first sign of respiratory symptoms or radiological changes. The fact that most ILD events were low-grade (Grade 1-2) suggests that with proactive management, these combinations can be administered, but the risk-benefit ratio must be individualized.
Expert Commentary: Mechanistic Rationale and Clinical Implications
The biological rationale for these combinations is sound. The “bystander effect” of T-DXd allows the deruxtecan payload to cross cell membranes and kill neighboring cells regardless of their HER2 expression levels. By adding agents like capivasertib, clinicians may be able to sensitize cells that are otherwise resistant to apoptosis or have upregulated survival pathways. Furthermore, the high ORR seen with anastrozole suggests a potential synergy between HER2-directed ADCs and estrogen receptor modulation, potentially delaying the need for aggressive single-agent chemotherapy.
However, clinicians must weigh these efficacy signals against the increased burden of toxicity. The higher rates of Grade 3+ AEs compared to T-DXd monotherapy suggest that patient selection will be paramount. Those with significant comorbidities or baseline pulmonary issues may not be ideal candidates for these intensive combination regimens.
Conclusion: A Foundation for Future Trials
DESTINY-Breast08 successfully met its primary objectives by establishing the safety and RP2Ds for several T-DXd-based combinations in HER2-low mBC. The preliminary clinical activity is promising, particularly the 71.4% ORR in the anastrozole module. While ILD remains a significant risk that requires vigilant management, these data provide a strong foundation for phase 2 and 3 trials. As the oncology community moves toward more personalized ADC applications, DESTINY-Breast08 clarifies the potential for T-DXd to serve as a backbone for multifaceted therapeutic strategies in the metastatic setting.
References and Clinical Trial Information
1. Jhaveri K, et al. DESTINY-Breast08: a phase 1b study of trastuzumab deruxtecan in combination with other anticancer therapies in patients with HER2-low metastatic breast cancer. Clin Cancer Res. 2026. PMID: 41504632.
2. Modi S, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Metastatic Breast Cancer. N Engl J Med. 2022;387(1):9-20.
3. ClinicalTrials.gov Identifier: NCT04556773.
