This week the U.S. Food and Drug Administration (FDA) approved fam-trastuzumab deruxtecan-nxki (Enhertu®; Daiichi Sankyo and AstraZeneca)*, a HER2 directed antibody-drug conjugate or ADC, for the treatment of adult patients with advanced, unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based treatments in the metastatic setting.
Antibody-drug Conjugates or ADCs are highly targeted biopharmaceutical drugs that combine monoclonal antibodies specific to surface antigens present on particular tumor cells with highly potent anti-cancer agents linked via a chemical linker.
With seven approved drugs on the market, ADCs have become a powerful class of therapeutic agents in oncology and hematology.
The approval trastuzumab deruxtecan in the United States comes less than a week after the results of DESTINY-Breast01 clinical trial (NCT03248492), a pivotal phase II, single-arm, open-label, global, multicenter, two-part trial funded by Daiichi Sankyo and AstraZeneca, were presented at the 2019 San Antonio Breast Cancer Symposium (SABCS).
The data presented during the SABCS meeting was simultaneously published online in The New England Journal of Medicine (NEJM). The results demonstrated impressive, clinically meaningful and durable anti-tumor responses among the intended group of pretreated HER2-positive metastatic breast cancer patients. 
Targeted anti-cancer drug
Trastuzumab deruxtecan, formerly known as DS-8201, is a targeted anti-cancer drug that delivers a novel topoisomerase I inhibitor payload to cancer cells via a cleavable tetrapeptide-based linker attached to a monoclonal antibody. The antibody binds to specific HER2 targets expressed on cancer cells. The newly approved antibody-drug conjugates uses Daiichi Sankyo’s proprietary DXd ADC technology.
Trastuzumab deruxtecan was designed to improve on the most critical attributes of currently available antibody-drug conjugates such as trastuzumab emtansine. However, in contrast to trastuzumab emtansine, trastuzumab deruxtecan has a higher drug-to-antibody ratio, known as DAR (approximately 8 vs. 3 to 4), while, at the same time, retaining a favorable pharmacokinetic profile.
In addition, the proprietary tetrapeptide-based linker, which is selectively cleaved by cathepsins that are up-regulated in tumor cells, is stable in plasma.
Peptide-based linkers belong to protease-sensitivity linkers, also known as enzymatically cleavable linkers. Due to their superior plasma stability and controlled payload release mechanism, these type of linkers have become important in the development of antibody-drug conjugates. Peptide linkers, including tetrapeptide-based linkers, are recognized and cleaved by lysosomal enzymes to ensure intracelluar drug release once the ADC is internalized and trafficked to the lysozome.
Unlike trastuzumab emtansine, trastuzumab deruxtecan has a payload that, when release, easily crosses the cell membrane, which potentially allows for a potent cytotoxic effect on neighboring tumor cells regardless of target expression (also known as ‘bystander effect’). In addition, the released payload has a short half-life, which is designed to minimize unwanted systemic exposure.
Trastuzumab deruxtecan is approved under the FDA’s accelerated approval based on tumor response rate and duration of response. In essence, this means that continued approval for this indication may be contingent upon further verification and description of clinical benefit in a confirmatory trial.
HER2 positive cancer
Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells.  HER2-positive breast cancer is a type of breast cancer that tests positive for a protein called, which promotes the growth of cancer cells.
HER2 became clinically relevant after scientists understood that HER2-positive breast cancers has a worse prognosis than HER2-negative tumors. Furthermore, ongoing research demonstrated that HER2-positive breast cancer had a distinctive molecular signature. This includes extensive changes in the patterns of gene expression that distinguish these cancers from other types of breast cancer. These cancers also have distinctive clinical features.
To be considered HER2 positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+.7 A finding of IHC 3+ and/or FISH amplification is considered positive.
Approximately one in five breast cancers are HER2 positive.  Overexpression of HER2 has shown to be is an adverse prognostic factor associated with poorly differentiated, high-grade tumors, high rates of cell proliferation and lymph-node involvement. HER2-positive breast cancer has also demonstrated to be relative resistant to certain types of chemotherapy.
Advances in drug development
Despite recent improvements and approvals of new medicines, there remain significant clinical needs for patients with HER2-positive metastatic breast cancer. However, this disease remains incurable with patients eventually progressing after available treatment.8]
Commenting on the progress, Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research., noted: “There have been many advances in the development of drugs for HER2-positive breast cancer since the introduction of trastuzumab (Herceptin®; Genentech/Roche) in 1998.”
Trastuzumab is a humanized monoclonal antibody against HER2. The drug was created by inserting portions of the antigen-binding site of a mouse monoclonal antibody against HER2 into a human monoclonal antibody. Scientists developed the drug after recognizing that HER2 overexpression served as both a marker of aggressive disease and a target for treatment.
However, Padzur pointed out that approval of trastuzumab deruxtecan represents the newest treatment option for patients who have progressed on available HER2-directed therapies.
“Drug development in the area of targeted therapies builds on our scientific understanding of malignant diseases not only in breast cancer, but in multiple other diseases,” he added.
Understanding HER2 and the history of the development of treatment options with trastuzumab was considered a triumphal story of translational research. However, while beneficial, major unmet medical needs remained, and more targeted
The DESTINY-Breast01 trial evaluated the safety and efficacy of trastuzumab deruxtecan (5.4 mg/kg) monotherapy in 184 patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche).
Patients enrolled in trial received a median of five prior regimens (range: 2 -17) in the locally advanced/metastatic setting. All patients received prior trastuzumab, trastuzumab emtansine, and 66% had received a prior treatment with pertuzumab.
The primary endpoint of the trial was objective response rate, as determined by independent central review, with secondary objectives including pharmacokinetics, duration of response (DoR), disease control rate (DCR), clinical benefit rate, progression-free survival (PFS), overall survival (OS) and safety.
Trial results showed a confirmed objective response rate (ORR) of 60.3% (n=111; 95% CI: 52.9-67.4), including a 4.3% complete response rate (n=8) and a 56.0% partial response rate (n=103). A median duration of response of 14.8 months (95% CI: 13.8-16.9) was demonstrated as of August 1, 2019. In addition, a median progression free survival of 16.4 months (95% CI: 12.7-Not Estimable), based on a median follow-up of 11.1 months.
In addition to nausea and myelosuppression, interstitial lung disease (ILD) was observed in a subgroup of 9% of patients (a fatal outcome due to ILD and/or pneumonitis occurred in 2.6%; n=6). Median time to first onset was 4.1 months (range: 1.2 to 8.3). As a result, treatment and requires attention to pulmonary symptoms and careful monitoring for potential signs and symptoms.
Overall, the most common adverse reactions (frequency ≥20%) were nausea, fatigue, vomiting, alopecia, constipation, decreased appetite, anemia, neutropenia, diarrhea, leukopenia, cough and thrombocytopenia.
Potential Standard of Care
“Once patients with HER2 positive metastatic breast cancer progress following at least two HER2 targeted regimens in the metastatic setting, there are limited treatment options,” said Shanu Modi, MD, Breast Medical Oncologist, Memorial Sloan Kettering Cancer Center.
“[Trastuzumab deruxtecan] has the potential to become a new standard of care,” Modi said.
“The approval of [trastuzumab deruxtecan] underscores that this specifically engineered HER2 directed antibody-drug conjugate is delivering on its intent to establish an important new treatment for patients with HER2 positive metastatic breast cancer,” noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology R&D, Daiichi Sankyo.
“Since the beginning of our clinical trial program four years ago, we have focused on the opportunity to transform the treatment landscape for patients with HER2-positive metastatic breast cancer, and we are extremely proud of how quickly we delivered trastuzumab deruxtecan to patients in the U.S., as [this treatment option] represents one of the fastest developed biologics in oncology,” Yver observed.
“Trastuzumab deruxtecan has shown impressive results in women with HER2 positive metastatic breast cancer, with the majority of women benefiting from treatment and the median duration of response exceeding 14 months,” said José Baselga, MD, PhD, Executive Vice President, Oncology R&D, AstraZeneca.
“With this first approval, we are proud to bring [trastuzumab deruxtecan] to patients with high unmet need and we look forward to further exploring its potential in additional settings,” he added.
Trastuzumab deruxtecan will be available by prescription in the United States within the coming weeks. In a statement, Daiichi Sankyo and AstraZeneca confirmed that the companies are committed to ensure that patients in the U.S. who are prescribed fam-trastuzumab deruxtecan-nxki can access the medication and receive necessary financial support.
* Fam-trastuzumab deruxtecan-nxki in the US only, trastuzumab deruxtecan outside the United States.
Click here to download the full prescribing information, including Boxed WARNING, and Medication Guide. For provider and patient support, reimbursement and distribution visit the for ENHERTU in the U.S. visit the product website.
 Krop IE, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, André F, Iwata H, et al. [Fam-] trastuzumab deruxtecan (T-DXd; DS-8201a) in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: A phase 2, multicenter, open-label study (DESTINY-Breast01) GS1-03. Presentation during the 2019 San Antonio Breast Cancer Symposium, held December 10 – 14, 2019, San Antonio Texas. [Abstract]
 Modi S, Saura C, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer [published online ahead of print, 2019 Dec 11]. N Engl J Med. 2019;10.1056/NEJMoa1914510. doi:10.1056/NEJMoa1914510 [Pubmed]
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