Among patients with high-risk, HER2-positive primary breast cancer with residual invasive disease following neoadjuvant therapy, treatment with Enhertu (fam-trastuzumab deruxtecan-nxki; T-DXd) was associated with a statistically significant and clinically meaningful improvement in invasive disease–free survival (IDFS) versus Kadcyla (ado-trastuzumab emtansine; T-DM1), clinical trial results have shown.
Interim analysis findings from the phase 3 DESTINY-Breast05 trial were presented at the 2025 ESMO Congress.
Treatment with Enhertu (818 patients) led to a 53% reduction in the risk of invasive disease or death compared with Kadcyla (817 pstients). The three-year IDFS rates were 92.4% with Enhertu versus 83.7% with Kadcyla.
Glossary
Glossary:
·Invasive Disease–Free Survival (IDFS): the time a patient lives without the original cancer returning, without a new invasive cancer appearing, and without dying from any cause.
·Overall Survival (OS): the total length of time, usually measured from diagnosis or the start of treatment, that a patient is still alive.
·ECOG Performance Status (PS): a simple scale doctors use to measure how a patient's cancer is affecting their daily energy and ability to perform routine activities.
·Interstitial Lung Disease (ILD): a general term for a group of chronic lung disorders that cause inflammation and scarring of the lung tissue, which can make it hard to breathe.
·Distant Recurrence-Free Survival: the time a patient lives after treatment without the cancer coming back in a part of the body far away from the original tumor site.
·Radiation Pneumonitis: a side effect that causes inflammation and irritation of the lungs, typically occurring weeks to months after receiving radiation therapy to the chest area.
·Anemia: a common condition where the blood doesn't have enough healthy red blood cells to carry adequate oxygen from your lungs to the rest of your body, often leading to fatigue.
·Increased Aspartate Aminotransferase Levels (AST): a finding on a blood test that shows a higher-than-normal amount of the AST enzyme, which is often a sign of damage or irritation to the liver or other organs like muscle or heart.
·Increased Alanine Aminotransferase Levels (ALT): a finding on a blood test that shows a higher-than-normal amount of the ALT enzyme, which is a common indicator of liver injury or inflammation.
·Arthralgia: the medical term for pain or stiffness experienced in one or more joints, such as the knees, elbows, or wrists.
“Patients benefited [from Enhertu] irrespective of age cohorts, region of accrual, hormone receptor status, disease status at presentation, post-therapy pathologic nodal status and dual or single HER2-targeted therapy, as well as irrespective of the sequence or usage of radiation therapy for that minority of patients who did not receive [radiation] treatment,” Dr. Charles E. Geyer Jr. said in the presentation.
Geyer is a professor of medicine and chief of the Division of Malignant Hematology and Medical Oncology at the University of Pittsburgh Medical Center Hillman Cancer Center.
What Was the Rationale for DESTINY-Breast05?
Previously, the phase 3 KATHERINE trial showed that Kadcyla improved IDFS and overall survival compared with Herceptin (trastuzumab) in patients with HER2-positive early breast cancer with residual invasive disease after neoadjuvant therapy. However, patients with advanced locoregional disease or positive nodal status following neoadjuvant therapy had three-year IDFS rates of 76% and 83%, respectively; the seven-year IDFS rates were 67% and 72%, respectively. These data reinforce the unmet need for improved post-neoadjuvant treatment in this population, Geyer emphasized.
What Was the Design of DESTINY-Breast05?
This global, multicenter, randomized, open-label trial enrolled patients with residual invasive disease in the breast and/or axillary lymph nodes after neoadjuvant chemotherapy with a HER2-directed therapy. Patients needed to present with high-risk disease prior to neoadjuvant therapy, defined as inoperable early breast cancer or operable early breast cancer with axillary node–positive disease after neoadjuvant therapy. Patients also needed to have centrally confirmed HER2-positive disease and an ECOG performance status of 0 or 1. Enrolled patients were stratified by extent of disease at presentation (inoperable versus operable), type of HER2-targeted neoadjuvant therapy received (single versus dual), hormone receptor status (positive versus negative), and post-neoadjuvant therapy pathologic nodal status (positive versus negative).
Patients were randomly assigned to receive intravenous (IV) Enhertu at 5.4 mg/kg every three weeks for 14 cycles, or IV Kadcyla at 3.6 mg/kg every three weeks for 14 cycles. Treatment was followed by a 40-day safety follow-up period.
Notably, concomitant adjuvant endocrine therapy was allowed per local practice protocols. Additionally, radiotherapy, if administered, could be initiated concurrently with study therapy or completed prior to the initiation of study therapy per the investigator. An interstitial lung disease (ILD) monitoring program was required for patients who received radiotherapy.
IDFS served as the primary end point, with disease-free survival (DFS) as a key secondary end point. Other secondary end points included OS, distant recurrence–free interval (DRFI), brain metastasis–free interval (BMFI) and safety.
What Did the DESTINY-Breast05 Patient Population Look Like?
In total, 1635 patients were randomly assigned to receive Enhertu (818 patients) or Kadcyla (817 patients). In the Enhertu arm, 806 patients received treatment. A total of 27.7% of patients in this arm discontinued treatment due to side effects (17.9%), patient withdrawal (7.4%), disease recurrence (0.2%), physician decision (1.9%) and protocol deviation (0.2%). In total, 72.3% of patients in this arm completed study treatment, and the median study duration was 29.9 months.
In the Kadcyla arm, 801 patients received treatment. A total of 23.7% of patients in this arm discontinued treatment due to side effects (12.7%), patient withdrawal (6.2%), disease recurrence (3.7%), physician decision (0.6%), protocol deviation (0.1%) and other reasons (0.1%). In total, 76.3% of patients in this arm completed study treatment, and the median study duration was 29.7 months.
In the Enhertu arm, the median age was 50.3 years, Asian patients were the most predominant race (48.8%), and most patients had HER2 3+ disease by immunohistochemistry (IHC) (82.6%), hormone receptor–positive disease (71%), inoperable disease (52.7%), positive nodal status (80.7%), received dual HER2-targeted therapy with Herceptin plus Perjeta (pertuzumab) (77.9%), prior anthracycline use (51.7%) and received prior adjuvant radiotherapy (93.4%). In the Kadcyla arm, the median age was 50.6 years, Asian patients were the most predominant race (47.2%), and the highest proportions of patients had HER2 3+ disease by IHC (82.%), hormone receptor–positive disease (71.4%), inoperable disease (51.9%), positive nodal status (80.5%), received dual HER2-targeted therapy with Herceptin plus Perjeta (78.5%), prior anthracycline use (48.8%), and received prior adjuvant radiotherapy (92.9%).
