Ask AI
Back Back
HER2 Positive mBC Evolving 1L Tx
Thoughts on the Evolving Treatment Options for First-line Management of HER2-Positive mBC

Released: August 15, 2025

Shipra Gandhi
Shipra Gandhi, MD, MS
Laura Spring
Laura Spring, MD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • First-line therapy with T-DXd plus pertuzumab in HER2-positive mBC significantly improved median progression-free survival compared with the standard THP regimen, with no new safety signals.
  • According to experts, HCPs should implement shared decision-making regarding T-DXd plus pertuzumab therapy for patients with newly diagnosed HER2-positive mBC, and it is essential that HCPs consider patient-specific presentation factors.

In this commentary, Laura M. Spring, MD, and Shipra Gandhi, MD, MS, discuss and evaluate emerging data for patients with advanced or metastatic HER2-positive breast cancer in the first-line setting that were presented at recent oncology meetings. They also share their thoughts on how to integrate the new data into clinical practice and highlight resources from an educational program on this topic aimed at improving patient and healthcare professional communication and overall satisfaction with care.

Emerging Data for HER2-Positive Metastatic Breast Cancer

Laura M. Spring, MD:
The global, randomized phase III DESTINY-Breast09 study was a major presentation for HER2-positive breast cancer at the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting. This trial enrolled 1157 patients with previously untreated HER2-positive locally advanced or metastatic breast cancer (mBC). The study randomized patients in a 1:1:1 manner. One arm consisted of trastuzumab deruxtecan (T-DXd) plus pertuzumab. Another arm allocated patients to standard of care with trastuzumab, pertuzumab, and taxane (THP). The last arm, with data not presented at ASCO 2025, allocated patients to T-DXd plus placebo. Approximately 50% of patients had newly diagnosed mBC, 54% were hormone receptor positive, and most had previously received treatment in the (neo)adjuvant setting.

Efficacy results presented for DESTINY-Breast09 show a median progression-free survival (PFS) by blind independent central review of 40.7 months (95% CI: 36.5-not estimable) with T-DXd plus pertuzumab vs 26.9 months (95% CI: 21.8-not estimable) with THP (hazard ratio: 0.56; P = .00001). The 24-month PFS rates were 70.1% vs 52.1%, objective response rate was 85.1% vs 78.6%, and complete response rate was 15.1% vs 8.5%, all in favor of T-DXd plus pertuzumab vs THP. Overall survival data were immature in this analysis, but there was a trend favoring T-DXd plus pertuzumab.

The median treatment duration with T-DXd plus pertuzumab was 21.7 months compared with 16.9 months with THP. Grade ≥3 treatment-emergent adverse events (AEs) were similar between the 2 reported treatment arms with approximately 63% of patients in either arm experiencing such AEs. Serious treatment-emergent AEs were observed in 27.0% of patients receiving T-DXd plus pertuzumab vs 25.1% with THP. Regarding AEs of special interest, any-grade interstitial lung disease (ILD) occurred in 12.1% of patients in the T-DXd plus pertuzumab arm and in 1.0% of patients in the THP arm. There were no grade 3/4 ILD events reported. However, 1 (0.5%) grade 5 ILD event occurred in the T-DXd plus pertuzumab arm. Other common AEs in the T-DXd arm included nausea, vomiting, and constipation, and there were no new safety signals identified.

Shipra Gandhi, MD, MS:
These new data are very exciting. Results from DESTINY-Breast09 show that the combination of T-DXd plus pertuzumab significantly prolongs median PFS compared with the THP regimen and represents the first major advancement in the treatment of HER2-positive mBC in the first-line setting in more than a decade. These data are likely to establish a new standard of care. Based on the results from DESTINY-Breast09, the FDA granted breakthrough therapy designation to T-DXd in combination with pertuzumab for the first-line treatment of adult patients with unresectable or metastatic HER2-positive breast cancer.

However there remain numerous practical clinical questions that arise from the DESTINY-Breast09 study, including whether it would be possible to stop T-DXd after several cycles to improve tolerability, similar to the practice of stopping taxane after several cycles of THP and continuing treatment with HP alone. This is an approach that has yielded good quality of life for patients receiving THP.

Impact of New Data on Expert Recommendations in an Interactive Decision Support Tool for HER2-Positive mBC 

Shipra Gandhi, MD, MS:
As part of an educational program that we took part in from January 2025 to June 2025, we gathered input from 3 additional breast oncology experts (total of 5) regarding our treatment preference(s) for first-line management of mBC. In early 2025, all 5 experts (including us 2) agreed on the use of THP as the standard of care in the first-line HER2-positive mBC setting. At least 2 of the experts on our panel also indicated that they would consider stopping the taxane after several cycles because of the potential for cumulative toxicity and then continue treatment with HP maintenance. After the data from DESTINY-Breast09 were presented at ASCO 2025, all 5 of us began recommending T-DXd plus pertuzumab as first-line therapy for HER2-positive mBC. Moreover, at the 2024 San Antonio Breast Cancer Symposium, we also saw data presented from the phase III PATINA trial supporting the addition of palbociclib to maintenance HP and endocrine therapy following stable disease or better response after induction THP therapy for 6 cycles in patients with hormone receptor (HR)–positive/HER2-positive mBC. In PATINA we saw a remarkable improvement in PFS from 29.1 months to 44.3 months (hazard ratio: 0.74) with the addition of palbociclib to maintenance therapy. The 5 experts were queried about how their treatment recommendation may have changed for metastatic HR-positive/HER2-positive setting considering the available data. Unanimously, all of us agreed that we would still continue treating these patients with THP and would consider HP plus palbociclib and endocrine therapy based on PATINA.

We all agreed that given the emerging data, there has to be a shared decision-making process together with the patient. I say this because it is clear that T-DXd is an effective agent, both in the second-line and in the first-line setting, but given the potential for dose interruptions and dose reductions as seen on the clinical trials of T-DXd, the question remains as to when and how best to use this agent in the treatment paradigm.

Laura M. Spring, MD:
What are your thoughts on whether we should recommend T-DXd plus pertuzumab for all patients presenting with HER2-positive mBC or selectively for a subset of these patients?

Shipra Gandhi, MD, MS:
All 5 experts in the panel agreed that we would consider T-DXd plus pertuzumab for all patients, but we would prefer it in some patient populations such as those with brain metastases, patients with significant visceral disease, if PI3KCA mutations were present, and for those who have had recent disease progression on (neo)adjuvant HER2-targeted therapy. Of note, in DESTINY-Breast09, patient eligibility for first-line treatment included that the disease-free interval had to be >6 months, and approximately 30% also had PI3KCA mutations. Based on this, I would consider T-DXd plus pertuzumab in those patients who present with disease recurrence 6-12 months after completion of anti-HER2 therapy. Our panel also agreed that if a patient had a low volume or slow-growing disease, or a significant number of comorbidities, THP might be preferred.

Laura M. Spring, MD:
Often we are not as focused on genomic testing for first-line HER2-positive mBC. DESTINY-Breast09 could change that.

Shipra Gandhi, MD, MS:
I agree, and regarding HR-positive/HER2-positive mBC, the decision is more nuanced because in the DESTINY-Breast09 trial T-DXd was continued until disease progression. Thus it remains unknown whether we could somehow combine the approach of the DESTINY-Breast09 trial for induction and then consider adopting the PATINA trial maintenance therapy regimen for this patient population. Additional unanswered questions include whether T-DXd is needed for 6 or 8 cycles or until disease progression or should we wait until maximum disease response and then potentially switch from T-DXd to trastuzumab?

Laura M. Spring, MD:
I agree. Incorporating these emerging questions into ongoing and future trial design will be key to gaining a better understanding of the best duration of T-DXd in the first-line setting. Real-world data may also help clarify how these results are applied. I imagine a few different scenarios where T-DXd is either used until you reach a maximal response or a plateaued response.

Available Educational Resources for Patients

Shipra Gandhi, MD, MS:
The educational program also included a patient communication checklist resource and treatment options infographic for newly diagnosed HER2-positive mBC that can be shared with patients to help them during their discussions with healthcare professionals and to be informed about their options.

Your Thoughts
What are your thoughts on the evolving treatment landscape of patients with HER2-positive mBC? Answer the polling question and leave us a comment. Visit the program page, listen to a podcast, download patient resources, and access an interactive decision support tool on this topic.

 

Continue

Poll

1.

Please rate your agreement with this statement: I want to learn more about the safety, efficacy, and therapeutic sequencing impact of T-DXd plus pertuzumab as a possible first-line option for patients with HER2-positive mBC before I incorporate it into my practice.

Submit