The U.S. Food and Drug Administration (FDA) has 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.

Targeted anti-cancer drug
Fam-trastuzumab deruxtecan-nxki, formerly known as DS-8201, is a targeted anti-cancer drug that deliver novel topoisomerase I inhibitor payload, via a cleavable tetrapeptide-based linker attached to a HER2 monoclonal antibody, cancer cells. The antibody binds to a specific HER2 targets expressed on cancer cells. The antibody-drug conjugates uses Daiichi Sankyo’s proprietary DXd ADC technology.

Indication
This indication for fam-trastuzumab deruxtecan-nxki is approved under the FDA’s accelerated approval based on tumor response rate and duration of response.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

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Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells. [1] HER2-positive breast cancer is a type of breast cancer that tests positive for a protein called, which promotes the growth of cancer cells.

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.[1]

Approximately one in five breast cancers are HER2 positive. [2][3] The disease is an aggressive type of breast cancer and has a poor prognosis in patients diagnosed with the disease.

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.[4][5] However, this disease remains incurable, with patients eventually progressing after available treatment have failed.[4][5]

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.”

However, Padzur pointed out that approval of fam-trastuzumab deruxtecan-nxki 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.

Approval
The FDA’s approval announcement 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 was simultaneously published online in The New England Journal of Medicine (NEJM).

The published results demonstrated impressive, clinically meaningful and durable anti-tumor responses among the intended group of pretreated patients with HER2-positive metastatic breast cancer. [6][7]

Trial results
The DESTINY-Breast01 trial evaluated the safety and efficacy of fam-trastuzumab deruxtecan-nxki (5.4 mg/kg) monotherapy in 184 patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with ado-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, ado-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.

Limited treatment options
“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.

“[Fam-trastuzumab deruxtecan-nxki] has the potential to become a new standard of care.”

“The approval of [fam-trastuzumab deruxtecan-nxki] 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 fam-trastuzumab deruxtecan-nxki to patients in the U.S., as [this treatment option] represents one of the fastest developed biologics in oncology.”

“[fam-trastuzumab deruxtecan-nxki] 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 [fam-trastuzumab deruxtecan-nxki] to patients with high unmet need and we look forward to further exploring its potential in additional settings,” he added.

Availability
According to the latest information, fam-trastuzumab deruxtecan-nxki will be available by prescription in the United States within the coming weeks. In a statement, both 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.

Note
* Fam-trastuzumab deruxtecan-nxki in the US only, trastuzumab deruxtecan outside the United States.

Prescribing information
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.

References
[1] American Cancer Society. Breast Cancer HER2 Status. Online. Last accessed December 20, 2019.
[2] Tandon AK, Clark GM, Chamness GC, Ullrich A, McGuire WL. HER-2/neu oncogene protein and prognosis in breast cancer. J Clin Oncol. 1989;7(8):1120–1128. doi:10.1200/JCO.1989.7.8.1120 [Pubmed]
[3] Sledge GW, Mamounas EP, Hortobagyi GN, Burstein HJ, Goodwin PJ, Wolff AC. Past, present, and future challenges in breast cancer treatment. J Clin Oncol. 2014;32(19):1979–1986. doi:10.1200/JCO.2014.55.4139 [Pubmed]
[4] de Melo Gagliato D, Jardim DL, Marchesi MS, Hortobagyi GN. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget. 2016;7(39):64431–64446. doi:10.18632/oncotarget.7043 [Pubmed]
[5] National Comprehensive Cancer Network (NCCN). NCCN Guidelines. Breast Cancer. Online. Last accessed December 20, 2019.
[6] 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]
[7] 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]