Treatment Individualization Is Increasingly Vital With T-DXd Poised to Enter Early-Stage HER2+ Breast Cancer Paradigm

The treatment paradigm for early-stage HER2-positive breast cancer is rapidly evolving, with antibody-drug conjugates (ADC) like fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) poised to move from later-line metastatic use into curative-intent settings, according to Maxwell Lloyd, MD.

Lloyd highlighted data with T-DXd from the phase 3 DESTINY-Breast11 (NCT04455841) and DESTINY-Breast05 (NCT04154956) trials, which have suggested that incorporating this highly active ADC in the neoadjuvant and adjuvant settings may improve pathologic complete response (pCR) and invasive disease–free survival (iDFS) outcomes in select high-risk populations, while simultaneously reframing ongoing discussions around escalation, de-escalation, and risk-adaptive treatment strategies in HER2-positive disease. Primary findings from DESTINY-Breast11 and DESTINY-Breast05 were shared at the 2025 ESMO Congress, and updates from both trials were presented at the 2025 San Antonio Breast Cancer Symposium^1-4

“We are seeing T-DXd move earlier and earlier in these treatment settings—first into second- and third-line metastatic disease, with a more recent approval in the first line [in combination with pertuzumab (Perjeta)]for metastatic disease, and now with evidence of efficacy in the neoadjuvant and adjuvant spaces,” Lloyd, a hematology/oncology fellow in the Department of Medicine at Beth Israel Deaconess Medical Center in Boston, Massachusetts. “This ADC is truly shaping the treatment paradigm for HER2-positive breast cancer.”

In an interview with OncLive®, Lloyd spotlighted emerging data supporting de-escalated strategies in early-stage HER2-positive breast cancer; discussed the implications of data from DESTINY-Breast11 and DESTINY-Breast05; highlighted the importance of identifying high-risk patients who may benefit from T-DXd; and detailed the need for further research on treatment sequencing and risk-adaptive strategies.

OncLive: What are some unmet needs experienced by patients with early-stage HER2-positive breast cancer?

Lloyd:In such a rapidly evolving space as the one we are looking at here, some of the major unmet needs still involve being able to personalize and tailor therapies for patients with early-stage HER2-positive breast cancer in order to maximize benefit while minimizing unnecessary toxicities. To this end, we have seen both escalation and de-escalation strategies in this space using risk-adaptive therapeutic approaches to truly individualize treatments for patients; however, there is clearly a lot of room where we can do better in terms of predicting which patients might need more active therapies and those for whom we could potentially use fewer chemotherapeutic agents.

We have seen a significant amount of emerging data that supports de-escalated strategies in early-stage HER2-positive disease, including the [phase 3] NeoCARHP [NCT04858529], [phase 2] HELEN-006 [NCT04547907], and [phase 2] COMPASS-HER2-pCR [NCT04266249] trials. These support treatment with a taxane, trastuzumab [Herceptin], and pertuzumab [THP] rather than THP plus carboplatin [TCHP] as being a potentially similarly effective regimen to achieve a pCR in some patients, while being less toxic by dropping carboplatin from that neoadjuvant regimen. Based on these data and current practice, providers need to consider which patients with stage II or even stage III disease need TCHP vs those who could potentially achieve a pCR with THP alone.

We are also seeing data from the DESTINY-Breast11 and DESTINY-Breast05 trials incorporating T-DXd into these neoadjuvant/adjuvant regimens, and we are seeing improved outcomes with these strategies. A major unmet need is identifying those patients for whom we need to incorporate an ADC for their treatment, and those for whom we might be able to potentially de-escalate chemotherapies and still achieve durable, long-term outcomes.

What are the implications of data from DESTINY-Breast11 for the use of T-DXd vs doxorubicin/cyclophosphamide-THP (ddAC-THP) for approaches in the neoadjuvant setting?

DESTINY-Breast11 [was a] large, randomized, international study [evaluating T-DXd] in the neoadjuvant setting.¹ It enrolled patients to receive either T-DXd followed by THP, standard of care [SOC] ddAC-THP, or T-DXd monotherapy—however, that monotherapy arm was discontinued early because the Data Safety Monitoring Board saw lower pCR rates.

This trial enrolled patients with high-risk HER2-positive breast cancer, including those with a clinical T3 or greater tumor burden, node-positive disease, or even inflammatory breast cancer. A majority of patients on this trial had node-positive disease.

In terms of the primary end point, we saw that the T-DXd [plus THP] arm had a higher pCR rate vs ddAC-THP. This [translated to] an absolute benefit of 11.2% between the experimental and control arms, which was both statistically significant and clinically meaningful. Seeing a greater than 10% improvement in pCR rate is important, as we know from other research that it is a prognostic indicator of event-free survival [EFS].

Subgroup analyses of this trial showed that the benefit with T-DXd was maintained across subgroups, including [those with] hormone receptor–positive and hormone receptor–negative disease. The benefit of T-DXd plus THP over ddAC-THP was also seen in those with HER2 2+ by immunohistochemistry [IHC] rather than 3+, which was a minority of patients. Although pCR rates were lower in both arms for the 2+ group, the improvement seen with the T-DXd regimen was maintained, which is nice to see in terms of the efficacy outcomes being more broadly applicable. Because HER2-positive breast cancer is a heterogeneous term, being able to adopt a strategy across patient populations we see in the clinic is important.

Investigators also looked at important secondary end points, including EFS and safety. The EFS data are still immature; however, when this study was published in the Annals of Oncology in October 2025, it showed a trend favoring T-DXd plus THP [over ddAC-THP]. This will be important to follow for long-term outcomes.

Regarding safety, drug discontinuation rates were fairly similar between the [T-DXd plus THP and ddAC-THP] arms, at 16.9% and 13.8%, respectively, and nearly all patients experienced an adverse effect [AE] of any grade. However, grade 3 or higher AEs were more common in the ddAC-THP arm. This suggests the T-DXd regimen could potentially be a safer option [than ddAC-THP]. We did see higher rates of gastrointestinal [GI] toxicity with T-DXd, such as nausea and diarrhea, and increased transaminase levels were comparable across the studies. With ddAC-THP, cytopenias like neutropenia and anemia tended to be more common.

Interstitial lung disease [ILD] is something we must look at closely with any regimen incorporating T-DXd. Interestingly, the rate of ILD attributed to the drug was actually slightly higher in the ddAC-THP arm at 5.1% compared with 4.4% in the T-DXd arm, and the rate of grade 3 or higher ILD was also higher with ddAC-THP. Furthermore, the rates of cardiotoxicity, specifically left ventricle dysfunction, were higher in the ddAC-THP arm vs T-DXd arm, which is expected with an anthracycline-containing regimen.

These data are now with the FDA for evaluation. I believe we will have additional clarity from the FDA in terms of action later [in 2026], which will be informative.

What is the significance of iDFS data with adjuvant T-DXd vs ado-trastuzumab emtansine (Kadcyla; T-DM1) from DESTINY-Breast05 for patients with residual disease?

DESTINY-Breast05 looked at [T-DXd] in the adjuvant setting.² This was another large, randomized phase 3 trial enrolling over 1500 patients with HER2-positive breast cancer. These were patients who had inoperable disease at baseline, T4 disease, extensive nodal burden, or residual disease in the lymph nodes after receiving neoadjuvant systemic therapy. In my opinion, this trial enrolled a very high-risk population.

Patients were randomly assigned 1:1 to receive either T-DXd or T-DM1 every 3 weeks for 14 cycles. T-DXd was associated with higher 3-year iDFS rates of 91.8% vs 83.2% with T-DM1. The HR was 0.49, correlating with a 51% relative improvement with T-DXd. That benefit was seen irrespective of whether patients received a platinum- or anthracycline-containing regimen as neoadjuvant chemotherapy. These findings are statistically significant and clinically meaningful.

Key secondary end points, including distant recurrence-free survival, were also superior in the T-DXd arm. The overall survival data are still immature and will be incredibly important to follow, but we are starting to see a separation in those curves.

In terms of safety, drug discontinuation rates were 17.9% for T-DXd and 12.9% for T-DM1. Almost every patient on T-DXd experienced an AE of any grade, but [the incidence of] grade 3 or higher AEs was 50.6%, compared with 51.9% on T-DM1, making them fairly comparable. Expected GI toxicities and cytopenias were seen, and radiation pneumonitis occurred in both arms at [an incidence of approximately] 30%. With T-DM1, the more common AEs seen were transaminase level elevations and thrombocytopenia. However, patients on the T-DXd arm experienced ILD at a rate of 9.6% compared to 1.6% on T-DM1. Two patients actually died on the trial from ILD. This is an important AE of T-DXd that we must understand and monitor closely.

Again, these data need to be reviewed by the FDA, but for these select high-risk patients, adjuvant T-DXd appears to offer a significant iDFS benefit compared with T-DM1.

What role do you ultimately see for T-DXd in the early-stage setting, and how might your colleagues continue driving progress with personalized treatment?

Selecting the right patient with early-stage HER2-positive breast cancer in whom we should utilize neoadjuvant or adjuvant T-DXd remains of utmost importance to maximize benefit and minimize unnecessary toxicities. I expect there to be a shift in standard management paradigms in the near future for [early-stage] HER2-positive breast cancer. One of the questions surrounding these emerging data is whether we should utilize T-DXd in the neoadjuvant setting, the adjuvant setting, or in both.

While we are awaiting the FDA review of the data, the findings from these trials show statistically significant and clinically meaningful improvements in outcomes with T-DXd for these select patients with high-risk, HER2-positive disease. At the same time, this needs to be weighed against the de-escalation strategies that are emerging in early-stage HER2-positive breast cancer, such as looking at THP vs TCHP. Coming back to DESTINY-Breast11 in the neoadjuvant setting, finding the most appropriate high-risk patient populations who truly benefit from adding this ADC, rather than giving TCHP or de-escalated THP, is critical.

Identifying and validating clinical characteristics and biomarkers, which allow us to really personalize therapy for these individual patients, will help shape the future treatment paradigm, both in terms of selecting the right patient for de-escalated therapy and ensuring we are not missing those for whom we can incorporate an ADC into their neoadjuvant treatment regimen.

In terms of the adjuvant space, the superior iDFS benefit observed with T-DXd compared with standard T-DM1 in DESTINY-Breast05 is quite convincing. These patients had very high-risk residual disease burden in the lymph nodes and an inadequate response to neoadjuvant chemotherapy with HER2 antibodies. One of the bigger questions [surrounding] the adoption of this approach could be related to potential toxicity concerns associated with 14 cycles of T-DXd. Illustrating this point, nearly 10% of patients on T-DXd developed ILD, and there were 2 deaths due to ILD.

In the curative-intent setting, we really need to weigh those potential toxicities against the improved DFS benefit when making these treatment decisions. That being said, for these select patients with high-risk disease, T-DXd is clearly more active and efficacious, leading to superior outcomes. Based on these data, I believe we will see a shift in practice patterns with providers using T-DXd more and more for this patient population.

If T-DXd becomes a SOC in the first-line metastatic setting, what might this mean for patients who experience metastatic recurrent disease and have already received this agent?

These sequencing questions are increasingly important as we see more active agents move from later to earlier metastatic disease and into the curative-intent setting. We have to think about the sequencing of these agents and repeated exposures to the same agent or a similar drug class. In the near future, one of the things we could consider from an individual patient perspective is the time to recurrence or relapse after exposure to this agent.

If someone experiences fairly immediate metastatic recurrence—relapsing in under 1 year after exposure to T-DXd—I would not be too keen to re-expose them to that same therapy. I would be looking for an alternative cytotoxic or HER2-directed option that ideally has a different mechanism of action the tumor hasn't seen before, because I would be worried about the development of underlying resistance from that prior exposure. If they were being treated for curative intent, there might have been micrometastatic disease that saw the T-DXd and grew despite that exposure; therefore, I would be thinking about an alternative option.

However, if someone completes treatment and experiences relapse many years down the line, I think there is a reasonable approach to consider re-exposure to T-DXd. If there has been a significant gap between the adjuvant or neoadjuvant treatment and the metastatic treatment, we might still see disease that is sensitive to this incredibly active and efficacious agent. A similar paradigm is currently taken with patients receiving taxane therapy for HER2-positive disease. If they have an early relapse, I might reach for second-line regimen options, whereas with a later relapse, retreatment with a first-line THP regimen is a reasonable option years after neoadjuvant or adjuvant taxane therapy.

Taking that question one step earlier, an area of evolving uncertainty raised by DESTINY-Breast11 and DESTINY-Breast05 is where T-DXd should be prioritized in the curative-intent setting. If we can identify patients in need of T-DXd for curative treatment, one could argue that 4 cycles of T-DXd up-front with a goal of achieving a pCR might be more tolerable than 14 cycles on the back end, potentially with lower rates of ILD or other toxicities.

Right now, we do not have efficacy data comparing these 2 approaches or, more importantly, long-term outcomes of 4 neoadjuvant cycles vs 14 adjuvant cycles. This will be an incredibly important question [to answer] in the months and years to come. Additionally, it is not clear if there would be any benefit with adjuvant T-DXd if it were also given in the neoadjuvant setting. For a patient with high-risk HER2-positive breast cancer treated with the DESTINY-Breast11 approach who has residual disease in the lymph nodes at surgery, should we then give a DESTINY-Breast05-informed regimen as adjuvant treatment? We do not have the data available to inform that sequencing question yet, but it remains an area of active research as we think about the continuum from neoadjuvant to adjuvant to metastatic treatment.

Are there any other treatments in development that show promise for use for patients with early-stage breast cancer?

As we continue to think about how we refine these treatment approaches and give the right therapy to the right patient at the right time while not under-treating any patients, an approach focus on risk-adaptive neoadjuvant decision-making in addition to the standard risk-adaptive adjuvant decision-making has been proposed. [This approach is] further down the line and needs prospective validation.

Thinking about DESTINY-Breast11, DESTINY-Breast05, and other trials of escalated or de-escalated strategies, we could envision starting neoadjuvant treatment with a regimen like THP. After 4 cycles of THP, we could use diagnostic investigations to evaluate how patients are responding and adapt their treatment strategies accordingly. For example, if we had baseline and post-THP breast MRIs to evaluate for radiographic evidence of a pCR, we could move forward with taking a patient to surgery and making further treatment decisions in the adjuvant setting.

Conversely, if we do not see evidence of a radiographic pCR at that point, we could incorporate T-DXd, ddAC, or another chemotherapy-directed option to try to achieve a pCR before curative surgery. This would allow for a tailored therapeutic approach using T-DXd or other emerging neoadjuvant agents for specific high-risk patients with an inadequate response to THP, while potentially sparing unnecessary toxicities for patients who achieve a pCR with THP.

For those who may need less therapy for good long-term outcomes, we can still use our standard risk-adaptive approaches after surgery based on residual disease burden. If they have a pCR, we treat with one year of HP; if they have residual disease, we can consider whether they need T-DXd, T-DM1, or other therapies. This could be an evolving paradigm for HER2-positive breast cancer, [and should be] tested in current and future clinical trials to help clinicians guide and personalize treatment approaches.

References

1. Harbeck N, Modi S, Pusztai L, et al. DESTINY-Breast11: neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC). Ann Oncol. Published online October 21, 2025. doi:10.1016/j.annonc.2025.10.019
2. Geyer CE, Park YH, Shao Z-M, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with high-risk human epidermal growth factor receptor 2–positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy (tx): Interim analysis of DESTINY-Breast05. Ann Oncol. 2025;36(suppl 2):S1556-S1557.
3. Loibl S, Park YH, Shao Z, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with high-risk human epidermal growth factor receptor 2-positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy: Interim analysis of DESTINY-Breast05. Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF6-01.
4. Curiglian G, Harbeck N, Boileau J-F, et al. DESTINY-Breast11 (DB-11) safety: neoadjuvant trastuzumab deruxtecan (T-DXd) alone or followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in high-risk, HER2+ early-stage breast cancer (eBC). Presented at: 2025 San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, TX. Abstract RF6-02.