"Practice-Changing" Trial Introduces New Standard of Care for Breast Cancer Patients 

Breast Cancer

A practice-changing therapy will redefine how doctors look at metastatic breast cancer.

At the American Society of Clinical Oncology (ASCO) annual meeting in June, AstraZeneca and Daiichi Sankyo introduced new data using Enhertu (fam-trastuzumab deruxtecan-nxki), an antibody-drug conjugate (ADC), in patients with HER2-low metastatic breast cancer with both hormone receptor-positive and negative disease. Patients were randomized to receive Enhertu or chemotherapy, and compared to chemotherapy alone, the use of Enhertu improves both progression-free survival and overall survival.

HER2 is a specific protein that makes breast cancer cells grow. The HER2 gene plays a large role in the development of breast cancer and is used to help inform oncologists about the best treatment practice. HER2-positive breast cancer is diagnosed in patients with HER2 protein overexpression or gene amplification. If there are low levels or no HER2 proteins found in the tumor sample, the patient would have a tumor with a HER2 negative diagnosis, meaning that treatment options will not include HER2-targeted therapy. 

Prior to the introduction of this drug, metastatic breast cancer was viewed as having a positive or negative expression of HER2. But now, there's a third option – HER2-low.

HER2-low will now be recognized as a distinction for breast cancer patients, as the work done in this study focused on Enhertu's effects on this patient population. These patients show a lower expression of that protein than would typically be seen in HER2-positive disease, but a higher expression than in HER2-negative.  

This means metastatic breast cancer patients who were previously categorized as HER2-negative may actually be HER2-low. An abstract of the trial published in the Journal of Clinical Oncology reports that “about 55%” of metastatic breast cancer patients "typically categorized as HER2-negative express low levels of HER2." 

Because of the success of the DESTINY-Breast04 clinical trial,  Enhertu is expected to be established as a new standard of care for HER2-low metastatic breast cancer patients, provided it receives FDA approval. 

Results Worthy of a Standing Ovation

Dr. Eleonora Teplinsky, M.D., a medical oncologist who specializes in breast and gynecologic cancer, has attended ASCO conferences for over a decade. She told BioSpace there had been discussions about a potential breakthrough in breast cancer therapies, but no one at the conference knew specific details until the plenary session where the results of the DESTINY-Breast04 study were presented. 

Dr. Shanu Modi, M.D., the lead study author, presented the results to the crowd of oncologists, researchers, patient advocates and industry professionals while the information was simultaneously published to the New England Journal of Medicine. Modi told oncologists at ASCO that this trial showed a "statistically significant and clinically meaningful benefit" in both progression-free survival and overall survival compared to standard-of-care treatment for metastatic breast cancer patients diagnosed with HER2-low cancer. 

"The results of DESTINY-Breast04 are practice-changing,” Modi said at the conference."This new standard of care can improve survival for about 50% of all patients diagnosed with metastatic breast cancer today." 

Teplinsky told BioSpace that this news will change the way HER2 is classified. Teplinsky

"When you look at the patients who have metastatic cancer,  we no longer are going to classify the tumor as HER2-negative. Now it's going to be negative, low or positive," she stated. 

The oncologists in the audience were so excited about the results; they gave a standing ovation when the session was complete. 

"The standing ovation was honestly incredible," Teplinsky said. "After having been virtual at ASCO for two years, just seeing the thousands of people in the room excited and just energized by these improved outcomes is really incredible."

Sermo, a physician-first online community, estimates that the DESTINY-Breast04 abstract was the most highly attended track of the conference with 79% of surveyed oncologists who expressed interest in breast cancer data in attendance. Nearly 60% of surveyed oncologists also found the breast cancer data from this year's ASCO conference to be the most practice-changing. 

The National Comprehensive Cancer Network (NCCN) also updated its breast cancer guidelines to reflect "compelling" data that supports the use of Enhertu in patients with HER2-low metastatic breast cancer. 

DESTINY-Breast04: Inside the Numbers

The DESTINY-Breast04 trial was the first Phase III clinical trial of a HER2-directed therapy in metastatic HER2-low breast cancer patients. 

The double-blind trial enrolled 557 patients in Asia, Europe and North America with HER2-low metastatic breast cancer who had been treated with one to two prior lines of chemotherapy. Patients were randomly assigned to the physician's choice of chemotherapy or Enhertu. The median duration of treatment with Enhertu was 8.2 months and 3.5 months with chemotherapy.

Researchers noted that both hormone receptor-positive and negative HER2-low patients treated with Enhertu showed increased progression-free survival and overall survival compared to the patients who had received chemotherapy. Patients treated with Enhertu showed a 49% reduction in risk of disease progression and a 36% reduction in risk of death compared to patients who received standard chemotherapy, ASCO reported

The median progression-free survival among all 577 patients was 9.9 months for the Enhertu group and 5.1 months for the group treated with the physician's choice of therapy. Overall survival was 23.4 months for Enhertu patients, compared to 16.8 months for all other patients. 

Enhertu is currently FDA-approved to treat adults with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen or "in the neoadjuvant setting and have developed disease recurrence during or within six months of completing therapy." 

Hormone Receptors--An Additional Consideration

Estrogen and progesterone receptors also play a part in breast cancer diagnosis and treatment. Hormone receptor-positive cancers include one or both of the receptors that estrogen and progesterone attach to that stimulate cancer to spread. If the cancer does not have estrogen or progesterone receptors, it is called hormone receptor-negative. 

Of the 577 patients included in the randomized trial, 494 (88.7%) had hormone receptor-positive disease, and 63 (11.3%) had hormone receptor-negative disease. 

The hormone receptor-positive cohort saw a median progression-free survival of 10.1 months if treated with Enhertu, compared to 5.4 months for patients treated with chemotherapy. Overall survival was 23.9 months for Enhertu patients and 17.5 months for chemotherapy patients. 

Exploratory analysis of the trial data found that median progression-free survival was 8.5 months for the hormone receptor-negative subgroup treated with Enhertu compared to 2.9 months for hormone receptor-negative patients treated with standard therapies. Patients treated with Enhertu had a median overall survival rate of 18.2 months, compared to 8.3 months for patients treated with chemotherapy, ASCO reported.

"We're really excited about this data, and a lot of patients will benefit," Teplinsky said, adding that the improvement in survival for these patients is "really, really remarkable." 

Looking to the Future

By adding HER2-low expression to the previous HER2-positive or -negative binary, this study has effectively redefined how breast cancer is classified. This means that the population of patients who may be able to benefit from HER2-targeted therapy will expand and treatment options will change. 

Teplinsky said it's necessary to start thinking about new ways to look at HER2 and consider how oncologists might maximize drugs and responses. 

There is a DESTINY-Breast06 trial ongoing to "evaluate the efficacy, safety and tolerability" of Enhertu compared with chemotherapy in advanced breast cancer patients with tumors that are HER2-low and hormone receptor positive.

Back to news