The U.S. Food and Drug Administration (FDA) has granted trastuzumab deruxtecan* (Enhertu®; Daiichi Sankyo and AstraZeneca), a HER2 directed antibody-drug conjugate (ADC), Breakthrough Therapy Designation for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received one or more prior anti-HER2-based regimens.

Trastuzumab deruxtecan is designed using Daiichi Sankyo’s proprietary DXd ADC technology, and includes a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

The Breakthrough Therapy Designation is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need. These new medicine needs to have shown encouraging preliminary clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

Breast cancer
With more than two million cases diagnosed in 2020, resulting in nearly 685,000 deaths globally, breast cancer remains the most common cancer worldwide [1] Approximately one in five cases of breast cancer are considered HER2 positive.[2] And despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer often experience disease progression. [3] Hence, more effective options are needed to further delay progression and extend survival.[3][4][5]

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HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung, and colorectal cancers. [6] HER2 protein overexpression may occur as a result of HER2 gene amplification and is often associated with aggressive disease and poor prognosis in breast cancer. [7]

“By granting a fourth Breakthrough Therapy Designation to trastuzumab deruxtecan, the FDA continues to recognize the significant potential of this medicine across multiple HER2 targetable tumors,” noted Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo.

“With the unprecedented data recently reported from the DESTINY-Breast03 trial, we look forward to working closely with the FDA to bring trastuzumab deruxtecan to patients who have been previously treated for HER2 positive metastatic breast cancer as soon as possible.”

Important Step
“This is an important step in bringing trastuzumab deruxtecan as a potential new option in earlier lines of treatment for HER2 positive metastatic breast cancer, given the urgent need to improve outcomes,” explained Susan Galbraith, MBBChir, Ph.D., Executive Vice President, Oncology R&D, AstraZeneca.

“This recognition by the FDA underscores the transformative possibility of trastuzumab deruxtecan seen with the remarkable DESTINY-Breast03 results presented at the 2021 Congress of the European Society for Medical Oncology (ESMO) just two weeks ago.”

The FDA granted Breakthrough Therapy Designation based on data from the DESTINY-Breast03 trial, a global, head-to-head, randomized, open-label, pivotal trial presented during the ESMO Congress. In the study, the investigators evaluated the safety and efficacy of trastuzumab deruxtecan (5.4 mg/kg) versus ado-trastuzumab emtansine (T-DM1; Kadcyla™, Genentech/Roche), an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer, in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The primary efficacy endpoint of DESTINY-Breast03 is progression-free survival (PFS) based on blinded independent central
review.

Secondary efficacy endpoints include overall survival, objective response rate, duration of response, progression-free survival based on investigator assessment and safety. DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Oceania and South America.

The trial results with trastuzumab deruxtecan demonstrated a 72% reduction in the risk of disease progression or death compared to ado-trastuzumab emtansine (hazard ratio [HR] = 0.28; 95% CI: 0.22-0.37; p=7.8×10-22) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane.

Safety
The safety profile of the most common adverse events with trastuzumab deruxtecan in DESTINY-Breast03 was consistent with previous clinical trials with no new safety concerns identified. The most common grade 3 or higher drug-related treatment-emergent adverse events in the trastuzumab deruxtecan arm were neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increase in ALT (1.6%), decreased appetite (1.2%), increase in AST (0.8%), diarrhea (0.4%) and alopecia (0.4%). Overall, 10.5% of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee.

The majority of ILD events (9.7%) were low grade (grade 1 (2.7%) or grade 2 (7.0%)) with two grade 3 (0.8%) events reported. No grade 4 or grade 5 ILD or pneumonitis events occurred. Previous BTDs for trastuzumab deruxtecan were in late-line HER2 positive metastatic breast cancer in 2017 and HER2 mutant metastatic non-small cell lung cancer (NSCLC) and HER2 positive metastatic gastric cancer in 2020.

Note
* In the United States: fam-trastuzumab deruxtecan-nxki

Clinical Trial
DS-8201a Versus T-DM1 for Human Epidermal Growth Factor Receptor 2 (HER2)-Positive, Unresectable and/or Metastatic Breast Cancer Previously Treated With Trastuzumab and Taxane [DESTINY-Breast03] – NCT03529110

Highlights of Prescribing information
Trastuzumab deruxtecan* (Enhertu®; Daiichi Sankyo and AstraZeneca) [Prescribing Information]
Ado-trastuzumab Emtansine (T-DM1; Kadcyla™, Genentech/Roche) [Prescription information] [Drug Description]

Reference
[1] Sung H, Ferlay J. Siegel RL Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries CA Cancer J Clin. 2021; 10.3322/caac.21660. [Article]
[2] Ahn S, Woo JW, Lee K, Park SY. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med. 2020 Jan;54(1):34-44. doi: 10.4132/jptm.2019.11.03. Epub 2019 Nov 6. PMID: 31693827; PMCID: PMC6986968.
[3] Barok M, Joensuu H, Isola J. Trastuzumab emtansine: mechanisms of action and drug resistance. Breast Cancer Res. 2014 Mar 5;16(2):209. doi: 10.1186/bcr3621. PMID: 24887180; PMCID: PMC4058749.
[4] Mounsey LA, Deal AM, Keith KC, Benbow JM, Shachar SS, Zagar T, Dees EC, Carey LA, Ewend MG, Anders CK. Changing Natural History of HER2-Positive Breast Cancer Metastatic to the Brain in the Era of New Targeted Therapies. Clin Breast Cancer. 2018 Feb;18(1):29-37. doi: 10.1016/j.clbc.2017.07.017. Epub 2017 Aug 9. PMID: 28867445.
[5] Martínez-Sáez O, Prat A. Current and Future Management of HER2-Positive Metastatic Breast Cancer. JCO Oncol Pract. 2021 Oct;17(10):594-604. doi: 10.1200/OP.21.00172. Epub 2021 Jun 2. PMID: 34077236.
6 Pillai RN, Behera M, Berry LD, Rossi MR, Kris MG, Johnson BE, Bunn PA, Ramalingam SS, Khuri FR. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017 Nov 1;123(21):4099-4105. doi: 10.1002/cncr.30869. Epub 2017 Jul 25. PMID: 28743157; PMCID: PMC5650517.

Featured Image: ESMO 2017 | Special Session Clinical Practice Demands. Courtesy: © 2017. European Society of Medical Oncology | ESMO. Used with permission.

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