Too much, too soon?—trastuzumab deruxtecan in the first line metastatic setting

Over the last fifty years there have been tremendous gains in breast cancer associated mortality, with treatment advances for stage IV breast cancer attributing almost 30% to this reduction (1). This is especially true for human epidermal growth factor receptor 2 positive (HER2+) breast cancer where with the advent of HER2-targeting monoclonal antibodies, HER2+ breast cancers have transformed from one of the most aggressive subtypes to what many would consider to be one of the most treatable subtypes over the past twenty years.

The undisputed first line therapy for metastatic HER2+ breast cancer has been taxane, trastuzumab, and pertuzumab (THP) based on the results of the CLEOPATRA trial in 2012 which demonstrated a significant improvement in overall survival with dual HER2-targeting monoclonal antibodies (57.1 vs. 40.8 months with docetaxel + trastuzumab) (2,3). Several trials throughout the years evaluated other agents but none were able to unseat THP as the preferred first-line option (4-6). While HER2-targeted monoclonal antibodies played a large role in the initial wave of clinical improvement for HER2+ metastatic breast cancer, this second wave of clinical advances is being led by antibody drug conjugates (ADCs).

ADCs are monoclonal antibodies attached to a cytotoxic drug (“payload”) through a chemical linker. Currently two ADCs are approved for use in metastatic HER2+ breast cancer with trastuzumab emtansine (TDM-1) (7) approved in 2013 for second line and trastuzumab deruxtecan (T-DXd, previously known as DS-8201a) (8) approved initially in 2019 for the third line setting (9). T-DXd is a humanized IgG1 monoclonal HER2-directed antibody combined with a topoisomerase inhibitor conjugate through a tetrapeptide-based cleavable linker. Given the strong activity of T-DXd, subsequent approvals for second line in 2022 and most recently for first line in December 2025 as T-DXd plus pertuzumab unseated THP as the unrivaled first-line therapy based on the recently published DESTINY-Breast09 clinical trial (10).

With an expanding toolkit, stage IV HER-2 breast cancer is evolving into a chronic disease where the balance between efficacy and toxicity is essential. Despite a growing population of long-term survivors, a paucity of data exists to guide optimal supportive care and toxicity surveillance for those living with stage IV breast cancer (metavivorship). While short-term toxicities have been well described, the long-term toxicities of ADCs and their impact on long-term stage IV survivors have yet to be determined. Therefore, the onus lands on the treating physician to deftly sequence options in a rapidly evolving landscape that provides patients with the opportunity not only to live longer, but to live well with advanced HER2+ breast cancer.

Since the initial data from DESTINY-Breast01 was published in 2020, T-DXd has been marching towards the frontline (9). In the wake of excitement about the success of T-DXd in heavily pretreated patients, the DESTINY-Breast09 trial opened in April 2021 with the long awaited results now published (10). This phase 3, multinational, randomized trial enrolled 1157 patients with treatment naive advanced or metastatic HER-2+ breast cancer. Patients were randomized 1:1:1 to trastuzumab deruxtecan + pertuzumab (T-DXd + P) every 3 weeks, T-DXd + placebo every 3 weeks (arm not yet reported), or THP every 3 weeks for at least 6 cycles then transitioned to maintenance trastuzumab + pertuzumab (HP) per standard of care. Endocrine therapy (ET) was allowed for patients with hormone receptor positive disease but less than one third of eligible patients received concurrent ET (13.5% in T-DXd + P and 38.3% in THP). While multiple studies have shown the additional benefit that ET adds to PFS and OS, low utilization of endocrine maintenance in this trial and others highlights the potential lag of implementation into clinical practice as well as ongoing need to determine best maintenance therapy strategies for this population (11,12).

Data from the planned interim analysis confirmed superior progression-free survival (PFS) with T-DXd + P compared to THP (median PFS of 40.7 vs. 26.9 months; P<0.0001, respectively). Confirmed response was 85.1% for T-DXd + P compared to 78.6% with THP (Figure 1) with complete responses occurring in 15.1% of TDX-P and 8.5% THP (10). Durability of response to T-DXd + P was also evident with 24-month PFS at 70.1% vs. 52.1% for THP. Survival analysis is immature at this point, and the T-DXd monotherapy arm results will remain blinded until the final PFS analysis is completed. While the clinical improvement is very encouraging and T-DXd has undoubtably changed breast cancer care, the tolerability of T-DXd should remain a central point of conversations especially as T-DXd is moved earlier in the treatment algorithm.

Figure 1 Objective response rates for T-DXd in 1^st (DESTINY-Breast09) (10) 2^nd (DESTINY-Breast03) (8) and 3^rd line (DESTINY-Breast01) (9) metastatic HER2+ breast cancer. Of note, results from the T-DXd monotherapy arm of DESTINY-Breast09 is not available at this time. CR, complete response; N.E., not evaluable; P, pertuzumab; PD, progressive disease; PR, partial response; SD, stable disease; T-DXd, trastuzumab deruxtecan; TDM-1, trastuzumab emtansine.

The control arm of the Destiny-Breast09 was designed to model standard of care THP with at least 6 cycles of cytotoxic taxane (docetaxel or paclitaxel) with HP and then transition to maintenance HP. It should be noted that patients have relatively good quality of life on dual-HER2 monoclonal antibody therapy and this can be maintained over years after a good response to induction chemotherapy (13,14). This is particularly true for long-term responders who account for approximately 20% of patients treated with first line THP (2,15,16). Recently, several studies have evaluated the addition of oral agents to maintenance HP after induction chemotherapy to help further improve outcomes. While there are some differences in patient populations of these maintenance trials (i.e., de novo disease, bone only disease, central nervous system metastases, etc.) compared to the DESTINY-Breast-09 trial, the PATINA trial (maintenance palbociclib/ET with HP) (17) and HER2CLIMB-05 trial (maintenance tucatinib with HP) (18) both found significant improvements in PFS with the addition of oral agents in patients who responded to or had stable disease after induction therapy with THP (Figure 2).

Figure 2 Progression-free survival in first line HER2+ breast cancer—comparisons of recent clinical trial outcomes. It should be noted that the trials depicted above (DESTINY-Breast09, PATINA and HER2-CLIMB-05) had differences in patient populations (i.e., de novo metastases, bone only disease) and therefore are not directly comparable. ER, estrogen receptor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HP, trastuzumab + pertuzumab; T-DXd, trastuzumab deruxtecan; THP, docetaxel, trastuzumab, and pertuzumab.

In the phase 3 AFT-38 PATINA study, patients with metastatic hormone positive (ER+ and/or PR+), HER2+ breast cancer were randomized after induction chemotherapy (THP for 6–8 cycles) to receive ET + maintenance HP +/- palbociclib. A total of 518 patients were enrolled on the trial, completed an average of 6 cycles of THP and had a statistically significant improvement in PFS by 15.2 months with the addition of palbociclib + ET + HP (44.3 vs. 29.1 months with ET + HP) (17). Furthermore, there were no treatment related deaths on study, no significant increase in the occurrence of left ventricular dysfunction or cardiac heart failure over HP alone, and there were no new safety signals detected.

While PATINA was limited to ER/PR+, HER2+ only, the HER2CLIMB-05 trial included all patients with HER2+ irrespective of hormone receptor status. In this phase 3 trial, 654 patients with metastatic HER2+ breast cancer were randomized to HP +/− tucatinib. ET was allowed for patients with hormone receptor positive disease but less than half of eligible patients received concurrent ET. Patients received an average of 6 cycles of THP. The addition of tucatinib to HP significantly improved PFS to 24.9 months after randomization compared to only 16.3 months with HP alone. This improvement was seen in patients with both hormone receptor positive and negative, HER2+ breast cancer with a similar PFS advantage in both subgroups (ER+/HER2+ =24.9 months, ER−/HER2+ =25.0 months) (18). Of note, PFS was defined at time from randomization after induction chemotherapy to progression which makes direct comparison difficult however with 6 cycles of THP lasting around 4–5 months, the PFS estimate of 24.9 months is impressive. It should be noted that dose reductions (29.1%) or holds (49.4%) of tucatinib were common due to known side effects of diarrhea and elevated liver transaminases.

In the DESTINY-Breast09 trial, patients who received T-DXd + P had a higher rate of dose reductions (45.9% vs. 19.0% with THP) and a higher rate of discontinuation (68.8% vs. 49% with THP). Given T-DXd + P was administered every 3 weeks until progression or toxicity, it is not surprising that dose reductions and discontinuation rates were higher in the T-DXd + P arm than the THP arm where cytotoxic chemotherapy is stopped after 4–5 months (average cycles of THP completed =6 cycles; 4.1 months). Furthermore, grade 5 adverse events associated with death occurred in 3.4% of patients who received T-DXd + P compared to 0.8% with THP. While still a small number of patient deaths from T-DXd, the “high risk, high reward“ mentality of T-DXd use should be met with caution as many patients with metastatic HER2+ breast cancer can live for years (and sometimes exceptional responders alive more than a decade after diagnosis) (19,20).

Adverse events of interest were also more common with T-DXd + P including higher risk of pneumonitis (12.1% with T-DXd + P vs. 1.0% with THP) and higher risk of left ventricular dysfunction (11.0% with T-DXd + P vs. 7.0% with THP). To mitigate these risks, increased surveillance (CT imaging, close symptom monitoring, ECHOs) is recommended (10). While these diagnostics allow for more immediate intervention and greater odds of resolution, they add financial and time toxicities taken on by the patient. In addition, some of these side effects can be long-lasting and may impact the ability to deliver future therapies.

With regards to common side effects, rates of nausea and vomiting were also higher in the T-DXd + P arm (all grades: 71.1% and 42.0% respectively) compared to THP arm (all grades: 28.8% and 13.4% respectively). As expected peripheral sensory neuropathy remains higher with taxane therapy than with T-DXd + P (28.5% vs. 11.3%) but it should be noted that some low-grade neuropathy is reported with T-DXd-P. While rates of alopecia were comparable between arms (46.2% in T-DXd + P vs. 50.0% in THP), the duration of alopecia would be expected to be considerably longer in the T-DXd + P arm given established hair follicle regeneration during HP maintenance.

Overall, reported rates of adverse effects are in agreement with a pooled analysis (n=9) of the DESTINY trials (21); however, it is important to recognize differences between this clinical trial population and real-world population to which this data will be applied. A minority of patients enrolled in DESTINY-Breast09 were older than age 65 years (n=68) and all patients had performance statuses less than or equal to 1. This raises the concern that higher rates of bothersome adverse effects may be experienced by older populations and populations with a greater number of comorbidities than those included in the DESTINY-Breast09 analysis.

HER2+ breast cancer remains a heterogeneous disease with clinical presentations ranging from minimally symptomatic oligometastatic disease to visceral crisis at the time of diagnosis. For HER2+ metastatic breast cancer, both treating and preventing central nervous system (CNS; i.e., intraparenchymal metastases and leptomeningeal disease) metastases remains an unmet need (22). Incidence of CNS metastases in CLEOPATRA were similar between pertuzumab and placebo arms highlighting the need for better CNS penetrating agents (23). Previous studies evaluating intracranial responses of T-DXd have demonstrated intracranial responses ranging from 46% to 73% (24-26) making results from DESTINY-Breast09 particularly encouraging for improving frontline patients with known CNS metastases. With a clinical response rate of 85.1% (81.2–88.5%), T-DXd + P is similarly encouraging for patients with high volume of disease and high symptom burden most in need of a meaningful response to first line therapy. Conversely, patients with low-volume, minimally symptomatic disease may derive significant benefit from current first-line therapy and the multitude of emerging maintenance strategies. Overall, this speaks to a need to develop better tools to aid in prognostication. While certain clinical factors such as visceral disease, CNS disease, and multiple sites of disease are known to confer higher risk and there is ongoing work evaluating mechanisms of resistance such as PIK3CA/AKT and RAS/MEK/ERK pathways, there is currently a dearth of clinically applicable tools that allow for precise risk stratification of stage IV HER2+ disease (19,27).

T-DXd has excellent objective response rates in both the first-, second-, and third-line settings (Figure 1) highlighting the need for a more nuanced, patient-centered approach when selecting the optimal time for using T-DXd (8-10). Undoubtably the DESTINY-Breast09 trial results discussed here moves T-DXd + P into a favored front-line position due to the impressive improvement in PFS over THP. However, more research is needed to better delineate who would benefit from T-DXd + P and who would be a long-term responder to THP +/− a maintenance regimen. The broad application of T-DXd + P for all as first line therapy would subject a sizable patient population to a much greater physical and financial toxicity compared to the current standard of care. While not explicitly reported in the DESTINY-Breast09 trial, typically the median time to response with T-DXd has correlated with the first restaging scan after starting therapy. This rapid response to T-DXd makes an induction approach with 6 to 8 cycles of T-DXd + P followed by maintenance HP appealing to providers and patients alike (28). However, this trial was designed to continue T-DXd + P until progression or toxicity. With excellent PFS of PATINA and HER-2-CLIMB-05 (Figure 2), could a similar yet less toxic approach be possible with T-DXd? In addition, while the PFS2 (time from randomization to second progression or death) was superior with T-DXd + P over THP, the rapid ascension of T-DXd to front line has left many oncologists questioning the optimal sequence of subsequent therapies with few studies to date evaluating efficacy of established regimens. For example, if T-DXd + P is now first line therapy, where does THP fit within the treatment algorithm?

The DESTINY-Breast09 trial has changed the HER2+ metastatic breast cancer landscape but future research needs to determine (I) who benefits from first line T-DXd + P over THP, (II) incidence of long-term side effects of T-DXd, (III) the optimal induction regimen followed by maintenance opportunities, and (IV) therapeutic sequencing to achieve both longevity and quality for patients living with stage IV HER2+ breast cancer. As scientific advances improve patient outcomes, the onus to ensure that patients are living well with advanced breast cancer remains with the scientific community.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0209/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0209/coif). A.P.D. reports honorarium from NCCN for NCCN Tumor Board Presentation (10/2025) and honorarium from American Cancer Society (ACS) for serving on Project ECHO Improving Treatment of Advanced Breast Cancer Cohorts 1 and 2 during 2025-2026, which are unrelated to this work. M.E.G.M. reports institutional research funding by Sumitomo and Marengo; and ASCO advantage sponsored lecture on breast cancer and immunotherapy care. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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