FDA Approves Datopotamab Deruxtecan for Unresectable or Metastatic TNBC

The FDA has approved datopotamab deruxtecan-dlnk (Datroway; Dato-DXd) for the treatment of adult patients with unresectable or metastatic triple-negative breast cancer (TNBC) who are not candidates for PD-1/PD-L1 inhibitor therapy.¹

The approval is based on findings from the phase 3 TROPION-Breast02 trial (NCT05374512) which demonstrated a statistically significant and clinically meaningful improvement in median overall survival (OS) vs investigator’s choice of chemotherapy in patients with metastatic TNBC who are not candidates for PD-1/PD-L1 inhibitor therapy (HR, 0.79; 95% CI, 0.64-0.98; P = .0290). The median OS was 23.7 months in the Dato-DXd arm vs 18.7 months in the chemotherapy arm. Additionally, Dato-DXd reduced the risk of disease progression or death by 43% compared with chemotherapy as assessed by blinded independent central review (HR, 0.57; 95% CI, 0.47-0.69; P < .0001). The median progression-free survival (PFS) was 10.8 months with Dato-DXd vs 5.6 months with chemotherapy.

Moreover, the use of the antibody-drug conjugate (ADC) was associated with a higher objective response rate (ORR), at 64% vs 30% with chemotherapy.

"It's always good to have new therapies, especially for TNBC. When we're looking at survivals for HER2-positive metastatic and hormone receptor–positive metastatic [disease], we're looking at [median OS durations] of [approximately] 6 years. We all have patients who have been [alive] for much longer than that. We don't see that as often for TNBC. That's extremely rare, so having additional therapies is extremely important,” Rena D. Callahan, MD, a breast medical oncologist at UCLA Health and an associate clinical professor of medicine at the David Geffen School of Medicine at UCLA in Los Angeles, California, said in an interview with OncLive®.

The approval was announced just 3 months following the agent’s earlier priority review designation in February in this indication.²

What was the design of the pivotal TROPION-Breast02 trial and who was enrolled?

TROPION-Breast02 was a global, open-label, randomized trial that enrolled patients with histologically or cytologically confirmed locally recurrent unresectable or metastatic TNBC with no prior exposure to chemotherapy or targeted therapy in the locally recurrent inoperable or metastatic setting.³ Eligible patients were unfit to receive immunotherapy and had an ECOG performance status of 0 or 1.

Patients were randomly assigned 1:1 to receive 6 mg/kg of Dato-DXd on the first day of every 3-week cycle, or investigator’s choice of paclitaxel, nab-paclitaxel (Abraxane), capecitabine, eribulin mesylate/eribulin, or carboplatin.

What was the reported safety profile of Dato-DXd?

The safety profile of Dato-DXd was analyzed in the 319 who received the agent at the 6-mg/kg dose level in the TROPION-Breast02 trial.¹ The most common adverse effects (AEs) that occurred in at least 20% of patients included stomatitis, increased amylase, nausea, alopecia, decreased hemoglobin, decreased white blood cells, constipation, decreased calcium, decreased lymphocytes, fatigue, decreased neutrophils, increased alanine aminotransferase, increased aspartate aminotransferase, dry eye, keratitis, decreased albumin, vomiting, musculoskeletal pain, decreased sodium and increased blood alkaline phosphatase.

Serious AEs were reported in 17% of patients and those that occurred in at least 1% of the population that received Dato-DXd included pneumonia, vomiting, COVID-19, and anemia. Interstitial lung disease/pneumonitis led to death in 1 patient.

What is the significance of the approval?

“Another ADC is also something we want to incorporate into our practices. Generally, ADCs [are associated with] fewer or different toxicities than standard chemotherapy, and they have the potential to work better, as is the case with Dato-DXd, where we saw that it worked better [than standard chemotherapy], and there were no new safety signals. I will have patients who will want to use it in the first-line setting. It's also different than what we are using in the neoadjuvant and adjuvant settings. We've stepped up how much treatment we're giving in those settings, where we're giving patients 4 different chemotherapies and immunotherapy. If a patient recurs 1 year or 9 months after that, we're not going to be inclined to give them the same chemotherapy or similar chemotherapy again. We want a different option, and Dato-DXd presents us with that option," Callahan added.

References

1. Datroway approved in the U.S. as first TROP2 directed antibody drug conjugate for first-line treatment of patients with metastatic triple negative breast cancer who are not PD-1/PD-L1 inhibitor candidates. News release. Daiichi Sankyo. May 22, 2026. Accessed May 22, 2026. https://daiichisankyo.us/web/dsi/press-releases/-/article/datroway-approved-in-the-us-as-first-trop2-directed-antibody-drug-conjugate-for-first-line-treatment-of-patients-with-metastatic-triple-negative-breast-cancer-who-are-not-pd-1pd-l1-inhibitor-candidates
2. Datroway granted priority review in the US as first-line treatment for patients with metastatic triple negative breast cancer who are not candidates for immunotherapy. News release. Daiichi Sankyo. February 3, 2026. Accessed May 22, 2026. https://daiichisankyo.us/press-releases/-/article/datroway-granted-priority-review-in-the-us-as-first-line-treatment-for-patients-with-metastatic-triple-negative-breast-cancer-who-are-not-candidates-for-immunotherapy
3. Dent R, Shao Z, Schmid P, et al. Datopotamab deruxtecan in patients with untreated, advanced triple-negative breast cancer (TROPION-Breast02): a randomised, open-label, international, phase III trial. Ann Oncol. 2026;S0923-7534(26)00130-4. doi:10.1016/j.annonc.2026.03.008