T-DXd Plus Pertuzumab Could Disrupt First-Line SOC in HER2+ Metastatic Breast Cancer

Tess O’Meara, MD

The significant progression-free survival (PFS) benefit observed with fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) in the first-line setting for HER2-positive metastatic breast cancer marks the first time in over a decade that a regimen has demonstrated superior efficacy compared with the longstanding standard of care (SOC) of trastuzumab (Herceptin) plus pertuzumab and a taxane (THP) in this patient population, according to Tess O’Meara, MD.

Results from the phase 3 DESTINY-Breast09 trial (NCT04784715) presented at the 2025 ASCO Annual Meeting demonstrated that the median PFS was 40.7 months (95% CI, 36.5-not calculable [NC]) with T-DXd plus pertuzumab (n = 383) vs 26.9 months (95% CI, 21.8-NC) with THP (n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001). This PFS benefit with T-DXd was consistent across all prespecified subgroups, which included patients regardless of de novo or recurrent disease status, hormone receptor status, and PIK3CA mutation status. Although immature, early overall survival (OS) data trended in favor of T-DXd plus pertuzumab over THP.

“Many of us expect that [this regimen] will become a new SOC option for patients to receive in the first-line setting for HER2-positive metastatic breast cancer,” O’Meara stated in an interview with OncLive®. “That being said, this trial generated as many questions as it did answers.”

In the interview, O’Meara, a senior fellow in Breast Medical Oncology at Dana-Farber Cancer Institute/Massachusetts General Hospital in Boston, expanded on key efficacy and safety data from DESTINY-Breast09; detailed the potential implications of these findings for expanding the role of T-DXd in the first-line setting amidst the shifting antibody-drug conjugate (ADC) landscape; and shared anticipation for ongoing research focused on refining the sequencing and use of T-DXd in combination strategies.

OncLive: What was the design and rationale of DESTINY-Breast09?

O’Meara: DESTINY-Breast09 was a study of T-DXd, a HER2-directed ADC, that is being investigated in the first-line setting for [patients with] metastatic HER2-positive breast cancer. Patients were randomized to 1 of 3 treatment arms: T-DXd monotherapy, T-DXd plus pertuzumab, or the SOC, which—based on [data from the phase 3] CLEOPATRA trial [NCT00567190]—is THP.

What key efficacy findings from DESTINY-Breast09 were presented at the 2025 ASCO Annual Meeting?

We are very excited about the results of DESTINY-Breast09. There were high hopes for the study outcomes, and it met expectations. Based on the interim report, T-DXd plus pertuzumab demonstrated a significant benefit in terms of PFS compared with THP. The median PFS in the T-DXd arm was over 40 months, representing a substantial PFS benefit. Importantly, there was a 15.1% complete response [CR] rate in the T-DXd arm compared with an 8.5% CR rate in the control arm. In the first-line setting, achieving a high CR rate may eliminate clonal heterogeneity and increase the chance of achieving a durable response.

We did also saw a signal [toward] an improvement in OS in the T-DXd [plus pertuzumab] arm. One caveat to that is that there was a very low percentage of patients who crossed over from receiving T-DXd in the first line to receiving T-DXd in later lines based on this study, which precludes a better analysis of OS and PFS2.

What safety findings from this study are important to note?

[The regimen’s] safety [profile] was also promising. In terms of the safety signals observed, there were no unexpected rates of toxicity that emerged in DESTINY-Breast09 relative to what is already known about T-DXd from other trials. It is notable that the median time on treatment in the T-DXd [plus pertuzumab] arm was [21.7] months, whereas most patients in the control arm were receiving only 6 to 8 cycles of chemotherapy [median treatment duration, 16.9 months]. Consequently, most of the adverse effects [AEs] and toxicities in the control arm were concentrated in those initial months, compared with the longer time on treatment in the T-DXd arm. However, there were no significant differences in overall rates of toxicity between the 2 arms.

Two toxicities that stood out were a high rate of fatigue in the T-DXd arm—which is an important consideration for patients, especially given the potential for longer treatment durations of over 40 months—and several cases of high-grade interstitial lung disease, as well as some higher-grade left ventricular dysfunction. These are AEs that are concerning for clinicians and will require close vigilance in clinical practice moving forward.

What implications do these findings have for the potential incorporation of T-DXd plus pertuzumab in the first-line HER2+ breast cancer setting, and what key questions remain regarding patient selection and optimal treatment duration?

[Regarding] what it means for patients, the impetus is on us to figure out which patients, selected biologically, should be receiving T-DXd [in the] first line vs which patients could receive other, shorter cytotoxic therapies, sparing them from the long durations of [treatment with] T-DXd.One key question will be identifying those patients who might truly benefit from up-front T-DX.

Another important area is prospectively studying what kind of maintenance strategies T-DXd could be used for. Many clinicians are looking forward to studies that use T-DXd as an induction strategy, where patients receive a certain number of cycles of T-DXd and then transition to better-tolerated targeted therapies like trastuzumab plus pertuzumab. This will require further investigation.

In terms of determining the right number of T-DXd cycles up-front, questions remain about whether metrics like time to best overall response or circulating tumor DNA clearance could guide treatment duration. Ultimately, the focus needs to be on finding the right candidates and defining how much T-DXd should be given [to patients] before moving on to maintenance therapy.

Based on these data, how might the role of T-DXd evolve in the context of other emerging ADCs in HER2+ breast cancer?

There’s been a lot of exciting work [done with] ADCs in the past few years. Every month, there’s something new. A major theme with T-DXd has been figuring out how low we can go in terms of HER2 expression for which T-DXd is still efficacious. More and more data are showing that very low HER2 expression is [still] enough for T-DXd to have good clinical activity. T-DXd may even prove to be efficacious in the HER2-null population. That’s a quickly evolving story, and we’re all looking forward to data that focus on the HER2-null population.

There are also very exciting studies moving ADCs into earlier lines—not only into the first-line setting for metastatic breast cancer, but also into the adjuvant and neoadjuvant settings for residual disease.

Combination studies will also be needed, particularly as we look forward to induction and maintenance strategies. What will the maintenance regimen be? With the [phase 3 AFT-38] PATINA trial [NCT02947685] regimen [of palbociclib (Ibrance) plus anti-HER2 and endocrine therapy] now well studied, we know that the inclusion of a CDK4/6 inhibitor and endocrine therapy can be very beneficial for patients with hormone receptor–positive, HER2-positive [breast cancer]. If we use T-DXd in the first line, what should we use either in combination or as a maintenance strategy? [Perhaps] other TKIs in maintenance or CDK4/6 inhibitors? Should we be combining any of those with T-DXd up-front?

Supported in part by Daiichi Sankyo. Content produced and independently developed by OncLive.

Reference

Tolaney S, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab (P) vs taxane + trastuzumab + pertuzumab (THP) for first-line (1L) treatment of patients (pts) with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer (a/mBC): interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008