SABCS 2025: Transforming HER2+ Breast Cancer Care: Key Updates from HER2CLIMB-05, DESTINY, and PHILA Trials

Recent HER2+ breast cancer trials have highlighted advances in targeted, chemotherapy-sparing therapies across early and metastatic settings. The HER2CLIMB-05 trial demonstrated that adding tucatinib to trastuzumab + pertuzumab in first-line maintenance significantly improves progression-free survival (PFS), offering a potential new chemo-free maintenance standard. DESTINY-Breast11 showed that neoadjuvant trastuzumab deruxtecan (T-DXd), alone or followed by THP, achieves higher pathologic complete response rates than anthracycline-based regimens in high-risk early HER2+ disease. DESTINY-Breast09 revealed that T-DXd + pertuzumab provides durable PFS benefits in first-line metastatic HER2+ disease, positioning it as a potent non-taxane alternative to standard THP therapy. Finally, the PHILA trial found that pyrotinib combined with trastuzumab and docetaxel significantly improves PFS versus standard therapy, highlighting the efficacy of dual HER2 blockade with TKIs and antibodies. Collectively, these studies suggest a shift toward oral and targeted therapies, potentially reducing chemotherapy exposure while improving disease control and outcomes in HER2+ breast cancer.

HER2CLIMB-05 (NCT05132582)^{1, 2}

• Phase 3, randomized, double-blind study that evaluated adding the oral HER2-tyrosine kinase inhibitor (TKI) tucatinib (Tukysa) versus placebo to first-line maintenance therapy with trastuzumab + pertuzumab in patients with HER2+ metastatic breast cancer who had completed induction chemotherapy without progression.

• The trial met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS in the tucatinib arm compared to placebo, making the first potential update to first-line maintenance for HER2+ metastatic disease since 2012 and offering a chemotherapy-free maintenance strategy.

• If regulatory bodies endorse the findings, the addition of tucatinib to trastuzumab + pertuzumab in maintenance could become a new standard of care, potentially delaying disease progression and extending disease control without reintroducing cytotoxic chemotherapy, a major shift in how clinicians may manage HER2+ metastatic breast cancer in first-line maintenance.

DESTINY-Breast11 (NCT05113251)^{3, 4}

• Phase 3, global, randomized study in patients with high-risk, locally advanced or inflammatory HER2+ breast cancer in the early-stage (pre-surgery), that evaluated neoadjuvant T-DXd alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) versus standard dose-dense schedule of doxorubicin (Adriamycin) + Cyclophosphamide (ddAC)→THP.

• T-DXd→THP achieved significantly higher pathologic complete response (pCR) rates than ddAC→THP, representing the strongest pCR performance reported in a registrational HER2+ neoadjuvant study. Efficacy gains were consistent across HR+ and HR- subsets.

• These results suggest that T-DXd-based neoadjuvant therapy may outperform anthracycline-containing regimens while potentially reducing anthracycline exposure. If long-term outcomes confirm benefit, this regimen could redefine neoadjuvant standards for high-risk HER2+ early breast cancer.

DESTINY-Breast09 (NCT04784715)^{5, 6}

• Global, phase 3, randomized, open-label trial comparing first-line therapy with T-DXd ± Pertuzumab versus standard first-line therapy using THP in patients with metastatic/advanced HER2+ breast cancer who had not received prior systemic treatment for metastatic disease.

• In the planned interim analysis, the T-DXd + pertuzumab arm demonstrated a highly significant and clinically meaningful improvement in PFS over THP, with a 44% reduction in risk of progression or death. Median PFS in the T-DXd + pertuzumab arm exceeded three years, a landmark improvement for first-line metastatic HER2+ disease.

• These data support T-DXd + pertuzumab as a potent, non-taxane-based alternative first-line regimen for HER2+ metastatic breast cancer, potentially supplanting THP as standard of care. If confirmed with mature overall survival data and long-term safety, this regimen could shift first-line therapy paradigms and offer durable disease control, eliminating the need for initial chemotherapy.

PHILA (NCT03863223)^{7, 8}

• Phase 3, randomized, double-blind, placebo-controlled, multicenter trial comparing oral Pyrotinib + Trastuzumab + Docetaxel versus placebo + trastuzumab + docetaxel in previously untreated HER2+ metastatic breast cancer.

• The trial demonstrated a marked improvement in investigator-assessed PFS for the pyrotinib arm (median PFS 24.3 months versus 10.4 months in the control group (hazard ratio 0.41, P < 0.001)), indicating a robust benefit from combining a pan-HER TKI with trastuzumab and chemotherapy.

• These data support pyrotinib + trastuzumab + docetaxel as a potential first-line alternative to standard anti-HER2 regimens in HER2+ metastatic breast cancer, offering a dual HER2 blockade (antibody + TKI) that may deliver superior disease control. The favorable safety profile (toxicity manageable) further bolsters the regimen’s viability, especially in patients where maximizing PFS is prioritized.

Sources:

1. “TUKYSA Combination Significantly Improves Progression-Free Survival as First-Line Maintenance in HER2+ Metastatic Breast Cancer in HER2CLIMB-05 Trial | Pfizer.” Pfizer.com, 14 Oct. 2025, www.pfizer.com/news/press-release/press-release-detail/tukysa-combination-significantly-improves-progression-free. Accessed 8 Dec. 2025.
2. “A Study of Tucatinib or Placebo with Trastuzumab and Pertuzumab for Metastatic HER2+ Breast Cancer (HER2CLIMB-05).” Clinicaltrials.gov, 4 Dec. 2025, clinicaltrials.gov/study/NCT05132582. Accessed 8 Dec. 2025.
3. Harbeck, Nadia, et al. “Neoadjuvant Trastuzumab Deruxtecan Alone or Followed by Paclitaxel, Trastuzumab, and Pertuzumab for High-Risk HER2-Positive Early Breast Cancer (DESTINY-Breast11): A Randomised, Open-Label, Multicentre, Phase III Trial.” Annals of Oncology, 1 Oct. 2025, www.annalsofoncology.org/article/S0923-7534(25)04968-3/fulltext, https://doi.org/10.1016/j.annonc.2025.10.019. Accessed 8 Dec. 2025.
4. “Trastuzumab Deruxtecan (T-DXd) Alone or in Sequence with THP, versus Standard Treatment (DdAC-THP), in HER2-Positive Early Breast Cancer.” Clinicaltrials.gov, 18 Nov. 2025, clinicaltrials.gov/study/NCT05113251. Accessed 8 Dec. 2025.
5. Tolaney, Sara M., et al. “Trastuzumab Deruxtecan (T-DXd) + Pertuzumab (P) vs Taxane + Trastuzumab + Pertuzumab (THP) for First-Line (1L) Treatment of Patients (Pts) with Human Epidermal Growth Factor Receptor 2–Positive (HER2+) Advanced/Metastatic Breast Cancer (A/MBC): Interim Results from DESTINY-Breast09.” Journal of Clinical Oncology, vol. 43, no. 17_suppl, 10 June 2025, https://doi.org/10.1200/jco.2025.43.17_suppl.lba1008.
6. “Trastuzumab Deruxtecan (T-DXd) with or without Pertuzumab versus Taxane, Trastuzumab and Pertuzumab in HER2-Positive Metastatic Breast Cancer (DESTINY-Breast09).” Clinicaltrials.gov, 12 Nov. 2025, clinicaltrials.gov/study/NCT04784715. Accessed 8 Dec. 2025.
7. Xu, Binghe, et al. “Abstract GS1-03: Pyrotinib or Placebo in Combination with Trastuzumab and Docetaxel for Untreated HER2-Positive Metastatic Breast Cancer (MBC): Prespecified Final Analysis of Progression-Free Survival (PFS) of the Phase 3 PHILA Trial.” Clinical Cancer Research, vol. 31, no. 12_Supplement, 13 June 2025, pp. GS1-03, https://doi.org/10.1158/1557-3265.sabcs24-gs1-03. Accessed 16 Nov. 2025.
8. “A Study of Pyrotinib in Combination with Trastuzumab and Docetaxel in Patients with HER2 Metastatic Breast Cancer.” Clinicaltrials.gov, 23 Nov. 2022, clinicaltrials.gov/study/NCT03863223. Accessed 8 Dec. 2025.