The use of trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca), a new HER2-targeting antibody-drug conjugate, doubled progression-free survival (PFS) compared to standard-of-care treatment with conventional chemotherapy.
This conclusion is based on the results of the DESTINY-Breast04 study, funded by Daiichi Sankyo and AstraZeneca, which demonstrated 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 hybridization (ISH)-negative) unresectable and/or metastatic breast cancer, regardless of hormone receptor status (HR positive or HR negative disease), versus standard of care physician’s choice of chemotherapy.
The results of the study were presented at the annual meeting of the American Society of Clinical Oncology (ASCO), held June 3 – 7, 2022. The study results were simultaneously published in The New England Journal of Medicine (NEJM) 
The study findings are significant in that they help identify a new subset of breast cancer – called HER2-low – redefining how a large proportion of metastatic patients will be treated, and, as a results are considered practice-changing.
Antibody-drug Conjugates (ADC) are highly targeted and empowered antibodies (mAbs) designed to harness the targeting ability of monoclonal antibodies by linking them to cell-killing agents. Trastuzumab deruxtecan (T-DXd; previously known as DS-8201a) is a new ADC that links trastuzumab, a HER2 monoclonal antibody, to deruxtecan, a topoisomerase I inhibitor that interrupts DNA replication in cancer cells. The antibody trastuzumab (Herceptin®; Genentech/Roche) has been proven to be effective in cancers with high HER2 expression (called HER2-positive breast cancer) but not in cancers with low HER2 expression levels, hence trastuzumab has only been available for a subset of breast cancer patients.
In the DESTINY-Breast04 study, patients received either standard chemotherapy of the physicians’ choice (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel), or trastuzumab deruxtecan.
The primary endpoint analyses for patients with cancers that were HER2-low and hormone receptor positive (HR+), demonstrated a 49% reduction in the risk of disease progression or death, nearly doubling the results for trastuzumab deruxtecan vs. physician’s choice of chemotherapy (hazard ratio [HR] = 0.51; 95% confidence interval [CI]: 0.40-0.64; p<0.001).
A median Progression Free Survival (PFS) of 10.1 months (9.5-11.5) was seen in patients treated with trastuzumab deruxtecan compared to 5.4 months (4.4-7.1) with chemotherapy, as assessed by blinded independent central review (BICR).
The secondary endpoint of OS was also significantly better in the HER2-low, HR+ subgroup of patients who received trastuzumab deruxtecan compared to standard therapy. These results demonstrated a 36% reduction in the risk of death with trastuzumab deruxtecan compared to chemotherapy in patients with HR positive disease (HR = 0.64; 95% CI: 0.48-0.86; p=0.003) with a median OS of 23.9 months with trastuzumab deruxtecan (95% CI: 20.8-24.8) versus 17.5 months with chemotherapy (95% CI: 15.2-22.4).
Confirmed objective response rate (cORR) more than tripled in the trastuzumab deruxtecan arm versus the chemotherapy arm (52.6% [n=175/333; 95% CI: 47.0-58.0%] versus 16.3% [n=27/166; 95% CI: 11.0-22.8%], respectively).
Twelve (3.6%) complete responses (CR) and 164 (49.2%) partial responses (PR) were observed in patients with HR positive disease treated with trastuzumab deruxtecan compared to one (0.6%) CR and 26 (15.7%) PRs in those treated with chemotherapy. Median duration of response was 10.7 months for trastuzumab deruxtecan versus 6.8 months for chemotherapy.
Treatment-related adverse events were fewer in the trastuzumab deruxtecan group than in patients who received standard chemotherapy (52.6% vs 67.4%). This is consistent with previous clinical trials of these drugs. No new safety concerns were identified.
“Our study shows that trastuzumab deruxtecan may be a new and highly effective targeted therapy option available for this newly defined patient population,” noted lead author Shanu Modi, MD, who is a medical oncologist at Memorial Sloan Kettering Cancer Center in New York and principal investigator for the trial.
“The DESTINY-Breast04 study results 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,” he added.
“It is important for patients to know what level of HER2 their cancer expresses, not just whether it’s positive or negative, especially as HER2-low status can be determined using commonly available tests,” Modi added.
“The efficacy seen with trastuzumab deruxtecan 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,” he concluded.
HER2 expression is determined by a test that measures the amount of HER2 protein on a cancer cell and/or a test that counts the copies of the HER2 gene in cancer cells.
An estimated 290,560 new cases of breast cancer will be diagnosed in the United States in 2022. Of those people who receive a diagnosis of the most aggressive form of the disease, metastatic breast cancer, approximately 15-20% of such cancers will be considered HER2 positive and would be eligible to be treated with HER2-targeted therapies.
The remaining 80% or so of metastatic breast cancers are currently categorized as HER2-negative, and of these cancers, approximately 55-60% express low levels of HER2.
About the Study
DESTINY-Breast04, a double-blind phase III 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 for metastatic disease. Participants were randomly assigned, on a two-to-one basis, to either trastuzumab deruxtecan or the physician’s choice of several standard chemotherapy drugs.
All participating patients in DESTINY-Breast04 received at least one prior cancer therapy, including targeted therapy (trastuzumab deruxtecan = 279; chemotherapy = 140), a CDK4/6 inhibitor (trastuzumab deruxtecan = 239; chemotherapy = 119), endocrine therapy (trastuzumab deruxtecan = 347; chemotherapy = 165), chemotherapy (trastuzumab deruxtecan= 373; chemotherapy = 183). The median lines of prior systemic therapies in the metastatic setting were three (range 1-9). A prior CDK4/6 inhibitor was received by 70% of hormone receptor positive patients (trastuzumab deruxtecan = 233/331; chemotherapy = 115/163). As of data cut-off on January 11, 2022, 58 patients remained on treatment with trastuzumab deruxtecan and 3 patients on chemotherapy.
The primary endpoint was PFS in patients with HR+ disease. Key secondary endpoints included PFS for all patients (both HR+ and HR- disease) as well as OS in all patients and those with HR+ disease. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of patients with HR-negative disease.
Trastuzumab deruxtecan is already approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received prior anti-HER2-based treatment.
On April 27, 2022, the United States Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for trastuzumab deruxtecan in HER2-low metastatic breast cancer. 
Use of trastuzumab deruxtecan is currently being studied in patients with HER2-low metastatic breast cancer in several ongoing studies, several of which are exploring the minimum HER2-expression threshold required for trastuzumab deruxtecan activity.
Trastuzumab Deruxtecan (DS-8201a) Versus Investigator’s Choice for HER2-low Breast Cancer That Has Spread or Cannot be Surgically Removed [DESTINY-Breast04] – NCT03734029
 Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol 40, 2022 (suppl 17; abstr LBA501) | DOI 10.1200/JCO.2022.40.17_suppl.LBA501
 Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jun 5. doi: 10.1056/NEJMoa2203690. Epub ahead of print. PMID: 35665782.
 NCI SEER cancer statistics. Online. Last accesses on June 2, 2022.
 FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. Online. Last accesses on June 2, 2022.
Featured image: 2022 ASCO Annual Meeting, General Views during the meeting – Physicians, researchers, and health care professionals from over 100 countries are attending the 58th ASCO Annual Meeting. Photo courtesy: © 2022 ASCO/Todd Buchanan. Used with permission.