At the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, Dr Sara Tolaney (Dana-Farber Cancer Institute, Boston, MA, USA) presented interim results from the phase III DESTINY-Breast09 trial, investigating the use of trastuzumab deruxtecan (T-DXd) plus pertuzumab as a first-line treatment for patients with metastatic HER2-positive breast cancer. The study aimed to determine whether this antibody-drug conjugate could outperform the current standard regimen of taxane plus trastuzumab and pertuzumab (THP). Results showed a dramatic improvement in progression-free survival, suggesting T-DXd plus pertuzumab could become a new standard of care in this setting. The trial’s findings mark a significant step forward in HER2-positive breast cancer treatment.
The late-breaking abstract, ‘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’ (LBA1008) was presented at the American Society of Clinical Oncology on May 30 to June 3 2025 in Chicago, IL, USA.
Chapters
- Rationale (0:09.00)
- Methodology and trial design (1:12.00)
- Results (3:22.17)
- Conclusion (4:26.78)
Transcript
My name is Sarah Telaney, and I’m a breast medical oncologist at Dana Farber Cancer Institute. This year at ASCO, we presented interim results from DESTINY-Breast09, a randomized phase III study looking at Fam-trastuzumab deruxtecan-nxki plus pertuzumab compared to taxane plus trastuzumab and pertuzumab as first-line treatment for metastatic HER2 positive breast cancer.
We know that about 15-20% of breast cancers are HER2 positive and outcomes for metastatic HER2 positive breast cancer have really evolved over the last several years since we’ve seen the introduction of T-DXd, which is currently approved as the second-line standard of care based on the unprecedented outcomes we saw in DESTINY-Breast03, where we saw PFS of about 29 months. But there’s been a lot of interest to try to move T-DXd into the first-line setting since we know that the current standard of care is taxane with trastuzumab and pertuzumab or THP, and this has a PFS of a little under 19 months. And so DESTINY-Breast09 really looked to investigate if T-DXd could move into that first-line setting.
So the trial was designed to enroll patients who had never seen any prior systemic therapy for metastatic disease with the exception that they could have had a line of endocrine monotherapy before enrollment. And then patients were randomized to one of three arms, either T-DXd plus placebo or T-DXd plus pertuzumab or taxane with choice of paclitaxel or docetaxel with trastuzumab and pertuzumab, so what we would call the THP arm.
So for the two T-DXd arms, T-DXd was to be administered until time of disease progression. But if someone had to come off T-DXd early due to side effects, then they could switch and add trastuzumab, which was given alone in the T-DXd and placebo arm or given with pertuzumab in the tDxD plus pertuzumab arm. And for the THP arm, the taxane needed to be given for a minimum of six cycles or until development of toxicity, and then patients would switch to get trastuzumab and pertuzumab.
Physicians could elect to add endocrine therapy to those patients who had hormone receptor positive HER2 positive disease after they had finished at least six cycles of T-DXd or after they stopped their taxane therapy. And the trial was really designed to look at progression free survival, comparing the T-DXd and pertuzumab arm to THP and comparing the T-DXd placebo arm to THP, but the two T-DXd arms weren’t powered to be compared to each other.
And so at the time of the interim analysis, there were very stringent criteria set to demonstrate superiority. You had to have a p-value less than 0.00043, and this stringent criteria was met for the T-DXd and pertuzumab arm, but was not met for the T-DXd monotherapy arm. So the patients on the T-DXd monotherapy arm continue to be followed and are blinded and that their data will get reported at the time of the primary PFS analysis. But for this interim analysis, we presented the data foT-DXd and pertuzumab compared to THP.
And what we found was that T-DXd and pertuzumab led to a statistically significant and clinically meaningful improvement in PFS. So the PFS for T-DXd and pertuzumab was 40.7 months compared to 26.9 months for THP with a hazard ratio of 0.56. So I think a very dramatic difference, really in essence, a doubling of progression-free survival. We also saw that response rates were higher with T-DXd and pertuzumab. And interestingly, rates of complete response were almost double with T-DXd and pertuzumab. So 15% compared to almost 8%.
And we saw duration of response was much longer with T-DXd and pertuzumab as well. The overall survival data are highly immature at this early time point. We only have 16% of survival events that have been seen, so there was no formal statistical testing for survival. But we did see, just descriptively, there seemed to be a trend for benefit for overall survival for T-DXd and pertuzumab with a hazard ratio of 0.84.
So overall, you know, I think this suggests that T-DXd and pertuzumab is associated with a significant improvement in progression-free survival when compared to THP. In essence, again, almost a doubling of progression-free survival with a hazard ratio of 0.56. And that the benefit was really consistently seen across all the prespecified subsets of patients. And there were no new toxicities that were identified.
And so given these findings, it seems like given the strength of the findings that T-DXd and pertuzumab may be a potential new standard of care for our patients with metastatic HER2 positive breast cancer that are getting treated in the first line setting. So I think it’s great to see these improvements for our patients.
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Disclosures: Sara Tolaney is a consultant for: Novartis, Pfizer/SeaGen, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb/Systimmune, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, Launch Therapeutics, Zuellig Pharma, Johnson&Johnson/Ambrx, Bicycle Therapeutics, Summit Therapeutics. She has received grant/research support from: Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, AstraZeneca, NanoString Technologies, Gilead, SeaGen, OncoPep, Daiichi Sankyo, Menarini/Stemline, Jazz Pharma. she is a member of the advisory board for: Novartis, Pfizer/SeaGen, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb/Systimmune, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, Launch Therapeutics, Zuellig Pharma, Johnson&Johnson/Ambrx, Bicycle Therapeutics, Summit Therapeutics. She has received honoraria/honorarium from: Novartis, Pfizer/SeaGen, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb/Systimmune, Daiichi Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, Launch Therapeutics, Zuellig Pharma, Johnson&Johnson/Ambrx, Bicycle Therapeutics, Summit Therapeutics.
This content has been developed independently by Touch Medical Media for touchONCOLOGY. It is not affiliated with the American Society of Clinical Oncology (ASCO). Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Interviewer/Editor:Â Sophie Nickelson
Cite: #ASCO25: T-DXd plus pertuzumab doubles PFS in HER2+ in DESTINY-Breast09. touchONCOLOGY. June 12th, 2025.
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