In 2022, with an estimated 2.3 million new cases and nearly 700.000 deaths globally, breast cancer emerged as the most prevalent cancer after lung cancer. [1] Approximately 15–25% of patients diagnosed with breast cancer exhibit overexpression or amplification of human epidermal growth factor receptor 2 (HER2), which is characterized by high invasiveness and generally an unfavorable, poor, prognosis. [2][3]
The development and subsequent approval of trastuzumab (Herceptin®, Genentech/Roche) in 1998* revolutionized the treatment of highly aggressive HER2-positive breast cancer, and led to dramatic improvements in survival outcomes.
In the years that followed, progress in the development of HER2-positive targeting therapeutics (including, but not limited to, btrast cancer) has been swift, leading to an abundance of novel treatment options that include antibodies such as pertuzumab (Perjeta®; Genentech/Roche)**, margetuximab (Margenza®; MacroGenics) and zanidatamab (Ziihera®; Jazz Pharmaceuticals)***, tyrosine kinase inhibitors (TKIs), such as lapatinib (Tykerb®; Novartis)^, tucatinib (Tukysa®; Pfizer), neratinib (Nerlynx®; Puma Biotechnology), and antibody-drug conjugates (ADCs), including trastuzumab emtansine (Kadcyla®; Genentech/Roche) and trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca).
ADCs and HER2-positive Breast Cancer
Although in initial preclinical studies, early ADCs demonstrated some clinical benefit, they also exhibited serious safety issues and a relatively narrow therapeutic window. However, improvements in the conception, engineering, and manufacturing of ADCs resulted in a breakthrough, leading to the development of trastuzumab emtansine, the first ADC approved by the US Food and Drug Administration (FDA) for the treatment of a solid tumor, resulting in dramatic improvements in survival outcomes. [4]
Trastuzumab emtansine, the current standard treatment for patients with (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane, and trastuzumab deruxtecan, have profoundly transformed the treatment landscape of breast cancer and improved the overall survival (OS) in both the second and third-line settings with manageable adverse events. [5]
There is, however, no current standard treatment after the failure of trastuzumab emtansine. Several post-trastuzumab emtansine regimens for patients with unresectable and/or metastatic HER2-positive breast cancer, including the continuation of anti-HER2 therapy, have demonstrated some effectiveness. However, in clinical studies in Japan, this effectiveness remained insufficient. Hence, there are still unmet clinical needs requiring novel therapeutic options for further improvement of progression-free survival (PFS) and overall survival (OS) in later treatment settings.[6]
Novel HER2-targeting ADCs, using novel technological advances in the antibody, linker, and/or payloads, have demonstrated promising activity in preclinical and clinical studies and are being evaluated in larger clinical studies. But to date, there is no consensus on the superiority-inferiority differentiation of these novel HER2-targeting ADCs, including the first independently approved ADC in China, disitamab vedotin (RC48 | 爱地希® | Aidixi®; RemeGen).^^
Disitamab vedotin in Breast cancer
In preclinical studies, disitamab vedotin, composed of a fully humanized anti‐HER2 antibody linked to the microtubule inhibitor monomethyl auristatin E (MMAE) via a protease‐cleavable vedotin linker, has shown a higher affinity to immobilized HER2 than trastuzumab.
Following internalization, MMAE is released through proteolytic cleavage of the valine‐citrulline (vc) MMAE drug linker. Additionally, MMAE can also exert a bystander effect on adjacent tumor cells regardless of their HER2 status, leading to increased HER2 selectivity. In preclinical breast cancer studies, disitamab vedotin has shown potent antitumor activity, including HER2-low. [7]
SABCS 2024
During the ‘Novel HER2 Therapeutics‘ Poster Spotlight Session of the 47th San Antonio Breast Cancer Symposium (SABCS), held December 10 – 13, 2024, the first study results from a phase 3 clinical trial (NCT03500380) of disitamab vedotin in treating patients with HER2-positive advanced breast cancer with liver metastasis, were presented. [7][8]
This first prospective randomized phase 3 study demonstrated significant efficacy in patients with HER2-positive advanced breast cancer with liver metastasis. The study results were presented by Professor Jiayu Wang from the Cancer Hospital, Chinese Academy of Medical Sciences.
Approximately 45% of patients with HER2-positive advanced breast cancer have liver metastasis, which is a significant adverse predictor of overall survival (OS). Patients with HER2-positive advanced breast cancer with liver metastasis have a poor prognosis with a 5-year survival rate of only 8% to 12%, for whom no satisfactory therapies are currently available.
A RemeGen-sponsored, randomized, open-label, multicenter phase 3 study comparing the efficacy and safety of disitamab vedotin versus treatment with the tyrosine kinase inhibitor lapatinib + capecitabine in patients with HER2-positive advanced breast cancer with liver metastasis. A total of 104 patients were enrolled, of whom 53 received disitamab vedotin and 50 received lapatinib plus capecitabine. All patients had previously been treated with trastuzumab and taxanes.
As of data cutoff date (December 31, 2023), according to the assessment by the Independent Review Committee (IRC), DV significantly improved progression-free survival (PFS) versus lapatinib + capecitabine (median: 9.9 months vs. 4.9 months; hazard ratio [HR]: 0.56 [95% CI: 0.35-0.90]), which is consistent with the investigator-assessed PFS (HR: 0.62 [95% CI: 0.39-0.98]).
The overall survival (OS) data, though immature, indicated a benefit trend in favor of DV. The safety profile was consistent with past disitamab vedotin use experience, with no new safety signals detected.
“This is the first confirmatory phase III study that demonstrated promising efficacy of an HER2-targeting ADC in patients with HER2-positive advanced breast cancer with liver metastasis,” noted Professor Jiayu Wang.
“Disitamab vedotin demonstrated clinically meaningful benefit compared with lapatinib + capecitabine and a manageable safety profile, potentially offering a promising new treatment option for patients with HER2-positive advanced breast cancer with liver metastasis previously treated with trastuzumab and taxanes,” Wang added.
The Biologics License Application (BLA) filing for this indication of disitamab vedotin has been accepted by the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration in October 2024 and priority review was granted based on the breakthrough therapy designation.
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Note: * Trastuzumab was first approved by the U.S. Food and Drug Administration (FDA) on September 25, 1998 for the treatment of HER2-positive metastatic breast cancer. In 2006, the FDA approved trastuzumab for the treatment of HER2-positive early breast cancer.
** Pertuzumab is used in combination with trastuzumab and docetaxel (Taxotere®; Sanofi)
for the treatment of metastatic HER2-positive breast cancer. it is also used in the same combination as a neoadjuvant in early HER2-positive breast cancer.
*** On November 20, 2024, the U.S. Food and Drug Administration granted accelerated approval to zanidatamab, a bispecific HER2-directed antibody, for previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer (BTC).
^ Lapatinib, in combination with capecitabine is used to treat advanced or metastatic HER2-positive breast cancer. The drug is also approved in combination with letrozole for the treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer that overexpresses the HER2 receptor for whom hormonal therapy is indicated.
^^ Disitamab vedotin was approved on June 9, 2021 by the Chinese National Medical Products Administration (NMPA) for the treatment of locally advanced or metastatic gastric cancer (including gastroesophageal junction adenocarcinoma) with HER2 over-expression in patients who have received at least two types of systemic chemotherapy.
Poster presentation
- Title: Trastuzumab emtansine versus disitamab vedotin for HER2-positive metastatic breast cancer: a multicenter retrospective real-world study
- Presentation Number: P5-03-13/Abstract SESS-1497
- Presenter: Huihui Li M.D.
- Co-authors: Jie Huang, Dongdong Zhou, Fei Pan, Zheng lv, Wei Li, Yuhua Song, Yu Hu, Changping Shan, Li Meng, Li Xiang, Fei Qu, Lihua Song, Baoxuan Zhang, Fangchao Zheng, Liang Xu, Xinzhao Wang, Jiale Zhang, Shujuan Sun
- Onsite Poster display date: Thursday, December 12, 2024
Clinical trials
A Study of RC48-ADC Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer With or Without Liver Metastases – ClinicalTrials.gov ID NCT03500380
Highlights of Prescribing Information
Trastuzumab (Herceptin®, Genentech/Roche) [Prescribing Information]
Pertuzumab (Perjeta®; Genentech/Roche) [Prescribing Information]
Margetuximab (Margenza®; MacroGenics) [Prescribing Information]
Zanidatamab (Ziihera®; Jazz Pharmaceuticals) [Prescribing Information]
Lapatinib (Tykerb®; Novartis) [Prescribing Information]
Tucatinib (Tukysa®; Pfizer) [Prescribing Information]
Neratinib (Nerlynx®; Puma Biotechnology)[Prescribing Information]
Trastuzumab emtansine (Kadcyla®; Genentech/Roche)[Prescribing Information]
Trastuzumab deruxtecan (Enhertu®; Daiichi Sankyo and AstraZeneca)[Prescribing Information]
Capecitabine (Xeloda®; Genentech/Roche)[Prescribing Information]
Disitamab vedotin (RC48 | 爱地希® | Aidixi®; RemeGen)
Reference
[1] Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024 May-Jun;74(3):229-263. doi: 10.3322/caac.21834. Epub 2024 Apr 4. PMID: 38572751.
[2] Owens MA, Horten BC, Da Silva MM. HER2 amplification ratios by fluorescence in situ hybridization and correlation with immunohistochemistry in a cohort of 6556 breast cancer tissues. Clin Breast Cancer. 2004 Apr;5(1):63-9. doi: 10.3816/cbc.2004.n.011. PMID: 15140287.
[3] Cronin KA, Harlan LC, Dodd KW, Abrams JS, Ballard-Barbash R. Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US. Cancer Invest. 2010 Nov;28(9):963-8. doi: 10.3109/07357907.2010.496759. PMID: 20690807; PMCID: PMC5094051.
[4] Oostra DR, Macrae ER. Role of trastuzumab emtansine in the treatment of HER2-positive breast cancer. Breast Cancer (Dove Med Press). 2014 Jul 23;6:103-13. doi: 10.2147/BCTT.S67297. PMID: 25114588; PMCID: PMC4112743.
[5] Cortés J, Kim SB, Chung WP, Im SA, Park YH, Hegg R, Kim MH, Tseng LM, Petry V, Chung CF, Iwata H, Hamilton E, Curigliano G, Xu B, Huang CS, Kim JH, Chiu JWY, Pedrini JL, Lee C, Liu Y, Cathcart J, Bako E, Verma S, Hurvitz SA; DESTINY-Breast03 Trial Investigators. Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer. N Engl J Med. 2022 Mar 24;386(12):1143-1154. doi: 10.1056/NEJMoa2115022. PMID: 35320644.
[6] Nakayama T, Yoshinami T, Yasojima H, Kittaka N, Takahashi M, Ohtani S, Kim SJ, Kurakami H, Yamamoto N, Yamada T, Takata T, Masuda N. Real-world effectiveness of post-trastuzumab emtansine treatment in patients with HER2-positive, unresectable and/or metastatic breast cancer: a retrospective observational study (KBCSG-TR 1917). BMC Cancer. 2021 Jul 9;21(1):795. doi: 10.1186/s12885-021-08504-1. PMID: 34238257; PMCID: PMC8268506.
[7] Wang J, Liu Y, Zhang Q, Li W, Feng J, Wang X, Fang J, Han Y, Xu B. Disitamab vedotin, a HER2-directed antibody-drug conjugate, in patients with HER2-overexpression and HER2-low advanced breast cancer: a phase I/Ib study. Cancer Commun (Lond). 2024 Jul;44(7):833-851. doi: 10.1002/cac2.12577. Epub 2024 Jun 28. PMID: 38940019; PMCID: PMC11260767.
Featured image: SABCS 2024 San Antonio Breast Cancer Symposium. Photo courtesy © 2024 AACR/SABCS/Todd Buchanan. Used with permission.
This article was first published in ADC Review | J. Antibody-drug Conjugates on December 13, 2024
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