3 Things You Should Know About ADCs in Early-Stage TNBC and Considerations for Implementation

LEARNING OBJECTIVES

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

• Apply effective methods mitigating adverse effects associated with ADCs in patients with metastatic TNBC

RELEASE DATE: December 1, 2025
EXPIRATION DATE: December 1, 2026

Accreditation/Credit Designation

Physicians’ Education Resource^®, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians’ Education Resource^®, LLC, designates this enduring material for a maximum of 0.25 AMA PRA Category 1 Credits.™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Acknowledgement of Commercial Support

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

Off-Label Disclosure and Disclaimer

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members, and do not reflect those of PER^® or any company that provided commercial support for this activity.

INSTRUCTIONS FOR PARTICIPATION and HOW TO RECEIVE CREDIT

1. Read this activity in its entirety.

2. Go to https://gotoper.com/tnbc25acdici-postref to access and complete the posttest.

3. Answer the evaluation questions.

4. Request credit using the drop-down menu.

YOU MAY IMMEDIATELY DOWNLOAD YOUR CERTIFICATE.

Treatment options are limited, and the prognosis is often poor for patients with triple-negative breast cancer (TNBC). Taxane or gemcitabine plus carboplatin chemotherapy is the standard-of-care first-line treatment for patients with metastatic TNBC.¹ For patients whose PD-L1 combined positive score (CPS) is at least 10, pembrolizumab can be added to the chemotherapy backbone. PARP inhibitors are the preferred first-line treatment for patients whose PD-L1 CPS is less than 10 and who harbor a germline BRCA1/2 mutation.

Antibody-drug conjugates (ADCs) combine the specificity of a monoclonal antibody with the cytotoxic capability of chemotherapy. The ADCs sacituzumab govitecan-hziy (SG) and fam-trastuzumab deruxtecan-nxki (T-DXd) are approved for use in TNBC, and datopotamab deruxtecan-dlnk (Dato-DXd) and sacituzumab tirumotecan (sac-TMT) are under investigation. All 4 incorporate a topoisomerase I inhibitor cytotoxic payload. Because the mechanism of action of these ADCs differs from that of first-line chemotherapy options, patients who develop resistance to first-line chemotherapy may still respond to ADC therapy in the second or third line. Here are 3 things you should know about ADCs in early-stage TNBC and considerations for implementation.

1/ ADCs are under investigation to treat patients with early-stage TNBC.

Given their efficacy in advanced TNBC and tolerable safety profiles, ADCs are also being evaluated to reduce recurrence for patients with early-stage disease. The phase 2 NeoSTAR trial (NCT04230109) evaluated the combination of SG and pembrolizumab as neoadjuvant therapy in early-stage TNBC.² Forty-eight patients with stage II disease and 2 patients with stage III disease received SG on days 1 and 8 and pembrolizumab on day 1 of a 21-day cycle for 4 cycles. Any patients with no residual disease suspected at the week 12 imaging went on to surgery. The pathologic complete response (pCR) rate was 34% (95% CI, 19.5%-46.7%). The overall response rate was 66% (95% CI, 50%-78%), including complete clinical response in 30% of patients. Additional neoadjuvant chemotherapy was administered to 26 patients, of whom 9 achieved pCR, bringing the total number of patients with pCR at surgery to 25 of 50. Patients who achieved pCR received 4 cycles of taxane/carboplatin adjuvant therapy with pembrolizumab administered every 3 weeks to complete 1 year at investigator’s discretion. Patients who did not achieve pCR received adjuvant therapy of investigator’s choice. The 18-month event-free survival rate was 90.6% (95% CI, 89.2%-100.0%). The most common adverse events (AEs) in the NeoSTAR trial were nausea (56%), alopecia (52%), fatigue (46%), and diarrhea (44%). Four patients required dose reductions.

The phase 3 ASCENT-05 trial (NCT05633654) is comparing SG plus pembrolizumab vs pembrolizumab with or without capecitabine in approximately 1500 patients with early-stage TNBC who harbor residual disease after neoadjuvant therapy and surgery.³ The primary end point is invasive disease-free survival (iDFS). The phase 3 SASCIA trial (NCT04595565) is evaluating SG monotherapy vs treatment of physician’s choice in approximately 1200 patients with HER2-negative breast cancer (including TNBC) who did not achieve pCR after neoadjuvant chemotherapy. The primary end point for this trial will also be iDFS.⁴

“[It is] great to see these studies in early breast cancer, which will hopefully continue to improve the outcomes for our patients with cancer.” —Aditya Bardia, MD, MPH, FASCO

Dato-DXd is under evaluation in the phase 3 TROPION Breast03 trial (NCT05629585) as an adjuvant therapy with or without durvalumab vs investigator’s choice of therapy in 1075 patients with TNBC who did not achieve pCR after neoadjuvant therapy.⁵ The primary end point is iDFS. The phase 3 TROPION Breast04 trial (NCT06112379) will compare Dato-DXd plus durvalumab with or without chemotherapy as neoadjuvant therapy vs standard of care for 1728 patients with early-stage TNBC.⁶ The dual primary end points are pCR and event-free survival.

2/ Toxicity profiles differ among ADCs.

T-DXd, SG, Dato-DXd, and sac-TMT each exhibit a unique safety profile, including hematological, gastrointestinal, and skin toxicities (Figure 1).^7-10 Dose reductions or interruptions are options to alleviate AEs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) support and dose reduction are often sufficient to boost neutrophil counts in patients who experience hematological AEs. Long-acting versions of GM-CSF are preferred for patients who cannot come to the clinic daily.

Interstitial lung disease (ILD) or pneumonitis is an AE of particular concern with T-DXd. In the phase 3 DESTINY-Breast04 trial (NCT03734029), ILD was reported in 45 patients (12.1%) in the T-DXd arm, including 13 grade 1 events, 24 grade 2 events, 5 grade 3 events, and 3 grade 5 events.⁷ AEs of particular concern with SG are rash, which occurred in 9% of patients in the phase 3 ASCENT trial (NCT02574455), and ocular toxicities, which occurred in 5% of participants in this trial.⁸ The most common hematological AEs of any grade reported in patients receiving Dato-DXd in the phase 1 TROPION-PanTumor-01 study (NCT03401385) were anemia (15.9%) and neutropenia (20.5%).⁹ In the phase 1/2 first-in-human MK-2870-001 study (NCT04152499) of sac-TMT in patients with metastatic TNBC and HR-positive/HER2-negative breast cancer, dose-limiting toxicities were grade 3 stomatitis, grade 3 rash, and grade 3 urticaria.¹⁰

3/ Dosing schedules differ among ADCs.

Although linking the chemotherapeutic payload to a monoclonal antibody increases its stability, the half-lives of these 4 ADCs vary greatly. Of these, SG has the shortest half-life, 11 to 15 hours.¹¹ In the development of sac-TMT, this time span was lengthened to 57 hours.¹² Dato-DXd and T-DXd have the longest half-lives, approximately 5 and 7 days, respectively.^13,14 As a result, these 4 ADCs have differing dosing schedules. SG is given on days 1 and 8 of a 3-week cycle, sac-TMT is given every 2 weeks, and both T-DXd and Dato-DXd are given every 3 weeks (Figure 2).^11-14

With 2 ADCs already approved for the treatment of TNBC and more under investigation, and the potential to use ADCs in the adjuvant and neoadjuvant setting in early-stage disease, data to inform the selection and sequencing of these ADCs will become crucial to the development of optimized individual treatment plans.

Key References

2. Abelman RO, McLaughlin S, Fell GG, et al. A phase 2 study of response-guided neoadjuvant sacituzumab govitecan and pembrolizumab (SG/P) in patients with early-stage triple-negative breast cancer: results from the NeoSTAR trial. J Clin Oncol. 2025;43(suppl 16):511. doi:10.1200/JCO.2025.43.16_suppl.511

7. Modi S, Jacot W, Yamashita T, et al; DESTINY-Breast04 Trial Investigators. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690

8. Bardia A, Hurvitz SA, Tolaney SM, et al; ASCENT Clinical Trial Investigators. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485

9. Bardia A, Krop IE, Kogawa T, et al. Datopotamab deruxtecan in advanced or metastatic HR+/HER2- and triple-negative breast cancer: results from the phase I TROPION-PanTumor01 study. J Clin Oncol. 2024;42(19):2281-2294. doi:10.1200/jco.23.01909

10. Ouyang Q, Rodon J, Liang Y, et al. Results of a phase 1/2 study of sacituzumab tirumotecan in patients with unresectable locally advanced or metastatic solid tumors refractory to standard therapies. J Hematol Oncol. 2025;18(1):61. doi:10.1186/s13045-025-01705-2

For FULL References List, visit https://www.gotoper.com/tnbc25acdici-postref

CME Posttest Questions

1/ Your 49-year-old patient with metastatic TNBC starts
treatment with sacituzumab govitecan (SG) and achieves a clinical response. However, after 2 months, her neutrophil count is 400 cells/µL, which remains the same after 1 week. SG is held, and her neutrophils recover to 1600 cells/µL after 2 weeks. Which of the following would be most appropriate at this time?

A. Reinitiate at the original dose with GM-CSF support

B. Reinitiate at a 25% reduced dose only

C. Reinitiate at a 25% reduced dose with GM-CSF support

D. Discontinue sacituzumab govitecan

2/ In the ASCENT trial, treatment with SG was associated with an increased risk of which of the following grade 3 or higher
adverse events compared with chemotherapy?

A. Asthenia and rash

B. Constipation and fatigue

C. Neuropathy and infection

D. Neutropenia and diarrhea

To learn more about this topic, including information on clinical trial data, go to https://www.gotoper.com/tnbc25acdici-activity and https://www.gotoper.com/tnbc25na-activity

Claim Your CME Credit at https://www.gotoper.com/tnbc25acdici-postref

CME Provider Contact Information

Physicians’ Education Resource^®, LLC

259 Prospect Plains Road,
Bldg H,
Cranbury, NJ 08512
Toll-Free: 888-949-0045
Local: 609-378-3701
Fax: 609-257-0705
info@gotoper.com