Blockbuster Drug Gets Breast Cancer Approvals in Curative Setting

The FDA on Friday approved two new trastuzumab deruxtecan (T-DXd; Enhertu) indications for treating early-stage breast cancer patients with HER2-positive disease.

In the neoadjuvant setting, the first indication is for stage II-III tumors and covers treatment with T-DXd followed by a taxane, trastuzumab (Herceptin), and pertuzumab (Perjeta), or THP.

And in the adjuvant setting, the second indication covers use of the antibody-drug conjugate for patients with residual invasive disease following neoadjuvant treatment with a taxane and trastuzumab (with or without pertuzumab).

The DESTINY-Breast11 (neoadjuvant) and DESTINY-Breast05 (adjuvant) trials supported the new indications.

In the neoadjuvant study, T-DXd followed by THP led to a pathologic complete response (pCR) rate of 67.3%, significantly better than the 56.3% pCR rate with dose-dense doxorubicin and cyclophosphamide followed by THP (P=0.003).

In the adjuvant study, T-DXd outperformed trastuzumab emtansine (Kadcyla) by improving invasive disease-free survival. At 3 years, 92.4% of patients assigned to T-DXd were alive and without invasive disease versus 83.7% of those randomized to trastuzumab emtansine (HR 0.47, 95% CI 0.34-0.66, P<0.0001).

FDA also approved two companion diagnostics to identify eligible patients.

“HER2-positive breast cancer is an aggressive disease, and our goal is to reduce the risk of recurrence for patients as early as possible to achieve the best long-term outcomes,” DESTINY-Breast11 investigator Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center in New York City, said in a press release from drugmaker AstraZeneca and Daiichi Sankyo.

“The neoadjuvant setting offers the earliest opportunity to improve outcomes, while the adjuvant setting provides another important chance to prevent recurrence for patients with residual disease after surgery,” she added. “These two new indications in HER2-positive early breast cancer will evolve how we treat patients in these settings and support trastuzumab deruxtecan as a potential new standard of care in early-stage disease.”

No new safety concerns were identified in the trials. The drug has an existing boxed warning for interstitial lung disease and pneumonitis. Risks for neutropenia and left ventricular dysfunction are also detailed in the warnings and precautions of the prescribing information.

Common adverse events with T-DXd in early breast cancer included diarrhea; alopecia; fatigue; decreases in hemoglobin, white blood cell counts, neutrophils, lymphocytes, blood potassium, and appetite; increases in alanine aminotransferase and aspartate aminotransferase; nausea and vomiting; peripheral neuropathy; rash; musculoskeletal pain; constipation; and stomatitis.

T-DXd is also approved for patients with HER2-positive metastatic breast cancer, locally advanced or metastatic gastric cancer, and unresectable or metastatic solid tumors. The antibody-drug conjugate also carries indications for HER2-low/ultralow metastatic breast cancer and HER2-mutant unresectable or metastatic non-small cell lung cancer.