Updates to the mTNBC Landscape

In mTNBC, PD-L1 expression (CPS ≥10) serves as a validated, predictive biomarker for checkpoint inhibitor benefit. Although PD-L1-positivity is identified in over one-third of mTNBC cases, making PD-L1 expression an essential part of the evaluation to guide first-line treatment selection.

The ASCENT-04/KEYNOTE-D19 trial demonstrated that SG plus pembrolizumab significantly improves PFS in mTNBC as compared to traditional chemotherapy plus pembrolizumab. The trial results established the SG plus pembrolizumab regimen as an effective alternative to traditional chemotherapy plus pembrolizumab for PD-L1 positive mTNBC. And while as APPs we do not typically choose the treatment regimen, we do need to know the data and be able to discuss it with our providers, to educate other APPs in community settings, and to educate our patients.

The ASCENT-03 trial evaluated the efficacy of SG as compared to standard chemotherapy and demonstrated a significant PFS benefit. These results led to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) recommendations supporting the use of SG as a first-line treatment option for patients with PD-L1 CPS <10 and no germline BRCA mutations. For patients who are gBRCA1/2 carriers, PARP inhibitors or platinum agents are NCCN Guidelines^® category 1, preferred options.

Similarly, the TROPION-Breast02 trial evaluated Dato-DXd versus investigator’s choice of chemotherapy in first-line mTNBC treatment, in patients who were unable to receive a PD-1/PD-L1 inhibitor. The trial met its dual primary endpoints showing statistically and clinically meaningful improvements in PFS and overall survival (OS). Following the readout of TROPION-Breast02, the NCCN Guidelines^® incorporated Dato-DXd as a first-line treatment option for patients with PD-L1 CPS <10 mTNBC and no germline BRCA mutations. Consequently, both ADCs now carry a category 1, preferred recommendation for first-line treatment of mTNBC.

Beyond significant PFS gains, both ADCs achieved longer duration of response (DoR) (Dato-DXd vs. chemotherapy: 5.2 month prolongation in median DoR; SG vs. chemotherapy: 5 month prolongation in median DoR) and lower discontinuation rates due to adverse events (AEs) compared to standard chemotherapy. These demonstrated survival gains support considering ADCs as a first-line treatment strategy.

It is also important to understand what a category 1, preferred designation means. The preferred designation indicates that the recommendation is based on superior efficacy, safety and evidence. A category 1 designation tells us that based on high-level evidence, with uniform consensus (≥85% of experts who serve on the panel) agree that the intervention or treatment is appropriate. As APPs, we do a lot of education, so make sure you highlight this to the patients, explain to them and help them understand why we’re choosing ADCs for their treatment and the impact we expect it to have on their care and outcomes.

TNBC is incredibly aggressive. Real-world studies have shown that a significant portion of patients with mTNBC never make it to a second-line treatment because their disease progresses too quickly, creating a real urgency to initiate treatment as soon as possible, and highlighting the importance of choosing the best therapy for the patients first-line.

Many factors should be considered when choosing a treatment regimen. You have to talk with your patients about their goals and what is important to them. Remember that we are treating metastatic disease, so while we aim to achieve longer treatment response, we have to also be mindful of their time, which is incredibly valuable. Consider the treatment schedule and how it fits into their lifestyle. Dato-DXd is administered on day 1 every 21 days, and SG is administered on days 1 and 8 of a 21-day cycle.

Individual patient tolerability must be a central consideration during treatment selection. While both ADCs demonstrate manageable safety profiles, even low-grade toxicities, if persistent, can significantly impact quality of life (QoL), and undermine treatment adherence. Consider patients’ lifestyles, for instance, chronic ocular toxicities like burning, stinging or blurred vision may directly affect the ability to drive or work at the computer. Similarly, for patients who may require growth factor support for neutropenia, practical, logistical challenges may need to be overcome. Aligning therapy with daily challenges and healthcare access barriers is essential to successful treatment and long-term compliance.

Unlike traditional drug classes where agents share predictable characteristics, variations in ADC design are intentional, leading to clinically distinct AE profiles, the management of which requires a paradigm shift. Successful patient outcomes require proactive, vigilant AE management.

SG has two key boxed warnings which include neutropenia and diarrhea.

Diarrhea can present as an acute cholinergic reaction, requiring IV or SubQ atropine administration (an anticholinergic agent). It can also present as delayed-onset secretory diarrhea, which, after ruling out infectious causes, should be managed with prompt initiation of high-dose loperamide at the first sign of loose stools (4 mg initially followed by 2 mg with every episode of diarrhea, not to exceed 16 mg in 24 hours), along with increased oral fluid intake. To set patients up for success, incorporate antidiarrheals like loperamide directly into the treatment plans. Ideally, have the pharmacy deliver the loperamide prescription directly to the patient while they are in the infusion chair so that the patient leaves clinic with loperamide in hand. Ensure the patient clearly understands what constitutes clinical diarrhea and exactly when to start taking loperamide.

Neutropenia should be managed with growth factor support. Consider primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) during cycle 1 for patients at increased risk of febrile neutropenia. When prescribing G-CSF to prevent treatment delays from bone marrow suppression, factor in the logistics, confirm whether the patient is actually able to return to clinic or the office, and if they are self-administering at home, ensure that they are capable of, and willing to do so.

Proactive symptom management ultimately relies on three key patient factors: accessibility (can they get the medication?), affordability (can they pay for it?), and adherence (will they actually take it?). Because symptoms often peak between scheduled clinic visits, mid-cycle follow-ups are critical. If a patient receives infusions on Days 1 and 8, diarrhea may begin on the days in-between treatments. Follow up with your patients mid-cycle and see how they are doing.

Key AEs associated with Dato-DXd include mucosal, ocular and pulmonary toxicities. Pulmonary toxicities, such as interstitial lung disease (or ILD) require vigilant monitoring for any changes in respiratory symptoms such as cough, dyspnea or fever. Dato-DXd must be immediately held whenever ILD is suspected and systemic steroids should be initiated promptly. Grade 2 or greater ILD/pneumonitis warrants permanent discontinuation of Dato-DXd.

Mucosal toxicities, such as stomatitis, warrant protocol-driven prophylactic interventions. Oral cryotherapy such as holding ice chips or ice water in the mouth throughout the duration of the infusion should be considered. Patients should also use steroid-containing mouthwashes.

Consider potential access hurdles such as dexamethasone mouth rinse availability or out-of-pocket prescription costs; reinforce that prophylactic mouthwash use from cycle 1 is vital to reducing the incidence and severity of painful oral lesions. Mouth sores tend to be less severe and resolve quicker if prophylactic rinses are used; however, once mouth sores develop, they can be very difficult to treat. If stomatitis develops, increase mouthwash frequency, optimize topical therapies and hold Dato-DXd according to severity grade.

Ocular toxicities require proactive, systematic monitoring, prophylaxis and management. Instruct patients to administer preservative-free lubricant eye drops at least four times daily and as needed. Consider that administering eye drops four times per day every day is not easy to do and may be difficult to be compliant, thus make sure that the patient understands the importance of their administration. Use of contact lenses during treatment should be avoided. Patients are required to obtain ophthalmic exams at treatment initiation, as indicated throughout therapy, and at the end of treatment. During treatment, preferably every 3 cycles, patients should undergo visual acuity testing and slit lamp examinations. Ocular toxicities should be managed at the first symptoms’ onset. If necessary, potential dose interruptions or dose reductions of Dato-DXd should be considered in order to prevent advanced corneal complications.

Lastly, patients are often overwhelmed during their complex oncology journey and patient education is critical to optimizing their treatment outcomes. Make sure that everyone that the patient interacts with throughout the treatment process reiterates the information related to toxicity management for any TROP2-directed ADC.

There is widespread recognition of the value of reflex testing for PD-L1 expression, and many cancer centers are working to integrate it into standard diagnostic pathways. The great news is that both TROP2-directed ADCs can be used in PD-L1 negative patients with mTNBC. SG, in combination with pembrolizumab, is also approved in PD-L1 positive (CPS ≥10) disease, therefore, PD-L1 positive patients should receive combination therapy with SG and pembrolizumab. The best news for the patients is that, whether they have PD-L1 positive or PD-L1 negative mTNBC, they are able to initiate therapy right away.

We definitely use TROP2-directed ADCs in the first-line setting. SG was already established as a second-line treatment in mTNBC and Dato-DXd was previously approved in pretreated hormone receptor-positive, HER2-negative metastatic breast cancer. Thus, following the results of ASCENT-03 and TROPION-Breast02, the use of both agents in the first-line, immediately following NCCN Guidelines^® updates, was an easy transition.

With the growing therapeutic options in mTNBC, we have to remember that there is always the right drug for the right patient. Because TNBC is aggressive, we must initiate treatment promptly to improve survival and response rates—but we must balance clinical urgency with the patient's lifestyle. Dato-DXd and SG are approved first-line ADCs with distinct administration schedules and adverse event profiles, which have to be considered when choosing a therapy for your patient. Ask the patient sitting in front of you what matters most. For many, "time toxicity" is critical—they are navigating treatment while still working and raising families.

Finally, remember that ADCs are structurally complex. Toxicities can stem from the target, the linker, the payload, or the patient's own comorbidities. Select an individualized first-line regimen based on patient characteristics and therapeutic goals. Support patients with timely education to ensure use of preventative strategies, and early recognition of and proactive management of AEs.