Antibody-drug targeting HER2 improves progression-free survival in women with fatal form of advanced breast cancer

A study by researchers at UCLA Jonsson Comprehensive Cancer Center found that treating women with HER2-positive metastatic breast cancer with the HER2-targeting antibody-drug conjugate trastuzumab deruxtecan (T-DXd) significantly prolongs the duration of of disease control and cancer growth is arrested compared to the current standard treatment, trastuzumab emtansine (T-DM1).

The drug T-Dxd is made up of a targeted HER2 monoclonal antibody that delivers high concentrations of chemotherapy directly to cancer cells that have HER2 on their surface. Patients who received the drug had a 72% improvement in progression-free survival compared to T-DM1.

Compared to 12 months, 76% of patients treated with T-DXd had not yet seen their disease progress, which means that their disease remained under control. For those treated with T-DM1, only 34% of patients did not see their disease progress by 12 months.

“It was a really substantial difference between the two treatment arms,” ​​said lead author Dr Sara Hurvitz, director of the clinical breast cancer research program at the Comprehensive Cancer Center of the. UCLA Jonsson. “These data are simply phenomenal and will change practice.”

The results (LBA1) of the clinical trial are presented at the Presidential Symposium of the Congress of the European Society of Medical Oncology (ESMO). This is the first phase III trial to report a comparison of the safety and efficacy of T-Dxd versus standard treatment in metastatic breast cancer.

Currently, the standard first-line treatment for patients with HER2-positive metastatic breast cancer is HER2 antibody therapy with pertuzumab / trastuzumab, plus chemotherapy. If the cancer progresses, the standard treatment is to switch to T-DM1, which is an antibody-drug conjugate made up of trastuzumab and chemotherapy.

Up to 20% of breast cancers are classified as HER2 positive, which means the tumor has extra copies of the HER2 gene and too much HER2 protein on the cell surface, which in turn causes the cancer to behave more aggressively. , which leads to worse outcomes, including a higher risk of metastasis or spread throughout the body. The development of treatments targeting HER2 such as trastuzumab, pertuzumab and T-DM1 have dramatically improved the outcomes, including survival, associated with this disease. However, the majority of patients with advanced disease will experience resistance and disease progression despite these targeted therapies.

Promising new drugs have emerged as effective options for these patients, including T-DXd, which received expedited approval by the U.S. Food and Drug Administration in 2019 for patients with HER2 breast cancer. -positive unresectable or metastatic who have received at least two anti- HER2-based regimens in the metastatic setting. This approval was based on a smaller, non-comparative trial, DESTINY-Breast01, which showed very promising efficacy in patients whose disease progressed after T-DM1.

The results of the recently published clinical trial, called DESTINY-Breast03, show that T-DXd is significantly better than T-DM1 when used after a patient’s disease has progressed on trastuzumab and chemotherapy.

“T-DM1 became the standard second-line treatment in 2013 and is the first antibody-drug conjugate approved by the FDA. It has a strong safety and efficacy profile, ”said Hurvitz, who is also a professor of medicine at the David Geffen School. of medicine at UCLA. “In the past eight years, we haven’t seen any other therapy try to beat it in a controlled trial. To see a new therapy demonstrate such a substantial improvement in progression-free survival over T-DM1 is really exciting for us. patients. “

The DESTINY-Breast03 trial included 524 patients who were randomized to the T-DXd arm or the T-DM1 comparator arm. The median age of the participants was 54 years old and ranged from 20 to 83 years old. All were previously treated with trastuzumab and chemotherapy before starting the clinical trial.

Along with longer progression-free survival in the T-DXd arm, nearly 80% of patients saw their tumors shrink compared to only 34% treated with T-DM1. And 16% of patients treated with T-DXd saw their illnesses go away completely.

The safety profile was consistent with other data reported for T-DXd. Treatment-related interstitial lung disease was observed in 10.5% of patients, most (9.7%) being classified as grade 1/2. No treatment-related Grade 4/5 interstitial lung disease events were observed and no drug-related deaths occurred in either arm.

The next step is to study T-DXd in the first-line metastatic setting and at the early stage of the disease. At UCLA’s Jonsson Comprehensive Cancer Center, Hurvitz is studying the effectiveness of T-DXd, alone or in combination with antiestrogen therapy, in treating patients with low HER2 hormone receptor positive breast cancer. (NCT04553770).

The other investigators are Javier Cortés, Sung-Bae Kim, Wei-Pang Chung, Seock-Ah Im, Yeon Hee Park, Roberto Hegg, Min-Hwan Kim, Ling-Ming Tseng, Vanessa Petry, Chi-Feng Chung, Hiroji Iwata, Erika Hamilton, Giuseppe Curigliano, Binghe Xu, Caleb Lee, Yali Liu, Jillian Cathcart, Emarjola Bako and Sunil Verma.