A first patient was dosed in DESTINY-Breast09 (NCT04784715), a global head-to-head Phase 3 clinical trial evaluating the safety and efficacy of trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca).

The DESTINY-Breast09 study is designed to evaluate trastuzumab deruxtecan with or without pertuzumab compared to standard of care (THP: taxane, trastuzumab, and pertuzumab) as a potential first-line treatment in patients with HER2 positive metastatic breast cancer.

This is the first trial to evaluate trastuzumab deruxtecan in the first-line metastatic setting in patients with HER2-positive breast cancer. Many patients with HER2 positive metastatic breast cancer have an aggressive form of the disease due to progression from an earlier stage cancer, with a significant proportion having their disease relapse after receiving THP or other standard anti-HER2 therapies in an adjuvant setting.[1]

Research has also shown that patients often progress in less than two years following initial treatment for HER2-positive metastatic breast cancer.1 While there have been substantial advances in the treatment of these patients, there remains an ongoing need to improve outcomes, and as a result, more effective HER2-directed treatments and novel combination regimens are needed.[1][2]

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HER2+ Breast cancer
Breast cancer remains the most common cancer and is one of the leading causes of cancer-related deaths in women worldwide. [3] More than two million cases of breast cancer are diagnosed each year, resulting in nearly 685,000 deaths globally.[3]

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.

Overexpression of HER2 may be associated with a specific HER2 gene alteration known as HER2 amplification and is often associated with aggressive disease and poor prognosis in breast cancer.[4] Approximately one in five cases of breast cancer are considered HER2 positive.[5]

In the first-line HER2 positive metastatic breast cancer setting, approximately 50% of cases are considered de novo, meaning the disease is metastatic from initial diagnosis, while the remaining cases occur due to disease progression from early-stage disease.[1]

While research has shown that patients with recurrent disease have worse clinical outcomes than patients with de novo metastatic disease, patients diagnosed with de novo metastatic disease also often progress in less than two years.[1] The current standard of care for patients with first-line metastatic breast cancer is the THP regimen, which was approved nearly a decade ago.[1][6]

More effective HER2-directed treatments and novel combination regimens are needed for patients with first-line HER2-positive metastatic breast cancer.[1][2]

Advances in first-line treatment
“There have been no significant advances in first-line metastatic breast cancer treatment in nearly a decade, and most patients still progress on the current standard of care THP regimen, highlighting the need for more effective HER2 directed treatments and novel combination regimens,” noted Gilles Gallant, BPharm, Ph.D., FOPQ, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo.

“Based on the encouraging results we are seeing in patients who have received prior treatment for HER2-positive metastatic breast cancer, we have initiated DESTINY-Breast09 to evaluate whether earlier use of trastuzumab deruxtecan alone or as part of a novel combination regimen may help improve outcomes for patients in the first-line metastatic setting as compared to the current standard of care,” Gallant concluded.

Clinical trial
An Observational Study in Patients With HER2 Positive Metastatic Breast Cancer (SystHERs Registry) – NCT01615068
Trastuzumab Deruxtecan (T-DXd) With or Without Pertuzumab Versus Taxane, Trastuzumab and Pertuzumab in HER2-positive Metastatic Breast Cancer (DESTINY-Breast09) – NCT04784715

Highlights of prescribing information
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Trastuzumab (Herceptin®; Genentech/Roche) [Prescribing Inform]
Pertuzumab (Perjeta®; Genentech/Roche)[Prescribing Information]
Docetaxel (Taxotere®; Sanofi) [Prescribing Infiormation]

[1] Tripathy D, Brufsky A, Cobleigh M, Jahanzeb M, Kaufman PA, Mason G, O’Shaughnessy J, Rugo HS, Swain SM, Yardley DA, Chu L, Li H, Antao V, Hurvitz SA. De Novo Versus Recurrent HER2-Positive Metastatic Breast Cancer: Patient Characteristics, Treatment, and Survival from the SystHERs Registry. Oncologist. 2020 Feb;25(2):e214-e222. doi: 10.1634/theoncologist.2019-0446. Epub 2019 Oct 14. PMID: 32043771; PMCID: PMC7011632.
[2] 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 Sep 27;7(39):64431-64446. doi: 10.18632/oncotarget.7043. PMID: 26824988; PMCID: PMC5325455.
[3] 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.
[4] 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.
[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] Blumenthal GM, Scher NS, Cortazar P, Chattopadhyay S, Tang S, Song P, Liu Q, Ringgold K, Pilaro AM, Tilley A, King KE, Graham L, Rellahan BL, Weinberg WC, Chi B, Thomas C, Hughes P, Ibrahim A, Justice R, Pazdur R. First FDA approval of dual anti-HER2 regimen: pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer. Clin Cancer Res. 2013 Sep 15;19(18):4911-6. doi: 10.1158/1078-0432.CCR-13-1212. Epub 2013 Jun 25. PMID: 23801166.

Featured Image: Pink ribbon for the breast cancer awareness. Courtesy: © 2016 – 2021 Fotolia/Adobe. Used with permission.

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