FDA Approves T-DXd Plus Pertuzumab for HER2+ Breast Cancer

The FDA has approved fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) in combination with pertuzumab (Perjeta) for use as frontline treatment in adult patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+ or in situ hybridization–positive) breast cancer, as determined by an FDA-approved test.

The regulatory decision was supported by data from the phase 3 DESTINY-Breast09 trial (NCT04784715), in which patients treated with T-DXd plus pertuzumab (n = 383) experienced a median progression-free survival (PFS) of 40.7 months (95% CI, 36.5-not estimable [NE]) by blinded independent review committee (BICR) assessment compared with 26.9 months (95% CI, 21.8-NE) for those given trastuzumab (Herceptin), pertuzumab, and a taxane (THP; n = 387; HR, 0.56; 95% CI, 0.44-0.71; P <.0001).

T-DXd plus pertuzumab elicited a confirmed objective response rate (ORR) of 87% (95% CI, 83%-90%) vs 81% (95% CI, 77%-85%) with THP.

Moreover, at the time of the PFS analysis, overall survival (OS) data were not mature; at this time point, 16% of patients had died across both arms in the overall population.

What was the design of DESTINY-Breast09?

The multicenter, open-label randomized phase 3 trial enrolled adult patients with HER2-positive advanced or metastatic breast cancer who had not received other previous systemic treatment and who had a disease-free interval greater than 6 months from last chemotherapy or HER2-targeted therapy in the neoadjuvant/adjuvant setting.2 One previous line of endocrine therapy was allowed for metastatic disease.

Study participants were randomly assigned 1:1:1 to receive T-DXd at 5.4 mg/kg paired with pertuzumab, THP, or an investigational therapy (n = 387) given every 3 weeks until intolerable toxicity or progressive disease.1 Stratification factors included type of metastatic disease (de novo vs recurrent), hormone receptor status (positive vs negative), and PIK3CA mutational status (detected vs not).2

The study's primary end point was PFS by BICR and RECIST 1.1 criteria. A key secondary end point was OS, and other secondary end points included investigator-assessed PFS; ORR by BICR and investigator assessment, duration of response by BICR and investigator assessment; PFS2 by investigator assessment; and safety and tolerability.

What additional data were shared during the 2025 ASCO Annual Meeting?

Of the 1703 patients who were screened, 1157 underwent randomization; 383 were randomized to receive T-DXd and pertuzumab, and 387 were randomized to receive THP. In the respective arms, 380 and 383 patients received treatment. Of those who discontinued treatment in the T-DXd arm, 21.3% did so because of disease progression, 20.8% due to toxicity, 11.1% because of patient decision, 3.9% because of death, and 2.4% due to other reasons.

The median patient age was 54 years (range, 20-85) across the T-DXd/pertuzumab and THP arms, and all were female. Just under half of patients were from Asia (49.1%; 49.4%), more than half had an ECOG performance status of 0 (66.8%; 63.6%), and most had a HER2 score of immunohistochemistry 3+ (83.0% vs 81.4%). Regarding hormone receptor status, in the T-DXd/pertuzumab arm, 54.0% were positive; this rate was 54.0% in the THP arm. About half of patients in both arms had de novo disease at diagnosis (52.2%; 51.7%), and most patients had visceral metastases (73.4%; 69.3%).

At the planned interim analysis, which had a data cutoff date of February 26, 2025, the median PFS by investigator assessment with T-DXd and pertuzumab was 40.7 months (95% CI, 36.5-NE) vs 20.7 months (95% CI, 17.3-23.5 (HR, 0.49; 95% CI, 0.39-0.61; P < .00001). The PFS benefit provided by T-DXd plus pertuzumab was consistent across prespecified subgroups, including stratification factors.

Early OS data suggested a positive trend that favored T-DXd plus pertuzumab over THP (HR, 0.84; 95% CI, 0.59-1.19). Moreover, a clinically meaningful improvement in PFS2 was reported with T-DXd plus pertuzumab vs THP, at NE and 36.5 months (95% CI, 36.1-NE), respectively (HR, 0.60; 95% CI, 0.45-0.79; P = .00038).

Moreover, 32.4% of those in the T-DXd plus pertuzumab arm received post-discontinuation therapy in the second-line setting, which included targeted therapy (29.0%) in the form of T-DXd (1.6%), trastuzumab emtansine (T-DM1; 1.8%), a trastuzumab (Herceptin)-containing regimen (20.4%), or a pertuzumab-containing regimen (13.8%); chemotherapy (17.8%) in the form of docetaxel (6.3%), paclitaxel (4.7%), or capecitabine (6.3%); or endocrine therapy (5.0%).

What was the safety profile of T-DXd plus pertuzumab in this population of patients with HER2-positive breast cancer?

The median treatment duration of T-DXd plus pertuzumab was 21.7 months (range, 0.3-44.5) and 16.9 months (range, 0.7-41.7) with THP. Any treatment-emergent adverse effects (TEAEs) were experienced by 99.7% of those in the T-DXd/pertuzumab arm vs 99.0% of those in the THP arm; 97.9% and 96.6% were potentially treatment related, of which 54.9% and 52.4% were grade 3 or higher. Serious TEAEs occurred in 27.0% and 25.1% of patients, respectively.

In the T-DXd plus pertuzumab arm, TEAEs were linked with dose reductions, interruptions, or treatment discontinuation in 45.9%, 68.8%, and 20.7% of patients, respectively; in the THP arm, these respective rates were 19.9%, 49.0%, and 28.3%.

The most common potentially treatment-related TEAEs of any grade reported in at least 20% of patients in the T-DXd/pertuzumab and THP arms, respectively, were nausea (71.1%; 28.8%), diarrhea (55.9%; 54.2%), neutropenia (48.8%; 44.5%), fatigue (48.3%; 34.6%), alopecia (46.2%; 50.0%), vomiting (42.0%; 13.4%), increased transaminases (36.0%; 18.8%), anemia (35.4%; 39.0%), leukopenia (29.4%; 30.6%), decreased appetite (28.6%; 15.4%), decreased weight (23.9%; 6.8%), thrombocytopenia (23.4%; 4.5%), constipation (22.3%; 6.8%), hypokalemia (21.5%; 6.3%), and peripheral sensory neuropathy (11.3%; 28.5%).

References

1. FDA approves fam-trastuzumab deruxtecan-nxki with pertuzumab for unresectable or metastatic HER2-positive breast cancer. FDA. December 15, 2025. Accessed December 15, 2025. https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-fam-trastuzumab-deruxtecan-nxki-pertuzumab-unresectable-or-metastatic-her2-positive
2. Tolaney SM, Jiang Z, Zhang Q, et al. Trastuzumab deruxtecan (T-DXd) + pertuzumab vs taxane + trastuzumab + pertuzumab (THP) for first-line treatment of patients with human epidermal growth factor receptor 2–positive (HER2+) advanced/metastatic breast cancer: interim results from DESTINY-Breast09. J Clin Oncol. 2025;43(suppl 17):LBA1008. doi:10.1200/JCO.2025.43.17_suppl.LBA1008