Neoadjuvant T-DXd Followed by THP Improves RCB in HER2+ Breast Cancer

Neoadjuvant treatment with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) followed by paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta; THP) reduced the extent of residual cancer burden (RCB) compared with dose-dense doxorubicin and cyclophosphamide (ddAC) followed by THP (ddAC-THP) in patients with high-risk, HER2-positive early-stage breast cancer, according to findings from an analysis of the phase 3 DESTINY-Breast11 trial (NCT05113251) presented at the 2026 ESMO Breast Cancer Congress.¹

The combined rate of RCB-0 and RCB-I, which are validated predictors of favorable long-term survival, was 81.3% with the T-DXd–containing regimen (n = 321) vs 69.1% with the comparator regimen (n = 320), with improvements observed across all prespecified patient subgroups. The RCB-0 rates were 68.8% and 57.5%, respectively.

“These results indicate that T-DXd/THP benefitted even patients who have not achieved a pathologic complete response [pCR], and this pattern of RCB shift in previous trials was strongly associated with subsequent improvements in recurrence-free survival,” lead study author Lajos Pusztai, MD, DPhil, said to OncLive^®.

Pusztai is a professor of medicine (Medical Oncology) at the Yale School of Medicine, as well as co-leader of Genetics, Genomics and Epigenetics at Yale Cancer Center in New Haven, Connecticut.

What was the design of the DESTINY-Breast11 trial?

This randomized, global, multicenter, open-label trial enrolled patients at least 18 years of age with previously untreated HER2-positive early breast cancer and confirmed high-risk status, defined as clinical stage T3 and N0 to N3, T0 to T4 and N1 to N3, or inflammatory breast cancer.

Patients were randomly assigned 1:1:1 to receive 1 of 3 neoadjuvant regimens:

• T-DXd for 4 cycles, followed by THP for 4 cycles
• ddAC for 4 cycles, followed by THP for 4 cycles
• T-DXd monotherapy for 8 cycles (this arm was closed early following an independent data monitoring committee recommendation)

The primary end point was pCR rate following surgery as assessed by blinded central review. Secondary end points included event-free survival (EFS), safety, overall survival, and health-related quality of life.

What key efficacy findings from DESTINY-Breast11 have been previously reported?

Data presented at the 2025 ESMO Congress showed that the pCR rate was 67.3% in the T-DXd/THP arm (n = 321) compared with 56.3% in the ddAC-THP arm (n = 320), representing a statistically significant and clinically meaningful improvement of 11.2% (95% CI, 4.0%-18.3%; P = .003).² Among patients with hormone receptor–positive disease, the pCR rates in these respective arms were 61.4% (n = 236) vs 52.3% (n = 235; difference, 9.1%; 95% CI, 0.2%-17.9%). In those with hormone receptor–negative disease, the pCR rates were 83.1% (n = 83) and 67.1% (n = 85), respectively (difference, 16.1%; 95% CI, 3.0%-28.8%).

How was RCB evaluated in DESTINY-Breast11?

The RCB index provides a continuous, quantitative measure of residual invasive disease in the breast and axillary nodes after neoadjuvant chemotherapy.¹ Patients were categorized into 4 classes based on validated cut-off values: RCB-0 (equivalent to pCR), RCB-I (minimal residual disease), RCB-II (moderate residual disease), and RCB-III (extensive residual disease). Lower RCB scores have been associated with meaningful EFS benefit, regardless of hormone receptor status.

What were additional key findings from the DESTINY-Breast11 RCB analysis?

The distribution of the RCB index showed a significant shift from the RCB-II class toward RCB-0 and RCB-I with T-DXd followed by THP compared with ddAC-THP (nominal P = .0059). Among patients who did not achieve a pCR (RCB > 0), the median RCB index was lower in the T-DXd/THP group at 1.5 compared with 1.7 in the ddAC-THP group.

The rate of RCB-II disease was reduced from 18.8% in the ddAC-THP arm to 10.6% in the T-DXd/THP arm, whereas RCB-III rates were 4.7% and 4.0% for ddAC-THP and T-DXd/THP, respectively. Consistent improvements in the combined RCB-0/I rates were observed with T-DXd followed by THP across all prespecified subgroups, including:

• Age and geographical region: Benefits were consistent in patients younger and older than 65 years of age and across Asia, Europe, and North America
• Hormone receptor status: In the T-DXd/THP arm, the combined RCB-0/I rate was 78.0% for patients with hormone receptor–positive disease and 90.4% for those with hormone receptor–negative disease, compared with 64.7% and 81.2% in the ddAC-THP arm, respectively.
• Disease stage: In the T-DXd/THP arm, the combined RCB-0/I rate was 83.6% for patients with stage II disease and 78.9% for those with stage III disease, compared with 71.7% and 66.0% in the ddAC-THP arm, respectively.
• Nodal stage: In the T-DXd/THP arm, the combined RCB-0/I rate was 80.8% for patients with node-negative disease and 81.5% for those with node-positive disease, compared with 68.9% and 69.8% in the ddAC-THP arm, respectively.

“The most important message from the RCB analysis is that T-DXd/THP has shifted the RCB distribution to lower values across the entire range,” Pusztai concluded. “Even patients who had residual cancer after the neoadjuvant therapy had smaller residual cancers if they received T-DXD/THP. This is important because the extent of residual cancer among those who do not achieve pCR is highly prognostic.”

Disclosures: Pusztai reported receiving consulting fees and honoraria for advisory board participation from AstraZeneca, Pfizer, Merck, Bristol-Myers Squibb, Menarini-Stemline, BeOne, Personalis, Natera, Agendia, Exact Sciences, and Radionetics; receiving institutional research funding from Pfizer, AstraZeneca, Merck, Menarini-Stemline, Radionetics, and Exact Sciences; and having stock ownership in Fourion Inc and stock options in Ataraxis.

References

1. Pusztai L, Harbeck N, Boileau J, et al. Residual cancer burden (RCB) following neoadjuvant treatment (NAT) with trastuzumab deruxtecan (T-DXd) followed by paclitaxel + trastuzumab + pertuzumab (THP) vs dose-dense doxorubicin + cyclophosphamide followed by THP (ddAC-THP) in highrisk HER2+ early-stage breast cancer (eBC). Presented at: 2025 ESMO Breast Cancer Congress. May 6-8, 2026; Berlin, Germany. Abstract LBA1.
2. Harbeck N, Modi S, Pusztai L, et al. DESTINY-Breast11: neoadjuvant trastuzumab deruxtecan alone (T-DXd) or followed by paclitaxel + trastuzumab + pertuzumab (T-DXd-THP) vs SOC for high-risk HER2+ early breast cancer (eBC). Ann Oncol. 2025;36(suppl 2):S302-S303. doi:10.1016/j.annonc.2025.08.720