The efficacy benefit observed with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) plus pertuzumab (Perjeta) compared with standard trastuzumab (Herceptin) plus pertuzumab and a taxane (THP) indicates that a potential shift in the first-line treatment paradigm for previously untreated HER2-positive advanced or metastatic breast cancer is on the horizon, according to Laura Huppert, MD, who adds that this raises new questions regarding optimal drug sequencing, maintenance strategies, and the future role of the THP regimen.
Interim data from the phase 3 DESTINY-Breast09 trial (NCT04784715), which were presented at the 2025 ASCO Annual Meeting, showed that patients with first-line HER2-positive advanced or metastatic breast cancer achieved a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not calculable [NC]) with T-DXd plus pertuzumab (n = 383) vs 26.9 months (95% CI, 21.8-NC) with THP (n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001).1
“[First-line maintenance therapy might be] an important strategy, especially [with] efforts to improve the maintenance [setting] and [have] several studies asking: Can we add a HER2[-targeted] TKI, or a PIK3CA inhibitor, for example, to improve the maintenance strategy?” Huppert said in an interview with OncLive®. “It will be interesting to optimize that piece of it.”
In the interview, Huppert discussed future implications of the DESTINY-Breast09 data, the need for further data with first-line T-DXd monotherapy in patients with HER2-positive disease, and the evolving role of maintenance therapy in this setting.
Huppert is an assistant professor of medicine at the University of California, San Francisco School of Medicine.
OncLive: What key findings from DESTINY-Breast09 were presented at ASCO 2025?
Huppert: The DESTINY-Breast09 trial evaluated first-line therapy for patients with metastatic HER2-positive breast cancer. It specifically enrolled patients who had not received prior therapy or [for whom it had been longer than] 6 months since their last chemotherapy or HER2-directed therapy in the early-stage setting. [The trial] randomly assigned patients 1:1:1 to receive the current standard of care [SOC]—the phase 3 CLEOPATRA trial [NCT00567190] regimen of THP—followed by HP maintenance vs T-DXd by itself vs T-DXd plus pertuzumab, with a primary end point of PFS. Importantly, in this trial, T-DXd was given indefinitely, so there wasn’t the induction and maintenance [phases] that we’re familiar with from using the THP regimen.
The outcomes from this trial were impressive. The median PFS by blinded independent central review was 26.9 months in the THP arm vs 40.7 months in the T-DXd plus pertuzumab arm, [translating to] a difference of 13.8 months, which was statistically significant. There weren’t enough events yet to report [PFS data for] the T-DXd alone arm, so we’re still waiting on those data, which will be reported in the future. The overall survival [OS] data are not yet mature.
[This readout showed] some data on time to second progression [PFS2], which [comprises outcomes with] the first-line therapy plus the next line of therapy. That favored using T-DXd plus pertuzumab in the first-line setting. Importantly, many of those patients didn’t have access to T-DXd in the second-line setting, so not all patients crossed over from the THP to receive T-DXd. That’s one caveat in assessing those PFS2 data. [These are] interesting and important data. It will likely be practice changing to have the option of using T-DXd with or without pertuzumab.
What future avenues of investigation do these findings open up?
We’ll need to see the data with T-DXd alone. It’ll also be important to understand more about the PFS2 and OS, particularly for patients who had access to T-DXd [in the second-line setting]. Does it help [more] to give THP or T-DXd before receiving other therapies? Can you wait to give T-DXd to some patients?
The other big question that came out of this [readout] was [whether we should use] indefinite T-DXd vs employing a maintenance strategy like we do for the CLEOPATRA regimen. Would it be efficacious to do that here with a certain number of cycles of T-DXd and then go into a maintenance [phase]? [That may] be beneficial for patients. Patients often do well on this maintenance strategy.
Other trials are ongoing to better optimize the maintenance strategy. [In December 2024], we saw the data from the phase 3 PATINA trial [NCT02947685] that investigated adding palbociclib [Ibrance] to [anti-HER2 therapy and] endocrine therapy [maintenance in patients with hormone receptor–positive, HER2-positive metastatic breast cancer]. There are other trials ongoing evaluating adding a HER2-targeted TKI [to established maintenance strategies].
It would be appealing to potentially study T-DXd induction therapy with a maintenance strategy to see if that could be an ongoing option for patients as well. The phase 2 DEMETHER trial [NCT06172127] is ongoing to assess that now; we’ll have a bit more data once that trial reads out. Additionally, if we do employ maintenance, could we rechallenge with T-DXd if the patients have progression again? A lot of questions remained after we saw these important [DESTINY-Breast09] data about where we could go with this as a field.
What other questions still need to be addressed from DESTINY-Breast09 regarding the optimal use of T-DXd in the frontline setting?
[Treatment] sequencing will be another question. Historically, we’ve used the THP regimen followed by T-DXd, and then often, the phase 2 HER2CLIMB trial [NCT02614794] regimen with capecitabine [Xeloda] plus tucatinib [Tukysa] and trastuzumab as a third-line regimen. However, if we move T-DXd into the first-line setting, [we may] use the HER2CLIMB regimen next.
We can still potentially use a taxane-based regimen with trastuzumab plus pertuzumab. Where should that fit? How effective will that be after [giving] some of these [other] agents? The sequencing of these agents as we move forward, understanding how the next lines of therapy will work, will be another important question to figure out.
If a T-DXd–based regimen becomes a frontline SOC for patients with HER2-positive breast cancer, how would that affect the role of the long-established THP regimen?
The short answer is that we don’t know. We don’t have much data with THP after T-DXd. We will likely still use [the THP] regimen, but whether it will be second or third, and how well it will work, are open questions.
If T-DXd becomes part of the first-line SOC for this population, what other sequencing questions will need to be addressed in later lines of therapy?
If we use T-DXd [in the frontline setting] and employ that maintenance strategy, one question will be: Can we rechallenge with T-DXd in patients [who have received] a maintenance strategy and then have further progression? We’ll need to have some experience with that and hopefully some trials to specifically answer that question.
Additionally, where will the taxanes fit in? Should we use the HER2CLIMB regimen followed by a taxane-based regimen? Which order makes sense? Are there patients for whom the THP regimen still makes sense and in whom we can save T-DXd for the second-line setting? We generally try to avoid that if a patient has more indolent disease or if they have pulmonary comorbidities where we are worried about interstitial lung disease. However, the question remains: Does everyone need T-DXd first, or are there certain older patients or other patients with other comorbidities where we might still want to employ THP [first]?
Given the established success of T-DXd and ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive breast cancer, how might the continued development of antibody-drug conjugates (ADCs) further affect this treatment paradigm?
We still need novel ADC options for patients with HER2-positive disease. Despite the tremendous efficacy of T-DXd and T-DM1, patients still progress on these agents. [We need] novel ADCs with novel payloads that are different than some of these existing payloads to have better third-, fourth-, and fifth-line options.
An area of unmet need in the field is [how we should treat] patients with HER2-positive disease after some of these later-line [therapies] . Our SOC options don’t tend to work as well and we often run into issues with central nervous system [CNS] metastases the further along we get with lines of treatment. Data [show] that patients [increasingly] develop brain metastases [in later lines of therapy], so having ADCs that better penetrate the CNS in that setting is important too. There’s room for novel development here.
Reference
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