DESTINY-Breast09: T-DXd plus pertuzumab improves PFS in HER2+ breast cancer

Treatment with trastuzumab deruxtecan (T-DXd) plus pertuzumab significantly improved progression-free survival (PFS) in patients with HER2+ advanced/metastatic breast cancer (a/mBC) compared with standard of care in the first-line setting, according to a planned interim analysis of the phase III DESTINY-Breast09 trial presented at ASCO 2025.

At a median follow-up of 29.2 months, the median PFS per BICR* was significantly longer in patients treated with T-DXd plus pertuzumab than those treated with THP** (40.7 vs 26.9 months), leading to a 44-percent reduction in the risk of disease progression or death (hazard ratio [HR], 0.56, 95 percent confidence interval [CI], 0.44–0.71; p<0.00001). [ASCO 2025, abstract LBA1008]

In addition, the investigator-assessed median PFS also favoured T-DXd plus pertuzumab over THP (median 40.7 vs 20.7 months; HR, 0.49, 95 percent CI, 0.39–0.61; p<0.00001).

The BICR-assessed PFS benefit with T-DXd plus pertuzumab vs THP was consistent across all subgroups, including prior treatment status, hormone receptor status, and PIKC3 mutation status.

“Taken together, T-DXd plus pertuzumab demonstrated a statistically significant and clinically meaningful PFS benefit … when compared with THP for first-line treatment of HER2+ a/mBC,” said lead author Dr Sara Tolaney from Dana-Farber Cancer Institute in Boston, Massachusetts, US.

The DESTINY-Breast09 trial enrolled 1,157 patients with HER2+ a/mBC recruited from 283 sites worldwide. Participants were randomized in a 1:1:1 ratio to receive T-DXd plus placebo (n=387), T-DXd plus pertuzumab (n=383), or THP (n=387). T-DXd recipients continued treatment until disease progression.

At the time of this analysis (February 26, 2025), only the results for the T-DXd plus pertuzumab and THP arms were presented.

Secondary endpoints

The objective response rate was numerically higher in the T-DXd plus pertuzumab arm than the THP arm (85.1 percent vs 78.6 percent), with a complete response rate of 15.1 percent vs 8.5 percent, which was almost double that of the patients treated with THP.

Patients on T-DXd plus pertuzumab vs those on THP also achieved a substantially longer median duration of response (39.2 vs 26.4 months), with 73 percent of patients in the T-DXd plus pertuzumab arm remaining in response for 24 months compared with 55 percent of those in the THP arm.

Although overall survival (OS) data were still immature at the time of this analysis, with a maturity rate of approximately 16 percent, early OS data indicated a positive trend favouring T-DXd plus pertuzumab over THP (HR, 0.84).

Safety endpoints

The rate of grade ≥3 and serious treatment-emergent adverse events was comparable between the T-DXd plus pertuzumab and THP arms (54.9 percent vs 52.4 percent and 27 percent vs 25.1 percent, respectively).

However, interstitial lung disease (ILD) occurred more frequently with T-DXd plus pertuzumab than with THP (12.1 percent vs 1 percent). “Majority of ILD events were low grade, only with the exception of two grade 5 events,” noted Tolaney.

There was also a higher rate of left ventricular dysfunction observed in the T-DXd plus pertuzumab arm vs the THP arm (11 percent vs 7 percent).

Nevertheless, the safety profile of T-DXd plus pertuzumab was consistent with known profiles of the individual agents, with no new toxicities identified, Tolaney noted.

New first-line standard of care?

“Patients with HER2+ a/mBC often experience disease progression around 2 years after initiating standard-of-care first-line treatment. With a median PFS of more than 3 years, the DESTINY-Breast09 results show trastuzumab deruxtecan combined with pertuzumab has the potential to become a new first-line standard of care for these patients,” Tolaney said in a press release. 

In addition, “given the near doubling of the duration of disease control with the use of T-DXd plus pertuzumab compared with the current standard, THP, there are plans to engage with health authorities and follow the process for regulatory approval. This would represent a paradigm shift, as THP has been a standard therapy approach for over a decade for [first-line] treatment of HER2+ a/mBC,” Tolaney stated.