T-DXd Followed by THP Elicits Deep MRI Responses in HER2+ Early Breast Cancer

Neoadjuvant fam-trastuzumab deruxtecan-nxki (Enhertu; T-DXd) followed by paclitaxel, trastuzumab (Herceptin), and pertuzumab (Perjeta) (THP) elicited faster and deeper tumor responses on MRI than dose-dense doxorubicin and cyclophosphamide (ddAC) followed by THP (ddAC-THP) in patients with HER2-positive early breast cancer, but MRI response did not reliably predict pathologic complete response (pCR), according to an exploratory analysis of the phase 3 DESTINY-Breast11 trial (NCT05113251) presented at the 2026 ESMO Congress.¹

Among MRI-evaluable patients (T-DXd arm, n = 309; ddAC arm, n = 313), the mid-treatment objective response rate (ORR) was 77.3% (95% CI, 72.3%-81.9%) with T-DXd/THP vs 50.8% (95% CI, 45.1%-56.5%) with ddAC-THP, translating to an absolute difference of 26.5%. The mid-treatment complete response (CR) rates were 13.3% vs 2.6%, respectively. At the end of treatment (EOT), the respective ORRs were 92.9% (95% CI, 89.4%-95.5%) vs 87.2% (95% CI, 83.0%-90.7%), translating to a difference of 5.7%, and the CR rates were 27.8% vs 24.6%, respectively.

Among patients with a mid-treatment CR on MRI, pCR occurred in 90.2% (95% CI, 76.9%-97.3%) of those receiving T-DXd/THP (n = 41) and 87.5% (95% CI, 47.3%-99.7%) of those receiving ddAC-THP (n = 8). However, pCR was still achieved by 54.3% (95% CI, 41.9%-66.3%) of patients without a CR or partial response (PR) on mid-treatment MRI with T-DXd/THP (n = 70) and 41.6% (95% CI, 33.7%-49.8%) of those with ddAC-THP (n = 154).

“The stronger response seen with T-DXd continued to deepen with the subsequent use of THP, highlighting the importance [of completing] the full neoadjuvant regimen,” Jean-François Boileau, MD, MSc, FRCSC, of the Segal Cancer Centre at Jewish General Hospital in Montreal, Canada, stated in a presentation of the data.

How was the DESTINY-Breast11 trial designed?

The global, multicenter, open-label trial enrolled adult patients with previously untreated HER2-positive early breast cancer considered high risk, a designation that required clinical T3 or larger disease with nodal stage N0-3, clinical T0-4 disease with nodal stage N1-3, or inflammatory breast cancer. Patients were randomly assigned 1:1:1, with stratification by hormone receptor and HER2 status, to receive 4 cycles of T-DXd followed by 4 cycles of THP (n = 321), 4 cycles of ddAC followed by 4 cycles of THP (n = 320), or 8 cycles of T-DXd alone (n = 286). An independent data monitoring committee recommended closing enrollment to the T-DXd monotherapy arm, and that arm was excluded from the current analysis.

The primary end point was pCR. The prespecified exploratory end point was ORR by RECIST 1.1 criteria on MRI, assessed by investigators among patients with a baseline scan. MRI was performed at baseline, at the start of cycle 5 after 4 cycles of T-DXd or ddAC (mid-treatment), and at EOT after THP. Local investigators or radiologists interpreted the scans without central review, and the link between MRI response and pCR was examined post hoc.

What did earlier DESTINY-Breast11 results show with T-DXd followed by THP in HER2-positive early breast cancer?

In May 2026, the FDA approved T-DXd followed by a taxane, trastuzumab, and pertuzumab in the neoadjuvant setting for adult patients with stage II or III breast cancer that is HER2-positive by immunohistochemistry 3+ or in situ hybridization, based on the findings of the primary analysis of DESTINY-Breast11.² In that analysis, the pCR rate was 67.3% (95% CI, 61.9%-72.4%) with T-DXd/THP vs 56.3% (95% CI, 50.6%-61.8%) with ddAC-THP (P = .003).

How did hormone receptor status and tumor shrinkage affect MRI responses with T-DXd–THP in DESTINY-Breast11?

By hormone receptor status, the mid-treatment ORR was 76.2% (95% CI, 70.1%-81.6%) with T-DXd/THP (n = 227) vs 48.5% (95% CI, 41.9%-55.1%) with ddAC-THP (n = 231) in patients with hormone receptor–positive disease, translating to a difference of 27.7%. In those with hormone receptor–negative disease, the mid-treatment ORRs were 80.0% (95% CI, 69.6%-88.1%; n = 80) vs 57.3% (95% CI, 45.9%-68.2%; n = 82), respectively, translating to a difference of 22.7%. The mid-treatment CR rates in these cohorts were 11.5% vs 2.2% and 18.8% vs 3.7%, respectively.

The median rate of reduction in summed target lesion diameters from baseline at mid-treatment was 59.0% with T-DXd–THP vs 34.8% with ddAC-THP, translating to a difference of 24.2%. At EOT, the reduction rates were 80.8% vs 74.4%, respectively, translating to a difference of 6.4%.

How well did MRI response predict pCR with T-DXd–THP in DESTINY-Breast11?

At mid-treatment, pCR occurred in 66.7% (95% CI, 59.6%-73.2%) of patients with a PR on T-DXd/THP (n = 198) vs 71.5% (95% CI, 63.6%-78.6%) of those with a PR on ddAC-THP (n = 151). Using CR as the cutoff, the sensitivity rate for pCR was 17.9% with T-DXd/THP vs 3.9% with ddAC-THP, and the specificity rates were 96.1% vs 99.3%, respectively. Using any objective response as the cutoff, the respective sensitivity rates were 81.6% vs 64.2%, and the respective specificity rates were 31.4% vs 67.2%.

At EOT, pCR occurred in 83.7% (95% CI, 74.2%-90.8%) of patients with a CR on T-DXd/THP (n = 86) vs 75.3% (95% CI, 64.2%-84.4%) of those with a CR on ddAC-THP (n = 77). However, 22.7% (95% CI, 7.8%-45.4%) of patients without a CR or PR on T-DXd/THP (n = 22) and 17.5% (95% CI, 7.3%-32.8%) of those without a CR or PR on ddAC-THP (n = 40) achieved pCR. With objective response as the EOT cutoff, the respective sensitivity rates were 97.6% vs 96.1%, and the respective specificity rates were 16.7% vs 24.6%.

What do the DESTINY-Breast11 MRI findings mean for the use of neoadjuvant T-DXd followed by THP in HER2-positive early breast cancer?

The investigators concluded that T-DXd led to quick, substantial tumor reduction that continued to build during THP, supporting T-DXd/THP as an effective neoadjuvant treatment option for patients with HER2-positive early breast cancer. They noted that although MRI response was more closely tied to pCR in patients with hormone receptor–negative disease, MRI response may not be a sensitive enough predictor of pCR to guide treatment decisions.

Disclosures: Boileau reported receiving institutional support from AbbVie, AstraZeneca, Bristol Myers Squibb, Exact Sciences, Lilly, Merck, Novartis, Pfizer, and Roche; and performing advisory, speaker, or committee roles for AstraZeneca, Daiichi Sankyo, Exact Sciences, Gilead, Lilly, Merck, Novartis, Pfizer, REAL Alliance/Breast Cancer Canada, and Roche.

References

1. Boileau JF, Pusztai L, Harbeck N, et al. DESTINY-Breast11: MRI-assessed objective responses during 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 HER2+ early breast cancer (eBC). Paper presented at: 2026 ESMO Congress; October 23-27, 2026; Madrid, Spain. Abstract 543RO.
2. FDA approves two separate indications for fam-trastuzumab deruxtecan-nxki in HER2-positive early-stage breast cancer. FDA. May 15, 2026. Accessed October 24, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-two-separate-indications-fam-trastuzumab-deruxtecan-nxki-her2-positive-early-stage