CHICAGO — First-line trastuzumab deruxtecan (T-DXd) combined with pertuzumab (Perjeta) improved progression-free survival (PFS) in HER2-positive locally advanced or metastatic breast cancer, according to the DESTINY-Breast09 trial.

In the phase III study after a median of follow-up of 29 months, patients randomized to T-DXd plus pertuzumab had a median PFS by blinded independent central review of 40.7 months versus 26.9 months for patients on standard-of-care (SoC) treatment (HR 0.56, P<0.00001, 95% CI, 0.44-0.71), for an absolute improvement of 13.8 months. SoC was taxane plus trastuzumab plus pertuzumab (THP).

As such, “the combination of T-DXd and pertuzumab may represent a new first-line standard of care for patients with metastatic HER2-positive breast cancer,” said Sara Tolaney, MD, MPH, of the Dana-Farber Cancer Institute in Boston, during a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting.

T-DXd (Enhertu) is currently approved as a standard second-line treatment option in the metastatic HER2-positive setting as a result of an unprecedented 29-month PFS observed in DESTINY-Breast03.

“There’s been much interest in trying to move T-DXd into the front-line setting, particularly given that we know that the current standard of care, THP, is associated with a PFS of a little under 19 months,” said Tolaney. “We also know that, unfortunately, about one-third of patients who initiate treatment for metastatic HER2-positive disease are not able to go on to receive a second line of therapy, either due to deterioration in health or death.”

DESTINY-Breast09 is a multicenter open-label three-arm study of 1,157 patients with HER2-positive advanced or metastatic breast cancer. They are disease free for >6 months from their last chemotherapy or HER2-targeted therapy in the neoadjuvant/adjuvant setting. Patients with asymptomatic and inactive brain metastases are eligible.

One prior line of endocrine therapy for metastatic breast cancer was permitted but no other prior systemic treatment in the metastatic setting was allowed. Patients were randomized 1:1:1 to T-DXd (5.4 mg/kg every 3 weeks) plus placebo or T-DXd plus pertuzumab or THP.

T-DXd was administered until time of disease progression. If T-DXd was discontinued due to toxicities, then trastuzumab could be added, which was given alone in the T-DXd plus placebo arm, or in combination with pertuzumab in the T-DXd plus pertuzumab arm.

At an interim analysis with a data cutoff (Feb. 26, 2025), data were immature but the criterion for PFS superiority (stringent P<0.00043 for comparison) was met for T-DXd plus pertuzumab vs THP. The criterion for PFS superiority was not met for the T-DXd plus placebo versus THP comparison, and this comparison therefore remains blinded until the final PFS analysis. The two T-DXd arms were not powered to be compared.

The Kaplan-Meier curves for PFS start to separate early, with differences already seen at the 6-month time point, with 12% of patients already progressing at 6 months within the THP arm, with half as many patients progressing at that time point in the TDXD plus pertuzumab arms. The PFS benefit with T-DXd plus pertuzumab was observed across subgroups (de novo or recurrent disease, hormone receptor status, PIK3CA mutation status).

At 24 months, 70.1% of patients in the T-DXd plus pertuzumab arm were free from disease progression compared to 52.1% in the THP group.

The median duration of response was 39 months with T-DXd plus pertuzumab. A complete response was observed in 15.1% of the experimental arm compared with 8.5% of the control group.

The overall survival (OS) analysis is immature, with only 16% of OS events that have occurred at the interim analysis, but suggest a trend in improvement in OS for patients in the T-DXd with pertuzumab arm, according to Tolaney.

T-DXd plus pertuzumab safety data were consistent with the known safety profiles of each. The rates of serious adverse events (AEs) were similar between the two arms, despite a longer length of treatment in patients receiving T-DXd plus pertuzumab. Gastrointestinal AEs — nausea, vomiting, and constipation — were more common in the experimental arm.

Interstitial lung disease, a known side effect of T-DXd, occurred in about 12% of patients in the T-DXd plus pertuzumab group, with cases being predominantly low grade, said Tolaney.

“This is a pivotal advancement in the treatment of HER2-positive metastatic breast cancer that is both clinically and statistically significant,” said ASCO expert Rebecca Dent, MD, of the National Cancer Center in Singapore.

The findings present several new challenges, said Dent. One is the need for biomarkers to help select patients best suited for T-DXd at the beginning of treatment of metastatic disease. “If you have a patient who has extensive disease with CNS [central nervous system] metastases, this compound clearly has impressive activity in the brain,” she said, so for these patients, “this is clearly your first-line choice.”

Optimal use of T-DXd also needs to be established. One possibility is induction therapy with T-DXd plus pertuzumab followed by maintenance T-DXd, she said.

Quality of life and financial toxicity also should be considered in the selection of combination therapy.

“Most importantly, this [T-DXd] is a very active compound that we’ve seen in later line[s] and now these impressive results in first line,” said Dent. “The best way to provide greater chance of cure is to incorporate this into the curative setting.”

Please enable JavaScript to view the

comments powered by Disqus.