Deeper Responses Linked to Improved Long-Term Outcomes With T-DXd/Pertuzumab in HER2+ Breast Cancer

Patients with HER2-positive advanced or metastatic breast cancer who achieved a complete response (CR) or deep partial response (PR) to first-line trastuzumab deruxtecan (T-DXd; Enhertu) plus pertuzumab (Perjeta) experienced improved long-term outcomes, including more durable progression-free survival (PFS) outcomes and longer treatment durations, compared with those who experienced responses that were less deep, according to an exploratory analysis of the phase 3 DESTINY-Breast09 trial (NCT04784715) presented at the 2026 ASCO Annual Meeting.¹

In the T-DXd/pertuzumab arm (n = 377), the 24-month PFS rate was 85.1% (95% CI, 72.2%-92.3%) in patients who achieved a CR (n = 58), 80.0% (95% CI, 71.7%-86.1%) in those who achieved a deep PR (n = 141; ≥ 80% tumor reduction), 64.3% (95% CI, 54.3%-72.8%) in those with a PR of less than 80% (n = 127), and 35.5% (95% CI, 21.1%-50.2%) in those with stable disease (SD) or progressive disease (PD; n = 51). The difference in 24-month PFS rates between the CR and deep PR subgroups was 5.1%, whereas the difference between the deep PR and PR subgroups was 15.7%.

“Depth of response does matter in terms of trying to understand long-term efficacy,” Sara M. Tolaney, MD, MPH, said in an interview with OncLive®. “Deep responses matter because [they are] associated with good PFS.”

Tolaney is a senior physician, chief of the Division of Breast Oncology, and associate director of the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute; as well as an associate professor of medicine at Harvard Medical School, both in Boston, Massachusetts.

What is the background for the DESTINY-Breast09 trial?

“For over a decade now, we’ve had the [phase 3] CLEOPATRA trial [NCT00567190] regimen as our first-line standard of care that involves giving upfront therapy with a taxane with trastuzumab [Herceptin] and pertuzumab [THP], followed by trastuzumab and pertuzumab maintenance,” Tolaney contextualized. “The DESTINY-Breast09 trial was designed to compare T-DXd alone vs the THP regimen, but also to compare T-DXd plus pertuzumab vs the THP regimen.”

DESTINY-Breast09 is a randomized, multicenter study that enrolled patients with HER2-positive advanced or metastatic breast cancer, including those with asymptomatic or inactive brain metastases, a disease-free interval of more than 6 months from last chemotherapy or HER2-targeted therapy in the neoadjuvant/adjuvant setting, and no prior systemic treatment for metastatic disease beyond up to 1 line of endocrine therapy. Patients were randomly assigned 1:1:1 to receive T-DXd plus placebo (n = 387; blinded until final PFS analysis), T-DXd plus pertuzumab (n = 383), or a taxane plus trastuzumab and pertuzumab (n = 387). The primary end point was PFS by blinded independent central review, and the key secondary end point was overall survival.

At the prespecified interim analysis (data cutoff, February 26, 2025), presented at the 2025 ASCO Annual Meeting, T-DXd plus pertuzumab (n = 383) met the trial’s primary end point, inducing a median PFS of 40.7 months (95% CI, 36.5-not calculable [NC]) vs 26.9 months (95% CI, 21.8-NC) with THP (HR, 0.56; 95% CI, 0.44-0.71; P < .00001).² The present exploratory analysis, which was not pre-defined and did not allow formal comparisons between the T-DXd plus pertuzumab and THP arms, evaluated the association between depth of response and long-term clinical benefit.¹ Responses were categorized as CR, deep PR, PR, and SD/PD per RECIST 1.1 criteria.

“We always wonder: Does it matter if [a patient] achieves a deep response to therapy?What are the implications for that in terms of long-term outcomes?” Tolaney noted. “In this exploratory analysis from DESTINY-Breast09, we looked at the relationship between depth of response and efficacy.”

How did long-term outcomes with T-DXd/pertuzumab in DESTINY-Breast09 differ by depth of response?

Among the full analysis set of the T-DXd/pertuzumab arm, 15.4% of patients achieved a CR, 37.4% of patients achieved a deep PR, 33.7% of patients achieved a PR of less than 80%, and 13.5% had SD/PD. Baseline characteristics were comparable across response subgroups.

The durability of response tracked with response depth. The median duration of best response was NC in the CR subgroup (95% CI, 35.1 months-NC), 39.2 months (95% CI, 35.3-NC) in the deep PR subgroup, and 34.8 months (95% CI, 22.8-NC) in the PR (<80%) subgroup. At 24 months, 85.0% (95% CI, 72.1%-92.3%) of patients who achieved CR, 78.9% (95% CI, 70.4%-85.2%) of those who achieved deep PR, and 60.4% (95% CI, 50%-69.3%) of those who achieved PR remained in their best response. By contrast, in the THP arm, achieving a deep PR was not associated with outcomes similar to those of a CR; the 24-month PFS rates in that arm were 76.7% (95% CI, 56.9%-88.2%) with a CR and 60.7% (95% CI, 39.8%-56.6%) with a deep PR.

How did response depth relate to treatment duration with T-DXd/pertuzumab in DESTINY-Breast09?

Patients who achieved a CR or deep PR with T-DXd plus pertuzumab had the longest median total treatment durations, at 28.0 months (range, 4.8-44.5) and 25.4 months (range, 3.4-42.7), respectively, compared with 20.6 months (range, 2.8-41.8) for those with a best response of PR and 4.4 months (range, 0.3-37.2) for those with a best response of SD/PD. Responses also deepened over time. The median time to best response was 8.4 months in the CR subgroup and 9.6 months in the deep PR subgroup, and 80% of patients in the intention-to-treat population achieved their maximal tumor reduction by 24 months. The investigators noted that these findings highlight the importance of maintaining first-line therapy to sustain clinical benefit.

What was the safety profile of T-DXd plus pertuzumab across response subgroups of patients with advanced/metastatic breast cancer?

The safety profile of the investigational combination was consistent across response subgroups. Exposure-adjusted incidence rates of possibly treatment-related grade 3 or higher adverse effects (AEs) per patient-year were 30% in the CR subgroup, 28% in the deep PR subgroup, 32% in the PR subgroup, and 57% in the SD/PD subgroup. Possibly treatment-related grade 3 or higher treatment-emergent AEs occurred in 63.8%, 54.2%, 53.1%, and 51.0% of patients in these subgroups, respectively. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 12.1% of patients who achieved CR, 15.5% of those who achieved deep PR, 7.8% of those who achieved PR, and 12.2% of those who achieved SD/PD; grade 3 or higher AEs of this nature were reported only in the SD/PD subgroup (4.1%). The investigators reported no new safety signals.

“These data did help inform a future study design,” Tolaney concluded. “Unfortunately, [these present ASCO data do not] answer the question of how long you need to treat [patients], but it’ll be nice to get more data to help us understand what happens if you do switch patients to a maintenance strategy after a year of upfront treatment.”

Supported in part by AstraZeneca and Daiichi Sankyo, content independently developed by OncLive.

References

1. Park YH, Tolaney SM, Saura C, et al. A DESTINY-Breast09 analysis of treatment duration and clinical outcomes by best response to trastuzumab deruxtecan (T-DXd) + pertuzumab (P). Presented at: 2026 ASCO Annual Meeting; May 29-June 2, 2026; Chicago, Illinois. Abstract 1021.
2. 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