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TROP2 ADCs in Metastatic TNBC: Addressing Challenges of Immunotherapy-Ineligible Patients

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Released: August 18, 2026

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For patients with metastatic triple-negative breast cancer who are not candidates for immunotherapy, treatment selection remains challenging because of aggressive disease biology, high symptom burden, generally poor outcomes, and variable access to emerging therapies across the globe. This commentary examines expert perspectives on the evolving role of TROP2-directed antibody–drug conjugates (ADCs), including sacituzumab govitecan and datopotamab deruxtecan, with attention to treatment sequencing, concerns for ADC availability, toxicity-informed treatment selection, and care team readiness for implementing ADC-based therapy in routine practice.

Thomas Bachelot
Thomas Bachelot, MD, PhD
Mafalda Oliveira
Mafalda Oliveira, MD, PhD
TROP2 ADCs in TNBC

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Key Takeaways
  • Most patients diagnosed with metastatic TNBC are ineligible for immunotherapy and have a poor prognosis.
  • The TROP2-directed ADCs datopotamab deruxtecan and sacituzumab govitecan are approved by the FDA and EMA as initial therapy for adults with unresectable/metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitors.
  • Key adverse events to monitor and manage include stomatitis and ocular events with datopotamab deruxtecan and diarrhea and neutropenia with sacituzumab govitecan.

In this commentary, Thomas Bachelot, MD, PhD, and Mafalda Oliveira, MD, PhD, discuss the evolving role of anti-TROP2 antibody–drug conjugates (ADCs) for patients with metastatic triple-negative breast cancer (TNBC), including those who are not candidates for immunotherapy. They address emerging questions and common challenges in integrating TROP2-directed ADCs into everyday TNBC practice, including varied regional access and reimbursement disparities. They also share practical strategies and established workflows for managing key AEs and supporting patient education in routine care.

For patients with metastatic TNBC who are not candidates for immunotherapy, what is your current treatment approach, and why is this a clinical challenge?

Thomas Bachelot, MD, PhD:
These patients are very difficult to treat because their metastatic TNBC is quite aggressive, and immunotherapy has become an important treatment option in this setting. When immunotherapy is not appropriate, first-line treatment selection becomes even more challenging. In that setting, we need to identify the most effective available therapy based on potential for a rapid response, long duration of response, and attainable overall survival benefit.

A new option in this setting is based on the phase III TROPION-Breast02 trial evaluating first-line datopotamab deruxtecan (Dato-DXd) vs investigator’s choice chemotherapy as first-line therapy for patients with metastatic TNBC not eligible for immunotherapy. In that study, Dato-DXd improved the primary endpoint of Blinded Independent Central Review (BICR)–assessed progression-free survival (PFS) (10.8 vs 5.6 months; HR: 0.57; P <.0001) and median overall survival (23.7 vs 18.7 months; HR: 0.79; P = .029). Responses were remarkable and favored Dato-DXd, with higher confirmed overall response rate (62.5% vs 29.3%) and longer median duration of response (12.3 vs 7.1 months). Common adverse events (AEs) included stomatitis (63%), nausea (48%), alopecia (43%), dry eye (26%), and keratitis (26%); most were grade 1/2, with grade 3/4 events reported in 8.0%, 0.6%, 0%, 1.3%, and 6.0% of patients, respectively. Serious AEs occurred in 17% of patients, and 1 patient (0.3%) experienced fatal interstitial lung disease/pneumonitis. These data supported FDA and European Medicines Agency approval of Dato-DXd for adults with unresectable or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy.

Another new option in this setting comes from the phase III ASCENT-03 trial evaluating first-line sacituzumab govitecan vs treatment of physician’s choice chemotherapy in patients with unresectable locally advanced or metastatic TNBC who were not candidates for PD-1/PD-L1 inhibitor therapy. The study met its primary endpoint of improving BICR-assessed PFS (9.7 vs 6.9 months; HR: 0.62; P <.0001); the response rate was similar between arms (50% vs 47%), but median duration of response was improved with sacituzumab govitecan (12.2 vs 7.2 months). These data supported FDA approval of sacituzumab govitecan as first-line monotherapy for adults with unresectable locally advanced or metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor–based immunotherapy.

Mafalda Oliveira, MD, PhD:
I agree that these patients’ disease is difficult to treat because their prognosis remains poor and better treatment options, including TROP2 ADCs, are needed. In Europe, implementation of novel TROP2 ADCs can lag behind emerging evidence because access after European Commission marketing authorization often depends on country-specific reimbursement, pricing, and formulary decisions. Even when an agent has European Commission marketing authorization, access to these agents varies by country.

Another challenge is that members of the care team need experience with newer drugs as they move into earlier lines of therapy. Many oncology care teams have already developed patient management protocols for ADCs approved in later-line settings. For instance, Dato-DXd is approved in Europe for unresectable or metastatic hormone receptor–positive/HER2-negative breast cancer after prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease. Sacituzumab govitecan is approved in Europe for unresectable locally advanced or metastatic TNBC after 2 or more prior systemic therapies, including at least 1 for advanced disease, and for unresectable or metastatic hormone receptor–positive/HER2-negative breast cancer after endocrine-based therapy and at least 2 additional systemic therapies in the advanced setting. As indications for these agents broaden into earlier lines of therapy, supporting infrastructure will remain important so that healthcare professionals can prescribe these agents confidently and manage key adverse events safely.

Thomas Bachelot, MD, PhD:
I believe that, when available, most medical oncologists will adapt readily because ADCs share many practical features with chemotherapy. However, some AEs differ from those typically seen with standard chemotherapy, including stomatitis and other ADC-associated AEs. As community oncologists gain experience recognizing and managing these AEs, implementation should become more straightforward.

How do immunotherapy-ineligible patients with metastatic TNBC typically present in your clinic, and where do TROP2 ADCs fit in Europe?

Mafalda Oliveira, MD, PhD:
It is important to note that patients with metastatic TNBC who are ineligible for first-line immunotherapy represent approximately 60% to 65% of patients in our practice. This proportion may increase as neoadjuvant immunotherapy becomes more common and more patients recur after receiving immunotherapy for early-stage TNBC. These patients often present with high disease burden and are expected to have short survival, frequently less than 2 years. These patients have an unmet need for treatments that can induce meaningful responses and reduce symptom burden. Unfortunately, in Spain, anti-TROP2 ADCs are not yet reimbursed in the first-line setting for PD-L1–negative or immunotherapy-ineligible metastatic TNBC so we must consider other options.

Thomas Bachelot, MD, PhD:
This is similar to the anti-TROP2 ADC reimbursement landscape in France. We are still waiting for reimbursement of Dato-DXd, and sacituzumab govitecan is currently available in routine practice only in later-line metastatic settings. In practice, reimbursement rules strongly influence how early we can use these agents.

We also see patients whose tumors were initially estrogen receptor positive but later relapse with loss of estrogen receptor expression, resulting in secondary TNBC. Given these limitations, our current strategy is to use the most effective reimbursed agent as soon as the patient becomes eligible. In France, trastuzumab deruxtecan (T-DXd) is reimbursed for patients with unresectable or metastatic HER2-low breast cancer after prior chemotherapy for metastatic disease or after recurrence during or within 6 months of completing adjuvant chemotherapy. For patients with HER2-low TNBC, this can make T-DXd accessible earlier than currently reimbursed TROP2-directed ADC options. We are waiting for broader access to TROP2-directed ADCs in the first-line setting, where they may be especially useful; after relapse, we may consider a TROP2-directed ADC, depending on eligibility and reimbursement.

How do AE profiles and patient comorbidities inform TROP2 ADC selection?

Mafalda Oliveira, MD, PhD:
Our clinical experience in Spain comes mainly from clinical trials. Moving forward, understanding the AE profile of each ADC in the real-world setting and explaining those risks clearly to patients will be central to treatment selection. With sacituzumab govitecan, key AEs include neutropenia and diarrhea, which are particularly relevant for patients with baseline gastrointestinal conditions or reduced bone marrow reserve after multiple prior cytotoxic therapies. Supportive measures, including blood count monitoring, granulocyte colony-stimulating factor prophylaxis for patients at increased risk of febrile neutropenia, and prompt diarrhea management with hydration, evaluation for infection, and loperamide when appropriate, should be incorporated into treatment planning.

With Dato-DXd, stomatitis and ocular surface toxicities require early attention and prophylaxis. For stomatitis, patient education, steroid-containing mouthwash, and ice chips or ice water during infusion are included in current management recommendations. For ocular surface toxicity, patients should be instructed to use preservative-free lubricating eye drops regularly and avoid contact lenses unless directed by an eye care professional. Ophthalmology referral and monitoring are useful when available, particularly early in treatment and for new or worsening symptoms, but treatment should not be unnecessarily delayed while awaiting assessment when there is no active ocular concern.

When ophthalmology access is limited, how do you manage ocular monitoring and referral for patients receiving Dato-DXd?

Mafalda Oliveira, MD, PhD:
In Spain, the main challenge is access. Ophthalmology departments are often focused on eye-specific pathology and may not be able to evaluate chemotherapy-associated or ADC-associated ocular toxicities quickly. In many public hospitals, routine consultation can take several months, which is too long when treatment decisions are time sensitive.

Thomas Bachelot, MD, PhD:
The situation is similar in France. In clinical trials, ophthalmology collaboration is preplanned, which makes monitoring easier. In routine practice, rapid access to ophthalmology may be more difficult.

Some patients can be identified in advance as higher risk based on baseline ocular conditions, but for many patients, treatment selection will evolve according to tolerability. Because the key AEs of Dato-DXd and sacituzumab govitecan differ, switching from one ADC to another may be a practical option when toxicity limits ongoing therapy, provided the patient remains eligible and the agent is accessible. This flexibility may help us adapt treatment to each patient’s tolerance, especially when toxicity cannot be predicted before treatment begins.

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