The U.S. Food and Drug Administration (FDA) has approved fam-trastuzumab deruxtecan-nxki (Enhertu®; Daiichi Sankyo and AstraZeneca) for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting.

The agent is also improved for in the neoadjuvant or adjuvant setting and in the treatment of patients who have developed disease recurrence during or within six months of completing therapy.

Clinical Practice Guide
Based on the DESTINY-Breast03 data, fam-trastuzumab deruxtecan-nxki (ENHERTU) recently was added to the NCCN Clinical Practical Guidelines in Oncology (NCCN Guidelines®) as the Category 1 preferred regimen as second-line therapy for recurrent unresectable (local or regional) or stage IV HER2+ disease.[1]

Specifically engineered
Trastuzumab deruxtecan is a specifically-engineered HER2-directed antibody-drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca. The drug consists of trastuzumab (Herceptin®; Genentech/Roche), a HER2 monoclonal antibody, attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker and is designed using Daiichi Sankyo’s proprietary DXd ADC technology.

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Real-Time Oncology Review
The approval was granted under the FDA’s Real-Time Oncology Review (RTOR) program following the recent Priority Review and Breakthrough Therapy Designation of trastuzumab deruxtecan in the U.S in this earlier disease setting and was based on data from the pivotal DESTINY-Breast03 phase 3 trial.

This study demonstrated that trastuzumab deruxtecan reduced the risk of disease progression or death by 72% versus trastuzumab emtansine (T-DM1; —-) (hazard ratio [HR] = 0.28; 95% confidence interval [CI]: 0.22-0.37; p<0.0001) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The median progression-free survival (PFS) for patients treated with ENHERTU was not reached (95% CI: 18.5-NE) compared to 6.8 months for T-DM1 (95% CI: 5.6-8.2) as assessed by blinded independent central review (BICR).

Confirmatory trial
Trastuzumab deruxtecan previously received accelerated approval for adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. The previously granted accelerated approval of trastuzumab deruxtecan in later line HER2 positive metastatic breast cancer is now converted to regular approval, broadening its breast cancer indication in the U.S. to earlier lines of use in patients with HER2 positive metastatic breast cancer.

DESTINY-Breast03 was the confirmatory trial for the accelerated approval. This global, head-to-head, randomized, open-label, pivotal phase 3 trial was designed to evaluating the efficacy and safety of trastuzumab deruxtecan (5.4 mg/kg) versus trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) in patients with HER2 positive unresectable and/or metastatic breast cancer previously treated with trastuzumab and a taxane. The primary efficacy endpoint of this study is PFS based on blinded independent central review. Secondary endpoints include overall survival, ORR, duration of response, PFS based on investigator assessment and safety. DESTINY-Breast03 enrolled 524 patients at multiple sites in Asia, Europe, North America, Oceania and South America.

A treatment of breast cancer and beyond
Breast cancer is the most common cancer worldwide, with more than two million cases diagnosed in 2020 globally. Approximately one in five cases of breast cancer are considered HER2 positive, one of the most aggressive and fast-growing forms of the disease. Despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer will often experience disease progression.

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide and in the U.S. [2][3] More than two million cases of breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally. [2] In the U.S., more than 290,000 new cases are expected to be diagnosed in 2022, with more than 43,000 deaths.[4] Approximately one in five cases of breast cancer are considered HER2 positive.[5]

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]

Despite initial treatment with trastuzumab and a taxane, patients with HER2 positive metastatic breast cancer will often experience disease progression.[8] More treatment options are needed to further delay progression and extend survival.[8][9][10]

Regulatory collaboration
As part of Project Orbis, trastuzumab deruxtecan is also is under regulatory review for the same indication by the Australian Therapeutic Goods Administration, Brazilian Health Regulatory Agency (ANVISA), Health Canada, Israel’s Ministry of Health Pharmaceutical Administration, and Switzerland’s Swissmedic.

“Trastuzumab deruxtecan has demonstrated significant progression-free survival in the earlier metastatic setting, potentially establishing it as a new standard of care in previously treated patients with HER2 positive metastatic breast cancer,” said Erika Hamilton, MD, Director, Breast Cancer and Gynecological Cancer Research Program, Sarah Cannon Research Institute, Nashville, Tennessee.

“Today’s approval is an important milestone for the clinical community as we will now be able to offer Trastuzumab deruxtecan to these patients earlier in their treatment,” Hamilton added.

“This is an important day for the breast cancer community,” explained Catherine Ormerod, Executive Vice President, Strategy and Mission, Living Beyond Breast Cancer.

“With this approval, trastuzumab deruxtecan now provides a new treatment option for patients with HER2 positive metastatic breast cancer, which can be used earlier in treatment to potentially delay progression of disease,” she noted.

The DESTINY-Breast03 phase 3 trial showed that confirmed objective response rate (ORR) was more than doubled in the ENHERTU arm (82.7%; n=205; 95% CI: 77.4-87.2) versus the T-DM1 arm (36.1%; n=87; 95% CI: 30.0-42.5). Thirty-nine (15.7%) complete responses (CR) and 166 (66.9%) partial responses (PR) were observed in patients treated with trastuzumab deruxtecan compared to 20 (8.3%) CRs and 67 (27.8%) PRs in patients treated with T-DM1. In addition, in the secondary endpoint analysis of PFS as assessed by investigator, which was published online in The New England Journal of Medicine, patients treated with trastuzumab deruxtecan had a median PFS of 25.1 months (95% CI: 22.1-NE) compared to 7.2 months (95% CI: 6.8-8.3) for T-DM1 (HR=0.26; 95% CI: 0.20-0.35). Overall survival (OS) was analyzed but immature at time of data cut-off of May 21, 2021 (HR=0.55; 95% CI: 0.36-0.86). Nearly all patients treated with trastuzumab deruxtecan were alive at one year (94.1%; 95% CI: 90.3-96.4) compared to 85.9% of patients treated with T- DM1 (95% CI: 80.9-89.7).

Adverse events
Trastuzumab deruxtecan is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and Embryo-Fetal toxicity. The safety of the drug was evaluated in 257 patients with unresectable or metastatic HER2 positive breast cancer who received at least one dose of trastuzumab deruxtecan (5.4 mg/kg) in the DESTINY-Breast03 trial.

The most common adverse reactions (frequency ≥20%), including laboratory abnormalities, were nausea, decreased white blood cell count, decreased neutrophil count, increased aspartate aminotransferase, decreased hemoglobin, decreased lymphocyte count, increased alanine aminotransferase, decreased platelet count, fatigue, vomiting, increased blood alkaline phosphatase, alopecia, hypokalemia, constipation, musculoskeletal pain, diarrhea, decreased appetite, headache, respiratory infection, abdominal pain, increased blood bilirubin, and stomatitis. Of the 28 ILD events (11%), 0.8% were recorded as grade 3 events. No grade 4 or grade 5 ILD or pneumonitis events were adjudicated as drug-related.

“Today’s FDA approval, which converts the accelerated approval of trastuzumab deruxtecan to regular approval, highlights the importance of the FDA’s accelerated pathway that allows for earlier approval of medicines to treat serious medical conditions such as breast cancer,” said Ken Keller, Global Head, Oncology Business, and President and CEO, Daiichi Sankyo.

“Data from DESTINY-Breast03 not only confirmed the results of DESTINY-Breast01 but also demonstrated the superiority of trastuzumab deruxtecan in prolonging progression-free survival compared to T-DM1 in an earlier setting of HER2 positive metastatic breast cancer,” Keller said.

“Trastuzumab deruxtecan is already established in the later-line treatment of patients with HER2 positive metastatic breast cancer, and we are thrilled that with this approval, patients in the U.S. will now be able to access the transformative potential of trastuzumab deruxtecan earlier in their treatment,” said Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca.

“We look forward to bringing this important, potentially paradigm-shifting medicine to even more patients across the globe in an earlier setting as quickly as possible,” Fredrickson concluded

Clinica trials
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
A Study of DS-8201a in Metastatic Breast Cancer Previously Treated With Trastuzumab Emtansine (T-DM1) – NCT03248492

Highlights of prescribing information
Trastuzumab (Herceptin®; Genentech/Roche) (Prescribing Information)
Trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche)(Prescription information)
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca) (Prescribing Information)

Reference
[1] NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V2.2022. ©National Comprehensive Cancer Network, Inc. 2022. Online. Last accessed May 4, 2022.
[2] 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 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.
[3] United States Cancer Statistics: Data Visualizations.Division of Cancer Prevention and Control Centers for Disease Control and Prevention Online Last accessed May 4, 2022
[4] Cancer Facts & Figures 2022 American Cancer Society. Online. Last accessed May 4, 2022.
[5] 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.
[6] Iqbal N, Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014;2014:852748. doi: 10.1155/2014/852748. Epub 2014 Sep 7. PMID: 25276427; PMCID: PMC4170925.
[7] 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.
[8] 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.
[9] 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.
[10] 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.

Featured image: Daiichi Sankyo Exhibition booth. Photo courtesy: © 2016 – 2022 Sunvalley Communication/Evan Wendt/ Used with permission.

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