1. Enhertu: A Paradigm Shift for HER2-Low Breast Cancer
Enhertu (trastuzumab deruxtecan), a HER2-targeted antibody-drug conjugate (ADC), has emerged as a game-changer for patients with HER2-low (IHC 1+ or 2+/ISH-) and HER2-ultralow (IHC 0 with membrane staining) breast cancer. In 2025, the FDA approved Enhertu for HR+/HER2-low/ultralow metastatic breast cancer progressing after endocrine therapy, based on the phase III DESTINY-Breast06 trial .
Key Findings from DESTINY-Breast06:
PFS Improvement: Enhertu significantly prolonged progression-free survival (PFS) compared to chemotherapy (13.2 vs. 8.1 months; HR=0.62, p<0.0001) .
Response Rates: The confirmed objective response rate (ORR) was 56.5% with Enhertu vs. 32.2% with chemotherapy in HER2-low patients, and 61.8% vs. 26.3% in HER2-ultralow patients .
Safety: Enhertu demonstrated manageable toxicity, with the most common adverse events being hematological and gastrointestinal .
Mechanism of Action:
Enhertu combines trastuzumab’s HER2-targeting ability with deruxtecan, a topoisomerase I inhibitor, enabling precise delivery of chemotherapy to cancer cells. Its “bystander effect” kills neighboring HER2-low/ultralow cells, even those with minimal HER2 expression .
Cost Considerations:
Enhertu’s monthly cost averages $13,300 in major markets, though this may vary by region and insurance coverage . Patients are encouraged to explore patient assistance programs or biosimilar alternatives as they become available.
2. Keytruda in TNBC: Advancing Combination Therapies
Keytruda (pembrolizumab), a PD-1 inhibitor, has established its role in TNBC through pivotal trials like KEYNOTE-522 and ASCENT-04.
Neoadjuvant and Adjuvant Use:
KEYNOTE-522: Keytruda combined with chemotherapy as neoadjuvant treatment followed by adjuvant Keytruda monotherapy improved pathological complete response (pCR) rates and event-free survival (EFS) in early-stage TNBC .
ASCENT-04/KEYNOTE-D19: In metastatic TNBC with PD-L1 CPS ≥10, Keytruda plus Trodelvy (sacituzumab govitecan) significantly improved PFS compared to Keytruda plus chemotherapy (median PFS: 11.8 vs. 7.7 months; HR=0.69, p=0.001) .
Mechanism of Action:
Keytruda blocks PD-1, reinvigorating T-cell activity against tumor cells. Its efficacy in TNBC is attributed to the high tumor mutational burden (TMB) and immune-inflamed phenotype of these cancers .
Cost and Accessibility:
Keytruda’s annual cost ranges from $75,000 to $150,000, depending on the regimen and region. Combination therapies like Keytruda+Trodelvy may incur higher costs but offer superior outcomes .
3. Emerging Immunotherapies and Combination Strategies
Beyond Enhertu and Keytruda, 2025 has seen advancements in other immunotherapeutic approaches.
mRNA Vaccines:
mRNA-4157 + Keytruda: This personalized neoantigen vaccine combined with Keytruda reduced recurrence risk by 49% in high-risk melanoma, with potential applications in breast cancer .
BNT116: A BioNTech mRNA vaccine targeting lung cancer antigens showed promising early results in combination with PD-1 inhibitors, highlighting the potential for cross-tumor applications .
Oncolytic Viruses and Bispecific Antibodies:
Oncolytic viruses like T-vec are being explored to enhance immune infiltration in tumors, while bispecific antibodies (e.g., targeting HER2 and CD3) aim to bridge T cells to cancer cells .
4. Cost-Effectiveness and Accessibility in 2025
The high cost of cancer immunotherapies remains a barrier for many patients. In 2025, strategies to improve accessibility include:
Biosimilars: Development of biosimilar versions of Keytruda and Enhertu could reduce costs by 30–50% .
Value-Based Pricing: Some regions are adopting outcomes-based reimbursement models, tying payments to treatment efficacy .
Patient Assistance Programs: Pharmaceutical companies offer financial support for eligible patients, covering copays or providing free medication .
5. Future Directions and Challenges
Biomarker Discovery: Identifying predictive biomarkers (e.g., TMB, PD-L1) will optimize patient selection for immunotherapies .
Combination Trials: Ongoing trials explore Enhertu+Keytruda or ADCs with immune checkpoint inhibitors to overcome resistance .
Manufacturing Innovations: Advances in cell-free production and decentralized manufacturing could lower costs and improve global access .
FAQs
Q: What is the difference between HER2-low and HER2-ultralow breast cancer?
A: HER2-low tumors have weak (IHC 1+) or moderate (IHC 2+/ISH-) HER2 expression, while HER2-ultralow tumors show minimal membrane staining (IHC 0 with partial positivity) .
Q: Can Keytruda be used in early-stage TNBC?
A: Yes. Keytruda is approved as part of neoadjuvant/adjuvant therapy for high-risk early TNBC, improving pCR and EFS .
Q: How long does Enhertu treatment last?
A: Typically until disease progression or intolerable toxicity, with median treatment duration exceeding 12 months in clinical trials .
Q: Are there alternatives to Enhertu for HER2-low breast cancer?
A: Currently, Enhertu is the only approved therapy for HER2-low/ultralow breast cancer. However, other ADCs (e.g., Sym015) are in development .
Conclusion
In 2025, cancer immunotherapy for breast cancer is marked by precision targeting and innovative combinations. Enhertu’s expanded role in HER2-low/ultralow disease and Keytruda’s efficacy in TNBC highlight the field’s rapid evolution. While costs remain a challenge, advancements in biosimilars and reimbursement models offer hope for broader access. Patients and clinicians must stay informed to navigate these transformative options effectively.