Enhertu Lowers Risk of Disease Progression, Death by 50% in HER2-Low Metastatic Breast Cancer

Treatment with trastuzumab deruxtecan (Enhertu; AstraZeneca and Daiichi Sankyo) produced superior and clinically meaningful progression-free survival (PFS) and overall survival (OS) in previously treated patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in-situ hybridisation [ISH]-negative) unresectable and/or metastatic breast cancer with hormone receptor (HR) positive or HR-negative disease compared with standard of care physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in the pivotal phase 3 DESTINY-Breast04 trial.

The results of the trial were presented during a Plenary Session today at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and also published in The New England Journal of Medicine.

The global, randomized, open-label, registrational DESTINY-Breast04 trial analyzed the efficacy and safety of trastuzumab deruxtecan compared with chemotherapy in patients with HR-positive or HR-negative HER2-low unresectable and/or metastatic breast cancer previously treated with 1 or 2 prior lines of chemotherapy. The trial randomized approximately 557 patients at multiple sites 2:1 to receive either trastuzumab deruxtecan or chemotherapy.

In the primary endpoint analysis of the trial, trastuzumab deruxtecan showed a 49% decrease in the risk of disease progression or death compared with physician’s choice of chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive disease (PFS hazard ratio [HR] 0.51; 95% confidence interval [CI]: 0.40-0.64; p<0.001). The investigators observed a median PFS of 10.1 months in patients administered trastuzumab deruxtecan versus 5.4 months with chemotherapy, as assessed by blinded independent central review (BICR).

“The results of DESTINY-Breast04 show for the first time that a HER2-directed therapy can provide a survival benefit to patients with low HER2 expression, indicating we must reconsider the way we categorize patients with metastatic breast cancer,” DESTINY-Breast04 principal investigator Shanu Modi, MD, medical oncologist, Memorial Sloan Kettering Cancer Center, said in a press release. “The efficacy seen with Enhertu also reinforces the potential to establish a new standard of care for more than half of all patients with breast cancer currently categorized as having HER2-negative disease, but who actually have tumors with low HER2 expression.”

Treatment with trastuzumab deruxtecan also produced a 36% decrease in the risk of death versus chemotherapy in patients with HR-positive disease (OS HR 0.64; 95% CI: 0.48-0.86; p=0.003), with a median OS of 23.9 months compared with 17.5 months in patients administered chemotherapy, which achieved a key secondary endpoint of DESTINY-Breast04. The investigators also observed consistent efficacy with trastuzumab deruxtecan in the overall trial population of patients with HER2-low metastatic breast cancer with HR-positive or HR-negative disease and across levels of HER2 expression (IHC 1+ and IHC 2+/ISH-).

In a key secondary endpoint analysis of PFS by BICR among all patients, the investigators observed a similar 50% decrease in the risk of disease progression or death between trastuzumab deruxtecan and chemotherapy (PFS HR 0.50; 95% CI: 0.40-0.63; p<0.001).

Data also showed a 36% decrease in the risk of death with trastuzumab deruxtecan versus chemotherapy (OS HR 0.64; 95% CI: 0.49-0.84; p=0.001), with a median OS of 23.4 months compared with 16.8 months in the chemotherapy cohort.

Trastuzumab deruxtecan is a specifically designed human epidermal growth factor receptor 2 (HER2)-directed antibody drug conjugate that was granted a full approval last month for adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer who were previously administered an anti–HER2-based regimen in the metastatic setting, in the neoadjuvant setting, or adjuvant setting, and who developed disease recurrence during or within 6 months of completing therapy.

In December 2019, the FDA granted trastuzumab deruxtecan an accelerated approval for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer previously administered 2 or more prior anti–HER2-based regimens in the metastatic setting. In April 2022, the FDA granted trastuzumab deruxtecan Breakthrough Therapy Designation for the treatment of patients with HER2-low metastatic breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy.

“Today’s results represent a pivotal moment demonstrating the potential for Enhertu to redefine the treatment of HER2-targetable cancers,” Susan Galbraith, executive vice president, Oncology R&D, AstraZeneca, said in a press release. “DESTINY-Breast04 validates targeting the lower end of the spectrum of HER2 expression, since Enhertu reduced the risk of disease progression or death across all types of patients in the trial by half, and reduced the risk of death by over a third. We must now evolve the way we classify and treat metastatic breast cancer to ensure these patients are effectively diagnosed and treated.”

Reference

Enhertu reduced the risk of disease progression or death by 50% vs. chemotherapy in patients with HER2-low metastatic breast cancer with HR-positive and HR-negative disease. AstraZeneca. News release. June 5, 2022. https://www.astrazeneca.com/media-centre/press-releases/2022/enhertu-efficacy-results-in-her2-low-breast-cancer.html