Trastuzumab Deruxtecan Wins Rapid Approval for HER2-Low Breast Cancer

The FDA on Friday approved trastuzumab deruxtecan (Enhertu) as the first targeted therapy to treat adult patients with unresectable or metastatic HER2-low breast cancer (immunohistochemistry [IHC] 1+ or IHC 2+/ISH-) in the metastatic setting, if patients have received prior chemotherapy or their disease returns within 6 months of receiving adjuvant chemotherapy.

The approval came exactly 2 months after results from the landmark DESTINY-Breast04 trial brought the crowd to its feet during the plenary session of the American Society of Clinical Oncology, as Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center presented results showing that the specially engineered antibody drug conjugate reduced the risk of disease progression or death by 50% compared with chemotherapy for HER2-low patients with both hormone receptor (HR)-positive and HR-negative disease.

Trastuzumab deruxtecan, jointly developed by Daiichi Sankyo and AstraZeneca, is among a group of therapies known as antibody-drug conjugates (ADCs), which connect monoclonal antibodies to tumor cells with a “linker,” causing a more targeted and potent effect on cancer. In this case, the well-known trastuzumab, which binds to HER2 receptors, works with deruxtecan to become embedded in the cancer cell, disrupting the cell’s DNA and leading to cell death.

The therapy was already approved to treat certain unresectable or metastatic HER2-positive breast cancer or gastric cancers.

FDA had granted trastuzumab deruxtecan breakthrough therapy status in this indication in April and granted Priority Review status on July 25, 2022 under the Real-Time Oncology Review Program; the original approval date was not scheduled until the fourth quarter of 2022. But as both FDA and Modi noted in their respective statements, this approval has the potential to reach a large number of patients—FDA estimated that about 143,000 patients per year are diagnosed with breast cancer previously classified as HER2-negative that can now be considered HER2-low.

“Approximately half of all patients with breast cancer have tumors that are HER2-low, which have previously been classified as HER2-negative and have not had effective treatment options with HER2-targeted medicines,” Modi said in her statement. Based on DESTINY-Breast04, “Clinicians are starting to differentiate levels of HER2 expression and redefine how metastatic breast cancer is classified with a distinct HER2-low patient population that may be eligible for trastuzumab deruxtecan.”

Data from DESTINY-Breast04 showed:

• Patients treated with trastuzumab derruxtecan had a median progression-free survival of 9.9 months vs 5.1 months for chemotherapy; for a hazard ratio [HR] 0.50; 95% CI 0.40-0.63; P < .0001).
• Results showed a median overall survival (OS) of 23.4 months for patients treated with trastuzumab deruxtecan vs 16.8 months for those treated with chemotherapy, for a 36% reduction in the risk of death (HR 0.64; 95% CI 0.49-0.84; P = .001).

Experts have described DESTINY-Breast04 as “historic” and “game-changing,” as the findings will not only change breast cancer treatment but also pathology, since tumors will now be classified differently—but this will present some challenges.

“It comprises about 55% of our advanced breast cancer patients,” Debra Patt, MD, PhD, MBA, executive vice president of Texas Oncology, said in a recent interview with The American Journal of Managed Care^®. “We need to make sure that IHC is being done by pathology. Also, IHC is a little bit tricky and can have interoperator variability. So, we need to make sure that we work with our pathologists to identify those that are IHC1+, IHC2+ and FISH [fluorescence in situ hybridization]-negative. This means working closely with our pathologist to identify this patient population.

“The rapid approval of Enhertu in HER2-low metastatic breast cancer by the FDA underscores the urgency to bring this transformational medicine to patients as quickly as possible,” Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, said in the statement. “Patients with HER2-low tumors, who are identified through existing HER2 testing methods, will now have the opportunity to be treated based upon their HER2 status.”