Medical Oncology: Targeted Therapies.

ADCs & TKIs: The Metastatic Breast Cancer Landscape in 2025

The treatment of metastatic breast cancer (mBC) has undergone a dramatic shift in the last two years, with advancements in antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs). Dr. Hassan GHAZAL’s January 2025 lecture summarizes these groundbreaking data, offering insights that will directly impact your clinical practice.

HER2-positive mBC – A New Standard of Care

Trastuzumab deruxtecan (T-DXd) has emerged as the new standard in second-line treatment for HER2-positive mBC. DESTINY-Breast03 demonstrated a remarkable ten-month overall survival gain with T-DXd compared to T-DM1 (52 vs 42 months, HR 0.64), almost quadrupling median progression-free survival (PFS) at 28.8 versus 6.8 months. Grade-5 interstitial lung disease (ILD) has been effectively mitigated through early CT screening and drug holds upon initial ground-glass changes.

Brain metastases are no longer a separate challenge in HER2-positive mBC. Pooled trials show a 45% intracranial response, with DESTINY-Breast12 confirming CNS activity prospectively, making T-DXd effective for both active and stable brain lesions. While tucatinib + capecitabine + trastuzumab (HER2CLIMB) remains valuable for active brain metastases in third-line settings, doubling two-year survival rates to 49% compared to 21%, the sequencing after T-DXd is largely empirical with options like neratinib (NALA) and T-DM1.

First-line treatment with taxane-trastuzumab-pertuzumab (THP) has dominated since 2015. However, DB-09 is currently randomized against THP ± pertuzumab versus T-DXd; early signals suggest a significant PFS improvement of at least nine months. Final results are anticipated in late 2025.

HR+/HER2+ – CDK4/6 Inhibitors After Chemotherapy

The addition of palbociclib to endocrine therapy and hormonal therapy (HP) after first-line chemotherapy significantly impacts the HR+/HER2+ mBC landscape. PATINA demonstrated a remarkable 15-month PFS advantage with this combination, reaching 44 months compared to 29 months in the control group (HR 0.76).

Triple-Negative mBC – Immunotherapy and ADCs Take Center Stage

For triple-negative mBC (TNBC) first-line treatment now involves pembrolizumab plus chemotherapy for patients with a CPS ≥10 (KEYNOTE-355), yielding a PFS of 9.7 months compared to 5.6 months and an OS HR of 0.73.

Patients with BRCA or PALB2 mutations benefit from PARP inhibitors (olaparib/talazoparib) post-chemotherapy, achieving a PFS of 7 months and ORR >60%.

Sacituzumab govitecan (SG), has emerged as a potent second-line option for TNBC. The ASCENT trial demonstrated a significant improvement in both PFS (5.6 vs 1.7 months) and OS (12.1 vs 6.7 months) regardless of TROP-2 level, highlighting SG’s broad efficacy. Datopotamab deruxtecan (Dato-DXd), an ADC targeting HER2, is now approved for HR+/HER2– after ≥1 prior chemotherapy (TROPION-Breast01: PFS 6.9 vs 4.9 months, HR 0.64) and is also being evaluated in TNBC trials.

Excitingly, the future holds promise with active phase-3 trials investigating SG + pembrolizumab and Dato-DXd + durvalumab as first-line options. Readouts are expected in 2026.

HER2-low & “Ultra-low” – A Paradigm Shift

DESTINY-Breast04, demonstrating the efficacy of T-DXd in HER2-low mBC (IHC 1+ or 2+/ISH-), has revolutionized this patient subset. T-DXd doubled both PFS (10.1 vs 5.4 months) and OS (23.9 vs 17.5 months). DB-06, expanding the inclusion criteria to include IHC 0 with ≤10% faint staining (“ultra-low”), continues to show identical benefit (HR 0.62), emphasizing that any level above true zero counts for HER2 expression.

Sequencing Cheat Sheet (2025)

• HER2+: THP → T-DXd → tucatinib-based → clinical trial / T-DM1 / neratinib
• TNBC CPS ≥10: chemo-pembro → SG or Dato-DXd → PARPi if BRCA → chemo
• HER2-low HR+: endocrine+CDK4/6 → chemo → T-DXd → SG/Dato-DXd → chemo
• HER2-low TNBC: chemo-pembro if CPS ≥10 → SG/Dato-DXd → clinical trial

Key Toxicities to Remember:

• T-DXd: Prophylactic triple antiemetics, baseline and q9-week CT chest to catch ILD early.
• SG/Dato-DXd: Neutropenia, ocular toxicity (Dato), pre-medicate with steroids and G-CSF PRN.
• Tucatinib/neratinib: Diarrhea prophylaxis (loperamide + budesonide).

The Bottom Line: ADCs have surpassed chemotherapy in every molecular subset. T-DXd is now the backbone for HER2-positive and HER2-low disease; SG and Dato-DXd dominate the triple-negative and HR-positive spaces.

Stay ahead of the curve by combining therapies early, sequencing treatments intelligently, monitoring toxicities closely, and eagerly anticipating first-line ADC and ADC-IO data later this year.

Text generated by AI from Hassan GHAZAL lecture at BCU conference Januaray 2025, reviewed and edited by Dr Jean-Philippe MINART

Selected Bibliography

1. Hurvitz SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: updated survival results from DESTINY-Breast03. Lancet. 2023;401:105-117.
2. Curigliano G, et al. DESTINY-Breast12: trastuzumab deruxtecan in patients with HER2+ mBC and brain metastases—primary outcome. Ann Oncol. 2025;36(Suppl 1):LBA1.
3. Murthy RK, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer (HER2CLIMB): final overall survival analysis. J Clin Oncol. 2023;41:3455-3464.
4. Loibl S, et al. Palbociclib plus endocrine therapy and trastuzumab/pertuzumab following chemotherapy in HER2+/HR+ metastatic breast cancer: primary results from PATINA. SABCS 2024. Abstract GS01-07.
5. Cortés J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (KEYNOTE-355): final overall survival results. Lancet Oncol. 2023;24:1124-1138.
6. Bardia A, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer (ASCENT): final overall survival analysis. N Engl J Med. 2021;384:1520-1531.
7. Jhaveri KL, et al. Datopotamab deruxtecan versus investigator’s choice chemotherapy for HR+/HER2– inoperable or metastatic breast cancer (TROPION-Breast01): primary analysis. Ann Oncol. 2024;35(Suppl 3):LBA15.
8. Modi S, et al. Trastuzumab deruxtecan in previously treated HER2-low metastatic breast cancer (DESTINY-Breast04): final overall survival results. N Engl J Med. 2022;387:9-20.
9. Jhaveri KL, et al. DESTINY-Breast06: trastuzumab deruxtecan vs chemotherapy in HER2-low and ultra-low HR+ metastatic breast cancer. Lancet. 2024;404:177-190.
10. Rugo HS, et al. Sacituzumab govitecan in HR+/HER2– metastatic breast cancer after ≥1 prior chemotherapy (TROPiCS-02): final analysis. J Clin Oncol. 2023;41:4534-4543.
11. Tutt ANJ, et al. Adjuvant olaparib for patients with germline BRCA1/2-mutated high-risk early breast cancer (OlympiA): updated overall survival. Nature Med. 2023;29:1853-1861.
12. Lin NU, et al. NALA: neratinib plus capecitabine vs lapatinib plus capecitabine in HER2-positive metastatic breast cancer. J Clin Oncol. 2020;38:3138-3149.