First-Line T-DXd ± Pertuzumab Yields Durable Responses in HER2+ Metastatic Breast Cancer

First-line treatment with fam-trastuzumab deruxtecan (T-DXd; Enhertu) with or without pertuzumab (Perjeta) generated responses in patients with HER2-positive metastatic breast cancer, according to updated data from the phase 1b/2 DESTINY-Breast07 trial (NCT04538742).1

Findings presented at the 2025 ESMO Targeted Anticancer Therapies Congress demonstrated that patients treated with T-DXd monotherapy (n = 75) achieved an investigator-assessed confirmed overall response rate (ORR) of 77.3% (80% CI, 70.0%-83.6%) per RECIST 1.1 criteria. The complete response (CR) and partial response (PR) rates were 10.7% and 66.7%, respectively, and the median duration of response (DOR) was not evaluable (NE; range, 2.3-37.0).

In patients administered T-DXd plus pertuzumab (n = 50), the confirmed ORR was 84.0% (80% CI, 75.3%-90.5%) with respective CR and PR rates of 20.0% and 64.0%. The median DOR was NE (range, 6.9-34.6).

Regarding safety, any-grade adverse effects (AEs) occurred in all patients in both arms. The rates of grade 3 or higher AEs were 53.3% for T-DXd alone and 60.0% for T-DXd plus pertuzumab. The respective rates of serious AEs were 18.7% and 26.0%. In the monotherapy arm, AEs led to dose interruptions in 66.7% of patients, dose reductions in 16.0% of patients, and treatment discontinuation in 12.0% of patients. In the combination arm, AEs led to T-DXd dose interruptions, dose reductions, and treatment discontinuation in 66.0%, 14.0%, and 18.8% of patients, respectively.

AEs led to death in 1 patient in the monotherapy arm (1.3%) and no patients in the combination arm.

“T-DXd [as a] single agent and T-DXd plus pertuzumab showed robust efficacy in the first-line setting for [patients with] HER2-overexpressing metastatic breast cancer,” lead study author Fabrice André, MD, PhD, of Gustave Roussy at Paris-Saclay University in Villejuif, France, said in a presentation of the data.

DESTINY-Breast07 Rationale and Breakdown

In May 2022, the FDA granted full approval to T-DXd as monotherapy for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of therapy completion.2 This decision was supported by data from the phase 3 DESTINY-Breast03 trial (NCT03529110).

DESTINY-Breast07 was a multicenter, open-label, 2-part, modular study investigating the antibody-drug conjugate in the frontline setting for patients for locally advanced or metastatic breast cancer that is HER2 positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization+).1 No prior therapy in the metastatic setting was permitted. Prior treatment in the neoadjuvant or adjuvant setting with a taxane, trastuzumab (Herceptin), and pertuzumab was allowed; however, patients who received perioperative anti-HER2 therapy or chemotherapy were required to have a disease-free interval of at least 12 months.

Other key inclusion criteria consisted of measurable disease per RECIST 1.1 criteria and an ECOG performance status of 0 or 1. Patients needed to have no brain metastases or previously treated, stable brain metastases.

Patients were randomly assigned to receive T-DXd alone at 5.4 mg/kg once every 3 weeks; or T-DXd on the same schedule in combination with pertuzumab at 420 mg once every 3 weeks following an 840-mg loading dose. The study also included a third module evaluating T-DXd in combination with durvalumab (Imfinzi); however, data from that cohort were not reported in this analysis.

The primary end point of the dose-expansion portion of the study was safety/tolerability. Secondary end points included ORR, investigator-assessed progression-free survival (PFS), and DOR.

At baseline, the median age was 57.0 years (range, 33.0-80.0) in the T-DXd monotherapy arm and 56.5 years (range, 24.0-75.0) in the combination arm. All patients in the combination arm were female, and 98.7% of patients in the monotherapy arm were female. Most patients were White (T-DXd monotherapy, 69.3%; T-DXd/pertuzumab, 74.0%), had IHC 3+ HER2 expression (80.0%; 82.0%), had hormone receptor–positive disease (62.7%; 68.0%), had de novo disease (64.0%; 60.0%), and had an ECOG performance status of 0 (65.3%; 74.0%).

In the T-DXd monotherapy arm, 34.7% of patients had a stromal tumor-infiltrating lymphocyte (TIL) level of at least 20%, 41.3% had a stromal TIL level below 20%, and stromal TIL status was unknown in 24.0% of patients. These respective rates were 38.0%, 52.0%, and 10.0% in the combination arm.

Prior anti-HER2 therapy in the monotherapy arm for those with recurrent metastatic breast cancer (n = 27) comprised trastuzumab (51.9%), pertuzumab (14.8%), and ado-trastuzumab emtansine (Kadcyla; 7.4%). Prior anti-HER2 therapies in the combination arm for those with recurrent disease (n = 20) included trastuzumab (65.0%) and pertuzumab (10.0%).

At a median follow-up of 31.3 months for the monotherapy arm, 49.3% of patients were ongoing treatment. Reasons for discontinuation in this group included disease progression (21.3%), AEs (10.7%), patient withdrawal (10.7%), and other (8.0%), including death (2.7%).

Forty-four percent of patients in the combination arm were still on treatment at a median follow-up of 32.8 months. Reasons for treatment discontinuation included disease progression (22.0%), AEs (20.0%), patient withdrawal (6.0%), and other (8.0%), including death (2.0%).

Additional Efficacy and Safety Data

Further findings showed that patients in the monotherapy arm experienced 12- and 18-month PFS rates of 82.6% (80% CI, 75.8%-87.7%) and 78.2% (80% CI, 70.9%-83.8%), respectively. In the combination arm, these respective rates were 87.5% (80% CI, 79.8%-92.4%) and 78.8% (80%, 69.9%-85.3%).

A subgroup analysis examining outcomes by baseline stromal TIL levels showed that in the monotherapy arm, the confirmed ORR was 80.8% (80% CI, 67.2%-90.3%) in patients with a level of at least 20% (n = 26), including CR, PR, stable disease, and progressive disease rates of 11.5%, 69.2%, 15.4%, and 3.8%, respectively. The 12- and 18-month PFS rates for this subgroup were 79.6% (80% CI, 66.6%-87.9%) and 75.4% (80% CI, 62.0%-84.6%), respectively.

The ORR was 80.6% (80% CI, 68.5%-89.5%) for those with levels below 20% given T-DXd alone (n = 31); the respective CR, PR, stable disease, and progressive disease rates were 6.5%, 74.2%, 16.1%, and 3.2%. The respective 12- and 18-month PFS rates were 90.1% (80% CI, 80.4%-95.2%) and 83.4% (80% CI, 72.5%-90.3%).

In the combination arm, patients with a baseline stromal TIL level of at least 20% (n = 19) achieved a confirmed ORR of 94.7% (80% CI, 81.0%-99.4%) with a CR rate of 26.3%, a PR rate of 68.4%, a stable disease rate of 5.3%, and a progressive disease rate of 0%. The 12- and 18-month PFS rates were 100% (80% CI, 100%-100%) and 94.1% (80% CI, 80.4%-98.3%), respectively.

In those with a stromal TIL level below 20% (n = 26), the confirmed ORR was 76.9% (80% CI, 63.0%-87.4%) with CR, PR, stable disease, and progressive disease rates of 11.5%, 65.4%, 15.4%, and 7.7%, respectively. The respective 12- and 18-month PFS rates were 76.6% (80% CI, 63.6%-85.4%) and 68.5% (80% CI, 55.0%-78.7%).

“Encouraging clinical activity of T-DXd [monotherapy] and T-DXd plus pertuzumab was observed irrespective of stromal TIL [levels at baseline,]” André explained.

Additional safety data revealed that the most common AEs reported in the monotherapy arm included nausea (any grade, 71%; grade ≥3, 4%), neutropenia (39%; 27%), vomiting (36%; 3%), diarrhea (35%; 4%), alopecia (35%; 0%), asthenia (31%; 1%), decreased appetite (27%; 0%), COVID-19 (24%; 1%), anemia (24%; 4%), constipation (23%; 0%), and fatigue (17%; 0%).

In the combination arm, the most frequently reported AEs comprised nausea (any grade, 68%; grade ≥3, 2%), neutropenia (40%; 24%), vomiting (42%; 0%), diarrhea (66%; 6%), alopecia (46%; 0%), asthenia (30%; 0%), decreased appetite (24%; 0%), COVID-19 (46%; 2%), anemia (40%; 14%), constipation (22%; 0%), and fatigue (30%; 2%).

In the monotherapy arm, interstitial lung disease (ILD)/pneumonitis deemed related to study treatment occurred in 14.7% of patients at grade 1 (4.0%) or grade 2 (10.7%). The overall treatment-related ILD/pneumonitis rate was 14.0% in the combination arm, which was reported at grade 2 (12.0%) or grade 3 (2.0%).

Left ventricular dysfunction that was possibly related to T-DXd occurred in 10.7% of patients in the monotherapy arm and 8.0% of patients in the combination arm.

The ongoing phase 3 DESTINY-Breast09 trial (NCT04784715) is further evaluating first-line treatment using T-DXd with or without pertuzumab compared with docetaxel plus trastuzumab and pertuzumab in patients with HER2-positive breast cancer.

“The data [from DESTINY-Breast07] highly support [the rationale] for the phase 3 [DESTINY-Breast09] trial,” André concluded.

Disclosures: André reported serving in a consulting or advisory role with AstraZeneca, Boston Pharmaceuticals, Daiichi Sankyo, Gilead Sciences, Guardant Health, Lilly, Novartis, N-Power Medicine, Owkin, Pfizer, Roche, and Servier; and receiving research funding from AstraZeneca, Daiichi Sankyo, Guardant Health, Lilly, Novartis, Owkin, Pfizer, and Roche.

References

1. 1.André F, Fabbri G, McEwen R, et al. Trastuzumab deruxtecan ± pertuzumab in previously untreated HER2+ metastatic breast cancer: clinical efficacy and exploratory subgroup analyses in DESTINY-Breast07. ESMO Open. 2025;10(suppl 2):104163. doi:10.1016/j.esmoop.2025.104163
2. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. FDA. Updated May 11, 2022. Accessed March 10, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-regular-approval-fam-trastuzumab-deruxtecan-nxki-breast-cancer