3 Things You Should Know About TROP2-Directed Antibody-Drug Conjugates in the Frontline Treatment of Metastatic Triple-Negative Breast Cancer

Learning Objectives

Upon successful completion of this activity, you should be better prepared to:

• Evaluate recent data from pivotal clinical trials investigating new frontline treatments for mTNBC
• Apply emerging evidence, PD-L1 status, and patient preferences to select optimal first-line therapy for patients with mTNBC
• Identify key adverse events and supportive care strategies associated with new treatment approaches for mTNBC

RELEASE DATE: April 9, 2026

EXPIRATION DATE: April 9, 2027

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This activity is supported by an educational grant from Gilead Sciences, Inc.

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Instructions for Participation and How to Receive Credit

1. Read this activity in its entirety.

2. Go to https://gotoper.com/trop2tnbc26podcasts-postref to access and complete the posttest.

3. Answer the evaluation questions.

4. Request credit using the drop-down menu.

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Most patients with metastatic triple-negative breast cancer (mTNBC) receive conventional cytotoxic chemotherapy as first-line treatment, either in combination with an immune checkpoint inhibitor for immunotherapy-eligible patients, or alone, for those ineligible for immunotherapy.¹ Antibody-drug conjugates (ADCs) have typically been used in the second-line setting or later. However, recent results from pivotal clinical trials investigating TROP2-directed ADCs in the first-line setting are challenging this paradigm. Here are 3 things you should know about the first-line treatment of mTNBC with TROP2-directed ADCs.

1) Substituting a TROP2-directed ADC for chemotherapy in combination with pembrolizumab improves progression-free survival for patients with immunotherapy-eligible mTNBC.

The phase 3 ASCENT-04/KEYNOTE-D19 study (NCT05382286) evaluated first-line pembrolizumab given in combination with either standard chemotherapy or sacituzumab govitecan (SG) in a cohort of 443 patients with PD-L1–positive (combined positive score [CPS] ≥10) mTNBC.² Chemotherapy options allowed were paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin. Patients assigned to the control group were permitted to receive SG as a single agent in the second-line setting upon disease progression.

Median progression-free survival (PFS) was longer in the SG plus pembrolizumab group than in the control group (11.2 vs 7.8 months; HR, 0.65; 95% CI, 0.51-0.84; P < .001; Table 1).² Benefit was consistent across most prespecified subgroups, except for patients previously treated with a (neo)adjuvant PD-(L)1 inhibitor. The SG combination also showed a numerically higher objective response rate (60% vs 53%) and a longer median duration of response (16.5 vs 9.2 months) than the control arm. Overall survival (OS) results were immature at the time of this analysis, but showed a positive trend favoring the SG arm (HR, 0.89; 95% CI, 0.62-1.29).

The ongoing phase 3 trial, TROPION-Breast05 (NCT06103864), is evaluating another TROP2-directed ADC, datopotamab deruxtecan (Dato-DXd), with or without the PD-L1 inhibitor durvalumab, against standard first-line chemotherapy combined with pembrolizumab for patients with PD-L1–positive (CPS ≥10) locally recurrent inoperable or mTNBC.³ Allowed chemotherapy options are paclitaxel, nab-paclitaxel, or gemcitabine plus carboplatin. The primary end point is PFS per blinded independent central review.

2) TROP2-directed ADCs improve PFS over standard first-line chemotherapy for immunotherapy-ineligible mTNBC.

Two large, randomized phase 3 trials have also investigated TROP2-directed ADCs as monotherapy vs first-line chemotherapy in patients with mTNBC who are ineligible for immunotherapy.

In the ASCENT-03 study (NCT05382299), eligible patients with mTNBC who had not yet received therapy for advanced or metastatic disease were randomly assigned to treatment with either SG or treatment of physician’s choice (paclitaxel, nab-paclitaxel, or carboplatin plus gemcitabine).⁴ Patients assigned to the control group were allowed to cross over to SG following disease progression. SG demonstrated a significant improvement in PFS, reducing the relative risk of disease progression or death by 38% (Table 2).⁴ Objective reponse rates were comparable between the 2 groups (48% with SG vs 46% with chemotherapy), while the median duration of response was longer in the SG arm (12.2 months [95% CI, 9.7-13.8] vs 7.2 months [95% CI, 5.7-8.4]). OS data were not mature and did not show a significant difference between groups at the time of analysis (HR, 0.98; 95% CI, 0.75-1.30). Notably, among the 179 patients in the control arm who received subsequent therapy, 82% crossed over to SG. Additionally, PFS after second-line therapy was longer with SG than chemotherapy (median, 18.2 vs 14.0 months; HR, 0.70; 95% CI, 0.55-0.90).

The first-line TROPION-Breast02 trial (NCT05374512) evaluated Dato-DXd vs standard chemotherapy in a similar population of patients with mTNBC who were not candidates for immunotherapy.⁵ Chemotherapy options in the control arm differed from those in ASCENT-03, and included paclitaxel, nab-paclitaxel, capecitabine, eribulin, and carboplatin. Patients in the control group who experienced disease progression could receive subsequent therapies, including approved ADCs, at the investigator’s discretion. Dato-DXd demonstrated a significant improvement in PFS, reducing the relative risk of disease progression or death by 43%, with consistent benefit across all evaluated subgroups (Table 2).⁵ A statistically significant improvement in the co–primary OS end point was also observed, with a reduction in the relative risk of death of 21% (HR, 0.79; 95% CI, 0.64-0.98).

3) Distinct adverse event profiles require proactive management.

Effective toxicity management is essential for delivering safe, optimal care while enhancing treatment tolerability and preserving patients’ quality of life. Despite SG and Dato-DXd having the same target and similar payloads, they each have distinct adverse event (AE) profiles, of which clinicians need to be aware (Table 3).^4,5

For SG, key AEs to consider are neutropenia and diarrhea.⁶ Guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor starting in the first cycle of treatment in all patients at increased risk of febrile neutropenia, including older patients, patients with previous neutropenia, poor performance status, organ dysfunction, or multiple comorbidities. Absolute neutrophil count (ANC) should be monitored during treatment. SG should be withheld for ANC below 1500/mm³ on day 1 of any cycle or below 1000/mm³ on day 8 of any cycle, or for neutropenic fever. Dose modifications may be utilized when appropriate. Patients should be prepared for the potential for diarrhea; if it occurs, after evaluation for infectious causes, loperamide should be initiated until resolution. Prophylaxis with antidiarrheals may be considered based on risk factors. Treatment with SG should be withheld for grade 3 to 4 diarrhea and resumed when the diarrhea has resolved to grade 1 or lower. Atropine may be necessary for excessive cholinergic response.

For Dato-DXd, oral mucositis/stomatitis and dry eye are the most distinctive AEs.⁷ Prophylaxis with corticosteroid mouthwash (eg, dexamethasone oral solution 0.1mg/mL) and good oral hygiene (to prevent stomatitis), preservative-free tears 4 times daily, and avoidance of contact lenses (to prevent dry eye) are recommended. A baseline ophthalmologic exam should be performed and repeated as needed. If stomatitis develops, optimize prophylactic and supportive medications, and incorporate lidocaine-based mouthwash. Ocular surface events should be managed per ophthalmology. Utilize dose reductions and/or delays as necessary for either of these events. There is also potential for interstitial lung disease (ILD) due to the deruxtecan payload, and patients should be educated on symptoms before initiating treatment. Contrast-enhanced CT scans should be performed every 9 to 12 weeks; treatment should be withheld if ILD occurs and managed similarly to trastuzumab deruxtecan.

Key References

2. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan plus pembrolizumab for advanced triple-negative breast cancer. N Engl J Med. 2026;394(4):354-366. doi:10.1056/NEJMoa2508959

4. Cortes J, Punie K, Barrios C, et al. Sacituzumab govitecan in untreated, advanced triple-negative breast cancer. N Engl J Med. 2025;393(19):1912-1925. doi:10.1056/NEJMoa2511734

5. Dent RA, Shao Z, Schmid P, et al. LBA21 First-line (1L) datopotamab deruxtecan (Dato-DXd) vs chemotherapy in patients with locally recurrent inoperable or metastatic triple-negative breast cancer (mTNBC) for whom immunotherapy was not an option: primary results from the randomised, phase III TROPION-Breast02 trial. Ann Oncol. 2025;36(suppl 2):S1566-S1567.

For references visit https://www.gotoper.com/trop2tnbc26podcasts-postref

CME Posttest Questions

1. A woman aged 37 years has been diagnosed with de novo mTNBC.
Molecular testing indicates the cancer is PD-L1 positive with a CPS of 10 or higher. Assuming availability and regulatory approval, which of the following options would you recommend for first-line therapy to optimize PFS?

A. Capecitabine + pembrolizumab

B. Gemcitabine + carboplatin + pembrolizumab

C. Paclitaxel + pembrolizumab

D. Sacituzumab govitecan + pembrolizumab

E. Trastuzumab deruxtecan + pembrolizumab

2. Which of the following TROP2-directed ADCs has been shown to improve progression-free survival compared with conventional chemotherapy in
the frontline setting in patients with mTNBC who are ineligible for
immunotherapy in a phase 3 trial?

A. Datopotamab deruxtecan (Dato-DXd)

B. Sacituzumab govitecan (SG)

C. Both Dato-DXd and SG

D. Neither Dato-DXd or SG

3. A patient aged 48 years with mTNBC will be starting treatment with SG. Which of the following AE management measures do you recommend?

A. Anticoagulant prophylaxis

B. Prophylactic growth factor support

C. Regular screening for ILD

D. Steroid-containing mouth rinse

4. When considering TROP2-directed ADCs that are being used or
investigated for patients with mTNBC, which of the following ADCs
requires prophylaxis against stomatitis and ocular surface toxicities?

A. Datopotamab deruxtecan

B. Sacituzumab govitecan

C. Sacituzumab tirumotecan

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To learn more about this topic, including information on optimizing the use of TROP2-directed ADCs in the first-line management of mTNBC, including patient selection and AE management insights, go to https://www.gotoper.com/trop2tnbc26podcasts-activity

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