Phase 3 Data Illuminate Advancing Roles for T-DXd and Combination Approaches in HER2+ Breast Cancer

In an interview with OncLive® following a recent State of the Science Summit™ on breast cancer, Yuan Yuan, MD, PhD, highlighted 3 pivotal studies in HER2-positive disease—the phase 3 DESTINY-Breast09 trial (NCT04784715), the phase 3 PATINA trial (NCT02947685), and the phase 3b/4 DESTINY-Breast12 study (NCT04739761)—and detailed their collective implications for the evolving treatment paradigm.

These trials addressed several areas of uncertainty in HER2-positive breast cancer regarding the efficacy of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in earlier lines, the agent’s activity in patients with central nervous system (CNS) metastases, and the therapeutic potential of dual-pathway inhibition in endocrine receptor (ER)-positive/HER2-positive metastatic breast cancer, Yuan explained. However, further evidence is required to determine the viability of T-DXd as an induction strategy followed by maintenance therapy, as well as to better characterize its mechanism of action within the CNS.

“We're looking at the early trajectory of the era of antibody-drug conjugates [ADCs],” said Yuan, who served as chair of the meeting. “We really want to understand how ADCs work for CNS metastasis. I'm hoping someone out there is doing some translational research to help us understand [its mechanism], because [T-DXd] is just one successful example.”

Yuan is a professor, director of Breast Medical Oncology Medicine, and medical director of the Breast Oncology Disease Research Group at Cedars-Sinai Medical Center in California, as well as a health sciences clinical professor at the University of California, Los Angeles.

OncLive: What do data from DESTINY-Breast09 signal about the future role of T-DXd in HER2-positive disease?

Yuan: DESTINY-Breast 09 tested the ADC T-DXd as a frontline therapy, in a head-to-head comparison with the old standard of care [SOC], which is the CLEOPATRA [NCT00567190] regimen utilizing chemotherapy in combination with dual HER2-targeted therapy.

Prior to the availability of these data, the phase 3 DESTINY-Breast03 [NCT03529110] and DESTINY-Breast02 [NCT03523585] trial evaluated [T-DXd monotherapy] was evaluated in

the second-line or third-line setting, where it has become the SOC with a very remarkable progression-free survival [PFS] benefit.

Now, the aim of DESTINY-Breast09 is to bring [T-DXd] upfront. It had a three-arm design. At the 2025 ASCO Annual Meeting, we only saw the data from T-DXd plus pertuzumab [Perjeta] vs the CLEOPATRA regimen. Not surprisingly, the PFS benefit was remarkable [at 40.7 months (95% CI, 36.5-not calculable).]¹

These are very welcome data, but [other questions have emerged] after these data became available. The CLEOPATRA regimen is typically [given to] patients for anywhere from 6 to 9 cycles, and then we do stop the taxane and continue with trastuzumab [Herceptin] and pertuzumab [HP] maintenance. Most people enjoy a very durable period of PFS without any intensive chemotherapy and [little related] toxicity; the quality of life is excellent using a CLEOPATRA approach.

The DESTINY-Breast 09 [regimen involves] continuous treatment. We all know that T-DXd has some non-trivial gastrointestinal toxicities, nausea, and also hair loss with accumulated dosing. There is an increased risk of interstitial lung disease [ILD], and the risk of ILD is approximately 12%. This can be a very serious [adverse effect (AE).]

What are some other ongoing efforts to elucidate the optimal sequencing of T-DXd in HER2-positive unresectable, locally recurrent, or metastatic breast cancer?

We are looking forward to the [phase 2] DEMETHER study [NCT06172127], which is testing T-DXd as upfront induction therapy for 6 cycles, followed by HP maintenance. I think this approach will be perhaps more welcomed in clinical practice. The difference between DEMETHER and DESTINY-Breast09 is that the DESTINY-Breast09 [regimen includes T-DXd plus] pertuzumab, while the DEMETHER [regimen comprises] T-DXd. Again, not every trial is comparable, but we're looking forward to the DEMETHER data to confirm the approach of induction followed by maintenance.

What are the implications of data from the prospective DESTINY-Breast12 study for the upfront use of T-DXd in HER2-positive breast cancer?

DESTINY-Breast12 is a phase 3/4 study asking a very valid question: Does T-DXd have CNS efficacy? [This study] enrolled patients who had brain metastases; some were treated and some were not treated by radiation. The promising finding here is that those patients who did not go through radiation therapy and just received systemic therapy with T-DXd, saw equal CNS responses [compared with those who did receive radiation].

That is an increase, giving our patients other options besides the phase 2 HER2CLIMB [NCT02614794] approach, which is a combination of tucatinib [Tukysa], ado-trastuzumab emtansine [Kadcyla], and capecitabine [Xeloda]. It used to be the gold standard, but now we are expanding our options.

What still needs to be learned about T-DXd in the treatment of patients with HER2-positive breast cancer and CNS metastasis?

We can link [this] back to DESTINY-Breast 09. Maybe one of the benefits of using the DESTINY-Breast 09 approach upfront is that we can prevent some CNS metastasis. This gives us a lot of comfort, although mechanism-of-action–wise, we still have [several questions, including]: How does the blood-brain barrier work? Why would this bulky molecule, T-DXd, have CNS penetration?

How do data from the PATINA trial reinforce the importance of optimizing dual-pathway targeting in ER-positive/HER2-positive metastatic disease?

The PATINA trial utilized the upfront CLEOPATRA approach for 6 cycles in patients with what we call double-positive breast cancer.²

[With] the current SOC [per] National Comprehensive Cancer Network (NCCN) guidelines, which is to use an aromatase inhibitor [AI] plus dual HER2-targeted therapy, we often do not see a prolonged median PFS. In these double-positive cases, we may have 2 drivers [of disease]. One driver is the HER2 pathway, but the other driver could be the ER pathway.

[In PATINA], they incorporated a CDK4/6 inhibitor into the maintenance strategy. [Patients were treated] with 6 cycles of THP followed by an AI in combination with palbociclib [Ibrance], a CDK4/6 inhibitor, plus HP. PATINA showed apromising, prolonged [median PFS of 4.3 months (95% CI, 32.4-60.9) with this approach]. That should be adopted now for every single patient we have in this space. [We’re still] learning from ER-positive disease and translating [our findings] into the double-positive setting.

References

1. Tolaney S, Jiang Z, Zhang Q, 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. J Clin Oncol. 2025;43(suppl 17):LBA1008
2. Pfizer’s IBRANCE® in combination with standard-of-care therapies extends median progression-free survival by over 15 months in phase 3 PATINA study in patients with HR+, HER2+ metastatic breast cancer. December 12, 2024. News Release. Pfizer. Accessed November 14, 2025. https://www.pfizer.com/news/press-release/press-release-detail/pfizers-ibrancer-combination-standard-care-therapies