Trastuzumab Deruxtecan Plus Pertuzumab Improves PFS vs Standard Care in HER2+ Breast Cancer

Trastuzumab deruxtecan (Enhertu; AstraZeneca/Daiichi Sankyo) in combination with pertuzumab (Perjeta; Genentech) demonstrated significantly longer progression-free survival (PFS) compared with the current standard of care for patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)–positive breast cancer in the DESTINY-Breast09 trial (NCT04784715).¹ The interim findings, which support the trastuzumab deruxtecan combination as a new standard of care, were presented in a late-breaking abstract at the 2025 American Society of Clinical Oncology (ASCO) annual meeting.

At a median follow-up of 29 months, the risk of disease progression or death after 2 years was 44% lower in the trastuzumab deruxtecan plus pertuzumab cohort compared with the standard treatment cohort.

Promising findings from the DESTINY-Breast09 trial were presented by Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute. | Image credit: Dana-Farber Cancer Institute

For more than a decade, the first-line standard of care for locally advanced or metastatic HER2-positive breast cancer has been a taxane given with trastuzumab (Herceptin; Genentech) and pertuzumab—a regimen known as THP. In the landmark CLEOPATRA study (NCT00567190), THP significantly improved median overall survival (OS) from 40.8 months (95% CI, 35.8-48.3) with placebo, trastuzumab, and docetaxel to 56.5 months (95% CI, 49.3-not reached) with pertuzumab, trastuzumab, and docetaxel,² which established the latter combination as the standard of care. At more than 8 years of follow-up in CLEOPATRA, the benefits of THP were maintained.³ However, THP is associated with a PFS of 18.5 months.⁴

The DESTINY-Breast09 trial randomized 1157 patients with locally advanced or metastatic HER2-positive breast cancer to receive either trastuzumab deruxtecan plus pertuzumab (n = 383), trastuzumab deruxtecan with a placebo (n = 387), or THP (n = 387).¹ Trastuzumab deruxtecan, a HER2-targeted antibody-drug conjugate comprised of trastuzumab attached to deruxtecan, has shown efficacy and been FDA approved for a range of solid-tumor cancers in the metastatic setting following disease progression on systemic therapy.⁵

There has been interest in moving the trastuzumab deruxtecan combination into the first-line setting given the PFS observed with THP, lead study author Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute, Boston, Massachusetts, explained while presenting the data at ASCO 2025.

The primary end point in DESTINY-Breast09 was PFS by blinded independent central review (BICR) in the intent-to-treat population, with other end points including OS, PFS by investigator (INV), objective response rate (ORR), duration of response (DOR), and safety.¹ In the trastuzumab deruxtecan combination and THP groups, 52% of patients had de novo disease, and 54% had hormone receptor–positive disease.

Median PFS by BICR was 40.7 months (95% CI, 36.5-not calculable [N]) in the trastuzumab deruxtecan combination cohort vs 26.9 months (95% CI, 21.8-NC) in the THP cohort (HR, 0.56; 95% CI, 0.44-0.71; P < .00001). Median PFS by INV was also significantly better in the trastuzumab deruxtecan plus pertuzumab cohort (40.7 months [95% CI, 36.5-NC]) than the THP cohort (20.7 months [95% CI, 17.3-23.5]). The PFS benefit was consistent across patient subgroups.

“These data suggest that the combination of trastuzumab deruxtecan plus pertuzumab may represent a new first-line standard of care for patients with metastatic, HER2-positive breast cancer,” Tolaney said.

The median DOR by BICR was 39.2 months (95% CI, 35.1-NC) in the trastuzumab deruxtecan combination cohort and 26.4 months (95% CI, 22.3-NC) in the THP cohort. OS data were immature at the time of the analysis.

The rate of grade 3 or higher treatment-emergent adverse events (TRAEs) was similar in the trastuzumab deruxtecan combination cohort (63.5%) and the THP cohort (62.3%), and serious TEAEs occurred in 27.0% and 25.1% of patients, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis—a known adverse event related to trastuzumab deruxtecan—occurred in 12.1% (n = 46) of patients in the trastuzumab deruxtecan combination cohort and 1% (n = 4) of the THP cohort. Most cases were not severe.

“I would echo Sara’s comments that this is a pivotal advancement in the treatment of HER2-positive metastatic breast cancer that is both clinically and statistically significant,” Rebecca Dent, MD, MSc, deputy chief executive officer (clinical) at National Cancer Center Singapore and an ASCO expert in breast cancer, said. “For many of us that have been treating metastatic HER2-positive breast cancer for more than 20 years, this was a death sentence when patients presented with metastatic disease. We’re now measuring their duration of therapy in years.”

Claudine Isaacs, MD, FRCPC, FASCO, of the Lombardi Cancer Center at Georgetown University, discussed the findings following Tolaney's presentation at the annual meeting. Her main takeaway was that while trastuzumab deruxtecan plus pertuzumab could be a new standard of care, questions remain—especially regarding optimal treatment sequencing and duration of therapy. She also highlighted a few trial design considerations.

Isaacs noted the differing lengths of treatment between arms, with patients on the investigational arm continuing trastuzumab deruxtecan until disease progression or intolerable toxicity, which was a median of 20 months. In the THP arm, treatment typically involved 6 to 8 cycles of chemotherapy followed by maintenance HP. She also pointed out that patients diagnosed in the early-stage setting did not receive the treatment that would be expected in a contemporary setting. Only 58% of patients received trastuzumab, 15% received pertuzumab, and 2% received ado-trastuzumab emtansine, she noted, adding that the concurrent use of endocrine therapy for hormone receptor–positive disease was also low.

Considering the relatively short follow-up and that 40% of patients were still receiving the trastuzumab deruxtecan combination, the median PFS could improve with longer follow-up, she explained. But in the real-world early-stage setting where patients receive more HER2-directed therapy, PFS may be shorter than in the trial, especially in the control arm.

"Now, I believe we would all agree that [trastuzumab deruxtecan], both in the first-line and second-line setting, is a highly active drug and one that we do want in our therapeutic armamentarium, but as given in this trial, it is an escalation of care," Isaacs said. "For me, the outstanding questions are related to sequencing. Namely, do we have to give it first line to everyone, or could we have a more selective approach?" If it is given in the first line, the question of optimal duration of treatment remains, she added. In the future, markers of treatment response may help answer these questions.

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): Primary results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):Abstract LBA1008.

2. Swain SM, Baselga J, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-734. doi:10.1056/NEJMoa1413513

3. Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2020;21(4):519-530. doi:10.1016/S1470-2045(19)30863-0

4. Baselga J, Cortés J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366(2):109-119. doi:10.1056/NEJMoa1113216

5. Enhertu. Prescribing information. Daiichi Sankyo; 2025. Accessed June 1, 2025. https://daiichisankyo.us/prescribing-information-portlet/getPIContent?productName=Enhertu&inline=true