New ADC Data Underscore Progress and Highlight Challenges in HER2+ Breast Cancer and TNBC Management

Recent data readouts with treatment standards like fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and sacituzumab govitecan-hziy (Trodelvy) may refine the optimal use of these agents in the HER2-positive and triple-negative breast cancer (TNBC) treatment settings. Additionally, continued research with newer antibody-drug conjugates (ADCs) may further expand the number of available treatment options for select patients.

“Now that we have data for T-DXd in the neoadjuvant and the adjuvant settings…we’re all going to have to grapple with [those] in clinic,” Neil M. Iyengar, MD, said in a recent OncLive® Peer Exchange. “This is a testament to how the clinical paradigm changes so quickly and how we have to frame our interpretation of clinical trials…. The adjuvant therapy paradigm is shifting under our feet. Once we get those long-term data, interpreting those is going to be interesting in the context of what we’re doing now in clinic.”

During the panel discussion, breast cancer experts gathered to discuss updates in HER2-positive and triple-negative disease management that were presented at the 2025 European Society for Medical Oncology (ESMO) Congress. They highlighted key datasets that support the use of T-DXd across several HER2-positive treatment settings, the efficacy of the HER2-targeted ADC trastuzumab botidotin (A166), and data with TROP2-directed ADCs that may broaden treatment options for patients with TNBC. Considerations about balancing the efficacy and safety profiles of ADCs, as well as the need to determine treatment de-escalation strategies for select patients, were featured in the discussion as well.

How might new T-DXd data help pinpoint the role of this agent across the neoadjuvant and adjuvant HER2-positive breast cancer settings?

Data from the phase 3 DESTINY-Breast11 trial (NCT05113251), presented at ESMO 2025, reinforce the benefit of using T-DXd–based regimens in the neoadjuvant HER2-positive setting. This trial, which investigated neoadjuvant T-DXd plus a taxane, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP; n = 321) in patients with high-risk, HER2-positive early breast cancer, showed improved outcomes, including a pathologic complete response (pCR) rate of 67.3% vs 56.3% in those treated with neoadjuvant dose-dense doxorubicin and cyclophosphamide plus THP (ddAC-THP; n = 320; difference, 11.2%; 95% CI, 4.0%-18.3%; P = .003).1 This advantage was observed regardless of hormone receptor status. Event-free survival (EFS) trends also favored the T-DXd arm, which had a 24-month EFS rate of 96.9% (95% CI, 93.5%-98.6%) vs 93.1% (95% CI, 88.7%-95.8%) in the ddAC-THP arm.

Despite the efficacy of T-DXd in this population, the panelists acknowledged the toxicity profile associated with this ADC. In DESTINY-Breast11, any-grade adverse effects (AEs) were reported in 98.1% of patients who received T-DXd, and the rate of grade 3 or higher AEs in this arm was 37.5%. Any-grade drug-related adjudicated interstitial lung disease (ILD) and left ventricular dysfunction were observed in 4.4% and 1.3% of patients, respectively. Although these rates were lower than those in the ddAC-THP arm, the experts emphasized the importance of AE monitoring and investigating treatment de-escalation strategies for eligible patients.

“Hopefully someday we’ll be able to figure out who those…patients are who could use less therapy and still achieve a pCR,” Sara A. Hurvitz, MD, FACP, said. “We’re grappling with what happens if you use T-DXd/THP in the neoadjuvant setting and there’s residual disease at the time of surgery. Do you give more T-DXd? That wasn’t tested. Do you give ado-trastuzumab emtansine [T-DM1; Kadcyla]? In this study, only [52.6%] of the patients received T-DM1 for residual disease. That’s probably speaking to the fact that this was an international study, and the study did not provide T-DM1 in the adjuvant setting.”

Interim findings from the phase 3 DESTINY-Breast05 trial (NCT04622319), also presented at ESMO 2025, may help refine the role of T-DXd in the adjuvant HER2-positive paradigm. This trial evaluated T-DXd vs T-DM1 in patients with high-risk, HER2-positive primary breast cancer with residual invasive disease after neoadjuvant therapy. In the trial, patients who received T-DXd (n = 818) achieved a 3-year invasive disease–free survival rate of 92.4% (95% CI, 89.7%-94.4%) compared with 83.7% (95% CI, 80.2%-86.7%) among those who received T-DM1 (n = 817).2 The T-DXd benefit translated to a 53% reduction in the risk of invasive disease or death vs T-DM1 (HR, 0.47; 95% CI, 0.34-0.66; P < .0001).

“In patients who are estrogen receptor positive, we’re going to be drawing in other therapies besides HER2-directed therapy,” William J. Gradishar, MD, noted about the overall changes that may occur in the HER2-positive treatment paradigm. “The adjuvant component of our therapies is going to change just as the front end is changing. We may be using CDK4/6 inhibitors, endocrine therapy, and an HP regimen or a T-DXd regimen post-operatively. Those are still open questions with the new data in the pre-operative setting.”

How might the further investigation of standard and novel ADCs continue to move the needle in HER2-positive breast cancer management?

Data from the primary analysis of the phase 3 DESTINY-Breast09 trial (NCT04784715), which were presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, showed that among patients with HER2-positive advanced or metastatic breast cancer, the median progression-free survival (PFS) by blinded independent central review (BICR) was 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).3 These data supported the July 2025 FDA breakthrough therapy designation that was granted to T-DXd plus pertuzumab for this indication.4

Findings from the subgroup analysis of DESTINY-Breast09 presented at ESMO 2025 demonstrated the superior efficacy of T-DXd plus pertuzumab vs THP across prespecified patient subgroups, regardless of prior treatment status, hormone receptor status, or PIK3CA mutation status. Notably, the biggest PFS advantage with the investigational regimen was observed among patients with de novo disease, who achieved a median PFS that was NC (95% CI, 36.5-NC) vs 31.2 months (95% CI, 23.5-NC) with THP.5

“At present, the T-DXd plus pertuzumab arm is looking good,” Gradishar said. “One of the questions that will come up is: Do all patients need T-DXd plus pertuzumab? In the past, we’ve tried to see if we could perhaps avoid the toxicity of a taxane [in the phase 3 CLEOPATRA trial (NCT00567190) regimen] by substituting T-DM1. Trials that have looked at that [have shown] no significant advantage of using TDM-1 with pertuzumab. The CLEOPATRA [regimen] continued to reign up until this point. T-DXd plus pertuzumab is not yet on the guidelines [for HER2-positive, unresectable or metastatic disease], but we’ll be discussing whether it should be [a regimen] we use in all patients, select patients, or patients with certain features that make us worried.”

Shifting the conversation to novel HER2-targeting ADCs, the panelists highlighted the efficacy findings from a phase 3 trial investigating trastuzumab botidotin vs T-DM1 in patients with HER2-positive unresectable or metastatic breast cancer. In the trial, treatment with trastuzumab botidotin (n = 182) elicited a median BICR-assessed PFS of 11.1 months (95% CI, 9.7-13.8) vs 4.4 months (95% CI, 4.2-5.7) with T-DM1 (n = 183; HR, 0.39; 0.30-0.51; P < .0001).6

“This trial has a similar design to the phase 3 DESTINY-Breast03 trial [NCT03529110], where T-DM1 was compared with T-DXd [in patients with HER2-positive unresectable and/or metastatic breast cancer who were previously treated with trastuzumab and a taxane],” Kamel Abou Hussein, MD, contextualized. “[Regarding] the safety of [trastuzumab botidotin], we see no high-risk gastrointestinal [GI]–related toxicity. We also see that it’s safe when it comes to hepatotoxicity or thrombocytopenia, which are issues with T-DM1. [We also see] a lower level of ILD [vs T-DM1]. That is encouraging to hear.”

The GI AEs seen in the trastuzumab botidotin arm were all grade 1 or 2 and consisted of nausea (5.5%), vomiting (3.3%), and diarrhea (2.7%). Increased aspartate aminotransferase levels (any-grade, 23%; grade ≥ 3, 1%), increased alanine aminotransferase levels (19%; 1%), and decreased platelet counts (8%; 0%) were also seen with the use of this agent. ILD/pneumonitis occurred in 2 patients in the trastuzumab botidotin arm (grade ≥ 3, n = 0) vs 5 patients in the T-DM1 arm (grade ≥ 3, n = 3).

What questions remain regarding choosing between TROP2-targeted ADCs for TNBC?

Primary results from the phase 3 ASCENT-03 trial(NCT05382299), which were presented at ESMO 2025, showed that sacituzumab govitecan (n = 279) induced a median PFS by BICR of 9.7 months (95% CI, 8.1-11.1) in patients with previously untreated, locally advanced unresectable, or metastatic TNBC who were not eligible for PD-1/PD-L1 inhibitors; this value was 6.9 months (95% CI, 5.6-8.2) with chemotherapy (n = 279; HR, 0.62; 95% CI, 0.50-0.77; P <.0001).7 Additionally, the overall response rate (ORR) was 48% (95% CI, 42%-54%) with the ADC vs 46% (95% CI, 40%-52%) with chemotherapy (stratified OR, 1.1; 95% CI, 0.8-1.6). The overall survival (OS) data were immature, however, a numerical OS advantage with sacituzumab govitecan was observed.

“The thought would be now, with [data from the phase 3] ASCENT-04 trial [NCT05382286] having just been presented at ASCO [2025] and being positive, sacituzumab govitecan would be given with pembrolizumab [Keytruda] in the frontline setting if [a patient is] PD-L1 positive, and in the frontline setting as a single agent if [they are] PD-L1 negative, based on the ASCENT-03 data,” Hurvitz explained.

Notably, ASCENT-04 showed a median PFS of 11.2 months (95% CI, 9.3-16.7) with sacituzumab govitecan plus pembrolizumab (n = 221) vs 7.8 months (95% CI, 7.3-9.3) with chemotherapy plus pembrolizumab (n = 222; HR, 0.65; 95% CI, 0.51-0.84; P < .001).8

However, positive findings from the phase 3 TROPION-Breast02 trial(NCT05374512), also presented at ESMO 2025, add complexity to first-line treatment decision-making for patients with locally recurrent unresectable or metastatic TNBC who are not eligible for immunotherapy. In TROPION-Breast02, the TROP2-targeted ADC datopotamab deruxtecan-dlnk (Dato-DXd; Datroway; n = 323) elicited a median PFS of 10.8 months (95% CI, 8.6-13.0) vs 5.6 months (95% CI, 5.0-7.0) with investigator’s choice of chemotherapy (n = 321; HR, 0.57; 95% CI, 0.47-0.69; P < .0001).9 The median OS was 23.7 months (95% CI, 19.8-25.6) with Dato-DXd vs 18.7 months (95% CI, 16.0-21.8) with chemotherapy (HR, 0.79; 95% CI, 0.64-0.98; P = .0291). Additionally, the respective ORRs were 62.5% and 29.3% (OR, 4.24; 95% CI, 3.03-5.95).

“They’re both important studies, and we’re going to have to be nuanced in how we apply these data if both these agents are approved [in this setting],” Hurvitz underscored. “We have to understand where to use them. Maybe Dato-DXd is reserved for very high-risk patients with treatment-resistant disease where you need to get a response, because a [62.5]% response rate is notable in this setting.”

“I don’t think it’s going to be valuable to [administer] these drugs one after the other, or go from sacituzumab govitecan or Dato-DXd to T-DXd, because there is cross-resistance between those drugs with similar payloads,” Kelly McCann, MD, PhD, cautioned. “Ultimately, it would be wonderful to have drugs that have different [payloads] attached to them.”

What research is needed to further expand and refine the HER2-positive and TNBC treatment arenas?

The panelists concluded their discussion by looking to the future of the HER2-positive and TNBC treatment paradigms and noting the unmet needs they hope will be addressed in the coming years.

“Moving the ADCs up into that frontline setting is exciting, because we lose patients early on in that frontline setting,” Hurvitz stated. “In [the HER2-positive and triple-negative] disease subtypes, [we] have to use our best agents up front. An area of huge unmet need in triple-negative [disease] especially is brain metastases. That is a huge problem, and we don’t have as many agents that cross the blood-brain barrier. That’s where I’m excited to see the field go further. We’re seeing a lot more novel immune-targeted therapies and combinations that we may be borrowing from our colleagues in other tumor histologies and learning from as we see the field move beyond just pembrolizumab. Maybe we’ll have some successes there.”

The experts also acknowledged the importance of making clinical research participation more inclusive and accessible for patients, particularly those with TNBC, so the treatment updates that may ensue are as effective as possible for as many patients as possible.

“A huge area of need is that we know that TNBC disproportionately affects underrepresented groups, and yet, we consistently see these groups continue to be underrepresented in our clinical trials,” Iyengar concluded. “We need to focus on understanding the efficacy of these novel therapies in those groups that are affected the most by these subtypes of breast cancer.”

Neil M. Iyengar, MD, is an associate professor and co-director of Breast Medical Oncology in the Department of Hematology and Medical Oncology at the Emory University School of Medicine; as well as the director of survivorship services at the Winship Cancer Institute of Emory University in Atlanta, Georgia.

Kelly E. McCann, MD, PhD, is a breast medical oncologist at UCLA Health and an assistant clinical professor of medicine at UCLA.

Kamel Abou Hussein, MD, is co-director of the Janet Knowles Breast Cancer Center, director of Breast Medical Oncology, director of Breast Cancer Clinical Trials, and a hematologist/medical oncologist at the MD Anderson Cancer Center at Cooper in Camden, New Jersey; as well as an assistant professor of medicine at the Cooper Medical School of Rowan University.

William J. Gradishar, MD, is the Betsy Bramsen Professor of Breast Oncology and a professor of medicine (hematology and oncology) at the Northwestern University Feinberg School of Medicine in Chicago, Illinois.

Sara A. Hurvitz, MD, FACP, is senior vice president, director of and a professor in the Clinical Research Division, the Smith Family Endowed Chair in Women’s Health, and an affiliate investigator in the Translational Science and Therapeutics Division at the Fred Hutchinson Cancer Center in Seattle, Washington; as well as a professor in and head of the Division of Hematology and Oncology in the Department of Medicine at the University of Washington.

References

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