T-DXd Plus Pertuzumab Could Add to Antibody-Drug Conjugate Arsenal in HER2+ Breast Cancer

After the combination of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and pertuzumab (Perjeta) demonstrated promising results in patients with previously untreated HER2-positive advanced or metastatic breast cancer, excitement has continued to flourish among investigators regarding growing role of antibody-drug conjugates (ADCs) within this treatment paradigm,according to Sarah Sammons, MD.

“We were very excited to look at the data that came out of [the phase 3] DESTINY-Breast09 [trial (NCT04784715)], which took patients with first-line, HER2-positive [metastatic] breast cancer and randomly assigned them to receive T-DXd [plus placebo], T-DXd plus pertuzumab, or the current standard of care [SOC], which is a taxane plus trastuzumab [Herceptin] and pertuzumab [THP] followed by maintenance trastuzumab and pertuzumab,” Sammons said in an interview with OncLive®. “The biggest difference between these treatment arms is a continuous [ADC] vs induction chemotherapy followed by maintenance, which would be a very large paradigm shift for our patients.”

During the 2025 ASCO Annual Meeting, investigators presented interim results from DESTINY-Breast09, which showed that patients who received T-DXd plus pertuzumab (n = 383) achieved a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not calculable [NC]) per blinded independent central review compared with 26.9 months (95% CI, 21.8-NC) among those who received THP (n = 387; HR, 0.56; 95% CI, 0.44-0.71; P < .00001). The 24-month PFS rates were 70.1% (95% CI, 64.8%-74.8%) and 52.1% (95% CI, 46.4%-57.5%), respectively. Additionally, the median time to second progression (PFS2) was NC in the combination arm compared with 36.5 months (95% CI, 36.1-NC) in the THP arm (HR, 0.60; 95% CI, 0.45-0.79; nominal P = .00038).

Sammons is the associate director of the Metastatic Breast Cancer Program and a senior physician at Dana-Faber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

In the interview, Sammons discussed the data from DESTINY-Breast09, remaining questions with the regimen examined in the trial, and other notable studies examining ADCs in patients with breast cancer.

OncLive: What were some notable aspects of the data read out from DESTINY-Breast09 during the ASCO Annual Meeting?

Sammons: The primary end point of PFS was positive. The PFS2 data are also important, because at this time patients can receive T-DXd in the second-line setting per the SOC. It is important to know how long patients can stay on T-DXd [with] continuous therapy and how that impacts their quality of life.

The patient subgroup [data are also notable]. Patients who [had a bigger PFS] benefit from this more intensive approach [with T-DXd plus pertuzumab] are those with de novo disease [HR, 0.49; 95% CI, 0.35-0.70] vs those with recurrent disease [HR, 0.63; 95% CI, 0.46-0.87]. There's a lot for us to closely look at when we're considering this potentially paradigm-shifting first-line trial.

What are the unanswered questions that remain with the DESTINY-Breast09 trial and the T-DXd plus pertuzumab regimen?

ADCs keep moving into earlier lines of therapy for our patients with metastatic HER2-positive breast cancer. Are we now giving our patients a first-line ADC? Topline results [from DESTINY-Breast09] show that this strategy is going to be successful. We'll need to subsequently answer the question of, how long do our patients need to receive this first-line ADC? Do they need to continue until disease progression? Or can we design better-tolerated maintenance strategies?

T-DXd is now being examined as part of a neoadjuvant regimen [in the phase 3 DESTINY-Breast11 trial (NCT05113251)] and as an adjuvant regimen in patients with residual disease after induction with a taxane and trastuzumab-based therapy [in the phase 3 DESTINY-Breast05 study (NCT04622319)]. As we keep moving these ADCs into earlier lines of therapy, we need to critically ask ourselves, as we improve patient outcomes, is this also tolerable for them? [We need to] thoughtfully balance adverse effects and efficacy.

What other studies of ADCs in breast cancer were notable at this year’s ASCO?

I’m excited about ADCs in [patients with] triple-negative breast cancer [TNBC], which is objectively our patient population that has the largest need for us to improve their outcomes. We saw the results of the [phase 3] ASCENT-04 trial [NCT05382286], which looked at sacituzumab govitecan-hziy [Trodelvy] plus pembrolizumab [Keytruda] in patients with [previously untreated], PD-L1–positive TNBC. I'm very excited to see how patients [continue to] do with that regimen.

We also saw data with another ADC, sacituzumab tirumotecan, in [patients with] PD-L1–negative, first-line TNBC. In the phase 2 OptiTROP-Breast05 study [NCT05445908], we saw [patients (n = 41) achieve] a median PFS of 13.4 months [95% CI, 9.9-18.2], which is the longest ever reported in first-line TNBC. I'm excited to see how ADCs will improve outcomes for these patients.

References

1. Tolaney SM, 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
2. Tolaney SM, de Azambuja E, Kalinsky K, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) vs chemotherapy (chemo) + pembro in previously untreated PD-L1–positive advanced triple-negative breast cancer (TNBC): Primary results from the randomized phase 3 ASCENT-04/KEYNOTE-D19 study. J Clin Oncol. 2025;43(suppl 17):LBA109. doi:10.1200/JCO.2025.43.17_suppl.LBA109