T-DXd Delivers Strong Breast Cancer Outcomes Across Groups

Two posters presented at this year’s San Antonio Breast Cancer Conference share a common goal: their research provides crucial insights on understanding the effectiveness and safety of trastuzumab deruxtecan (T-DXd) in treating HER2-positive (HER2+) metastatic breast cancer (mBC). Both draw on knowledge gained through the DESTINY-Breast clinical trials program, drilling down to more specific outcomes that encompass long-term safety and efficacy as seen in DESTINY-Breast03 (NCT03529110)¹ and the drug’s clinical benefit among minority racial and ethnic patient groups in the US, for whom limited data exist.²

T-DXd Long-Term Safety and Effectiveness¹

In DESTINY-Breast03, patients were randomized 1:1 to receive either 5.4-mg/kg T-DXd (n = 261; median age, 54.3 years) or 3.6-mg/kg trastuzumab emtansine (T-DM1; n = 263; median age, 54.2 years) every 3 weeks.³ There were statistically significant and clinically meaningful improvements seen in progression-free survival (PFS; the primary end point) and overall survival (OS; the key secondary end point) for the patients who received T-DXd vs T-DM1. For this final analysis, the data cutoff was June 27, 2025, with 24 patients in the T-DXd group vs 2 patients in the T-DM1 group still on treatment.

Five-year data show a much longer follow-up among those who received T-DXd compared with T-DM1: 50.9 months (range, 0.0-80.6) vs 35.4 months (0.0-80.4). Top reasons for treatment discontinuation were the same in both groups, respectively: progressive disease (44.7% and 70.9%) and adverse events (26.8% vs 10.0%). Also, fewer patients in the T-DXd group who discontinued treatment went on to receive additional systemic anticancer therapy (69.1% vs 78.4%).

Overall, the median treatment duration with T-DXd was 18.2 months (range, 0.7-76.0) vs 6.9 months (range, 0.7-65.1) with T-DM1, with patients in the former group experiencing a median PFS of 29.0 months (95% CI, 23.7-42.7) vs 7.8 months (95% CI, 6.8-8.3) in the latter, equating to a 67% reduced mortality risk (HR, 0.33; 95% CI, 0.26-0.41). At the 5-year mark, PFS was seen in 37.6% (95% CI, 30.8% vs 44.4%) of the T-DXd group but 10.0% (95% CI, 6.1%-15.0%) of the T-DM1 group; corresponding OS was 56.4 months (95% CI, 49.4-67.0) and 42.7 months (95% CI, 35.4-52.6); and 5-year estimated OS was 48.1% (95% CI, 41.7%-54.2%) and 36.9% (95% CI, 30.8%-43.1%).

There were no fatal treatment-emergent adverse events (TEAEs) in either patient group, but exposure-adjusted incidence rates for any-grade, grade 3 or above, and serious TEAEs favored T-DXd over T-DM1, indicating that T-DXd’s safety profile echoed previous reports and did not show new safety signals and confirming its superior efficacy.

T-DXd in Underrepresented Patient Groups²

Amid the ongoing call for greater diversity in clinical trials and oncology research overall,^4,5 a new investigation of patients of minority racial and ethnic groups calls attention to real-world outcomes of patients with HER2+ mBC who received T-DXd in the DESTINY-Breast clinical trials. These are patients treated in a community oncology setting.

Using data from the iKnowMed electronic health record, authors looked at outcomes among patients treated with T-DXd (their index event) between January 1, 2000, and April 30, 2024. All of these patients had 1 or more post–index event visits, reported a race/ethnicity of Black or Hispanic (the BH group; n = 81; mean age, 56.3 years) or White and non-Hispanic (Wt group; n = 81; mean age, 56.2 years), and were followed until death or final study contact, on or before April 30, 2024. These groups also were propensity score matched exactly for line of therapy but adjusted for age; time to treatment discontinuation (TTD), time to next treatment (TTNT), and real-world PFS (rwPFS) from the index date were estimated using the Kaplan-Meier method.

More patients in the BH group had visceral-only metastasis (65.4% vs 58.0%), hormone receptor–negative status (27.2% vs 22.2%), and received third-line or later T-DXd (49.4% vs 43.2%); a reduced real-world objective response rate (63.0% vs 67.9%); and longer follow-up (15.2 vs 13.6 months) vs the Wt group. The BH group also had better outcomes on 2 of the previously mentioned median indicators of disease progression:

• rwPFS: 16.6 months (95% CI, 9.9-21.4) vs 14.7 months (95% CI, 9.8-17.4)
• TTD: 12.5 months (95% CI, 9.7-14.9) vs 12.2 months (95% CI, 9.7-16.8)
• TTNT: 18.3 months (95% CI, 13.1-22.9) vs 18.4 months (95% CI, 13.2-21.1)

Rates of treatment-induced nausea, fatigue, vomiting, diarrhea, and alopecia were lower in the BH group, whereas rates of neutropenia and interstitial lung disease/pneumonitis were higher. Also, fewer patients in the BH group decided to start treatment beyond the index date; of these, T-DXd-based and T-DM1-based regimens were used the most.

References

1. Im SA, Cortes J, Kim SB, et al. Trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T‑DM1) in patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (mBC): final analysis from DESTINY-Breast03. Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, Texas. Poster PS5-01-30.
2. Mehta S, Stevens L, Shah R, et al. Real-world effectiveness of trastuzumab deruxtecan in HER2+ metastatic breast cancer by racial and ethnic group – data from US community practices. Presented at: San Antonio Breast Cancer Symposium; December 9-12, 2025; San Antonio, Texas. Poster PS5-01-15.
3. Shaw M. DESTINY-Breast data add to accolades for trastuzumab deruxtecan. AJMC^®. December 7, 2022. Accessed December 9, 2025. https://www.ajmc.com/view/destiny-breast-data-add-to-accolades-for-trastuzumab-deruxtecan
4. Caffrey M. Louisiana delivers innovative cancer treatments, but ensuring access is a work in progress. AJMC. November 25, 2025. Accessed December 9, 2025. https://www.ajmc.com/view/louisiana-delivers-innovative-cancer-treatments-but-ensuring-access-is-a-work-in-progress
5. Shaw M, Mewawalla P. Redesigning trials for real-world patient complexity: a Q&A with Prerna Mewawalla, MD. AJMC. December 4, 2025. Accessed December 9, 2025. https://www.ajmc.com/view/redesigning-trials-for-real-world-patient-complexity-a-q-a-with-prerna-mewawalla-md