T-DXd/Pertuzumab Earns Type II Application Validation in EU for HER2+ mBC

A Type II Variation marketing authorization application has been validated by the European Medicines Agency (EMA) for fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) as first-line treatment for patients with unresectable or metastatic HER2-positive breast cancer, according to a press release from Daiichi-Sankyo.¹

The News

This validation was based on results from the phase 3 DESTINY-Breast09 trial (NCT04784715).² The scientific review process by the Committee for Medicinal Products for Human Use is underway.

Data from the trial showed a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not calculable [NC]) in the T-DXd plus pertuzumab arm vs 26.9 months (95% CI, 21.8-NC) in the taxane plus trastuzumab (Herceptin) and pertuzumab arm (THP; HR, 0.56; 95% CI, 0.44-0.71; P <.00001). The PFS rates at 6 months were 93.0% (95% CI, 89.9%-95.2%) vs 87.8% (95% CI, 84.0%-90.7%), 85.9% (95% CI, 85.9% (95% CI, 81.9%-89.1%) vs 72.4% (95% CI, 67.4%-76.8%) at 12 months, and 70.1% (95% CI, 64.8%-74.8%) vs 52.1% (95% CI, 46.4%-52.3%) at 24 months between both arms, respectively.

The median duration of response was 39 months with T-DXd plus pertuzumab, and complete responses were noted in 15.1% vs 8.5% in the comparator arm. Overall survival data showed a trend towards improved outcomes in patients in the T-DXd plus pertuzumab arms.

“This validation in the [European Union] is an important step in moving us closer to offering [T-DXd] in combination with pertuzumab as a potential new first-line treatment option for patients with HER2-positive metastatic breast cancer,” said Ken Takeshita, MD, global head of Research & Development at Daiichi Sankyo, said in the press release. “Following the recent approval in the US for this indication, we look forward to working closely with the EMA to bring [T-DXd] to eligible patients in the [European Union] who may benefit from improved outcomes in a setting where the standard of care has not changed in more than a decade.”

Patients were randomly assigned 1:1:1 to receive 5.4 mg/kg of T-DXd every 3 weeks plus placebo (n = 387), T-DXd plus pertuzumab (n = 383), or paclitaxel or docetaxel in combination with trastuzumab and pertuzumab (n = 387). Results from the T-DXd plus placebo arm will remain blinded until the time of the final PFS analysis.

At the data cutoff of February 26, 2025, the data were immature, but the criteria for PFS superiority with a stringent P value of less than 0.00043 were met in the T-DXd plus pertuzumab arm compared with the THP arm.

Subgroup analyses demonstrated a benefit regardless of de novo or recurrent disease, hormone receptor status, or PIK3CA mutation status.

Safety remained comparable to prior reports of each agent. The most common any-grade treatment-emergent adverse effects included nausea (71.1% vs 28.8%), diarrhea (55.9% vs 54.2%), neutropenia (48.8% vs 44.5%), and fatigue (48.3%-34.6%) in each arm, respectively.

Subgroup Analysis

At the European Society for Medical Oncology Congress 2025, a subgroup analysis of the DESTINY-Breast09 data showed meaningful PFS benefit across the previously outlined groups.³

For those with de novo disease, the median PFS was NC (95% CI, 36.5-NC) vs 31.2 months (95% CI, 23.5-NC) for those treated with T-DXd plus pertuzumab vs THP (HR, 0.49; 95% CI, 0.35-0.70). The median PFS for those with recurrent disease in the T-DXd plus pertuzumab arm was 38.0 months (95% CI, 26.9-NC) and 22.5 months (95% CI, 18.1-NC) for those in the THP arm (HR, 0.63; 95% CI, 0.46-0.87).

For patients who had hormone receptor–positive disease, the median PFS was 38.0 months (95% CI, 36.0-NC) in the T-DXd plus pertuzumab arm and 27.7 months (95% CI, 22.4-NC) for patients in the THP arm (HR, 0.61; 95% CI, 0.44-0.84). For patients with hormone receptor–negative disease, the median PFS in the T-DXd plus pertuzumab arm was 40.7 months (95% CI, 40.7-NC) vs 22.6 months (95% CI, 17.3-32.7) in the THP arm (HR, 0.52; 95% CI, 0.37-0.73).

The median PFS for patients with PIK3CA mutation was 36.0 months (95% CI, 29.7-NC) and 18.1 months (95% CI, 15.1-25.6) in each arm, respectively (HR, 0.52; 95% CI, 0.35-0.77). For those with PIK3CA mutations not detected, the median PFS was 40.7 months (95% CI, 38.0-NC) for patients in the T-DXd plus pertuzumab arm and 32.7 months (95% CI, 24.2-NC) in the THP arm (HR, 0.57; 95% CI, 0.43-0.77).

FDA Actions

Following the DESTINY-Breast09 data presentation at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting, the FDA granted breakthrough therapy designation in July 2025 to T-DXd for patients with unresectable or metastatic HER2-positive breast cancer.⁴

In September 2025, the FDA granted priority review to T-DXd plus pertuzumab in the aforementioned population.⁵

In December 2025, the FDA approved T-DXd plus pertuzumab.⁶ In addition, the FDA approved the PATHWAY anti-HER-2/neu (5B5) Rabbit Monoclonal Primary Antibody HER2 Dual ISH Probe Cocktail as a companion diagnostic for selecting patients with HER2-positive breast cancer.

References

1. ENHERTU® plus pertuzumab Type II Variation Application Validated in the EU as first-line treatment of patients with HER2 positive metastatic breast cancer. News release. Daiichi-Sankyo. January 19, 2026. Accessed January 19, 2026. https://tinyurl.com/3vsm2s3d
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
3. Loibl S, Jiang Z, Barroso-Sousa R, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for patients with HER2+ advanced/metastatic breast cancer: additional analyses of DESTINY-Breast09 in key subgroups of interest. Ann Oncol. 2025;36(suppl 2):S1563-S1564. doi:10.1016/j.annonc.2025.09.028
4. ENHERTU® plus pertuzumab granted breakthrough therapy designation in the U.S. as first-line therapy for patients with HER2 positive metastatic breast cancer. News release. Saiichi-Dankyo. July 17, 2025. Accessed January 19, 2026. https://tinyurl.com/yyvfzskc
5. ENHERTU® (fam-trastuzumab deruxtecan-nxki) plus pertuzumab granted priority review in the US as 1st-line treatment for patients with HER2-positive metastatic breast cancer. News release. AstraZeneca. September 24, 2025. Accessed January 19, 2026. https://tinyurl.com/2256m25p
6. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. News release. FDA. December 15, 2025. Accessed January 19, 2026. https://tinyurl.com/59n2f8bs