The FDA has approved trastuzumab deruxtecan (T-DXd; Enhertu, Daiichi Sankyo/AstraZeneca) in combination with pertuzumab for the first-line treatment of unresectable or metastatic HER2-positive breast cancer as determined by an FDA-approved test.

The agency also gave the nod to two companion tests — Roche’s PATHWAY anti-HER-2/neu (4B5) Rabbit Monoclonal Primary Antibody and VENTANA HER2 Dual ISH DNA Probe Cocktail in situ hybridization assay — to identify patients eligible for treatment.

T-DXd, an anti-HER2 antibody-drug conjugate, was previously approved for unresectable or metastatic HER2-positive breast cancer in the second line, after at least one anti-HER2 regimen.

Approval for the first-line indication was based on the DESTINY-Breast09 (DB09) trial, which randomly assigned 1157 patients equally to either T-DXd plus pertuzumab, T-DXd alone, or standard-of-care treatment with taxane chemotherapy plus the HER2-targeted monoclonal antibodies trastuzumab and pertuzumab (THP).

In an interim analysis, median progression-free survival was 40.7 months in the T-DXd/pertuzumab arm vs 26.9 months with THP (hazard ratio, 0.56). Overall survival data were immature at the time of the analysis. The T-DXd monotherapy arm remains blinded.

Given the strength of the results, breast oncologists have anticipated the approval — and that T-DXd/pertuzumab will likely replace THP as the new standard of care — since the trial was presented in June at the American Society of Clinical Oncology annual meeting and published in The New England Journal of Medicine in October.

As with THP, however, there will probably still be a role for maintenance therapy after initial treatment with T-DXd, breast medical oncologist Erika Hamilton, MD, told Medscape Medical News recently at the San Antonio Breast Cancer Symposium.

Currently, after upfront treatment with THP, patients enter a maintenance phase with trastuzumab and pertuzumab alone to avoid adverse events with ongoing, long-term chemotherapy.

The chemotherapy payload of T-DXd presents a similar dilemma, said Hamilton, of the Sarah Cannon Research Institute in Nashville, Tennessee. 

In the DB09 trial, grade 3 or higher adverse events with T-DXd/pertuzumab included neutropenia (23.9%), hypokalemia (10.2%), anemia (8.4%), fatigue (7.9%), thrombocytopenia (6.3%), and diarrhea, among others. Interstitial lung disease/pneumonitis occurred in 12.1% of patients in the combination arm.

The prescribing information includes warnings and precautions for neutropenia and left ventricular dysfunction, the FDA said.

Hamilton also noted that the way T-DXd is delivered — an intravenous (IV) infusion with close monitoring — makes long-term treatment problematic.

“I don’t think that there’s going to be an appetite to continue trastuzumab- deruxtecan indefinitely for patients,” she said. “I think that even if people are using DB09, there’s still going to be a desire for a maintenance strategy.”

The recommended T-DXd dose for cycle 1, day 1 is 5.4 mg/kg, followed by pertuzumab 840 mg. For subsequent cycles, the recommended T-DXd dose is 5.4 mg/kg, followed by pertuzumab 420 mg by IV infusion every 3 weeks.

M. Alexander Otto is a physician assistant with a master’s degree in medical science and a journalism degree from Newhouse. He is an award-winning medical journalist who worked for several major news outlets before joining Medscape Medical News. Alex is also an MIT Knight Science Journalism fellow. Email: aotto@mdedge.com.