On April 22, 2020, the U.S. Food and Drug Administration (FDA) accelerated the approval of Trodelvy (sacituzumab govitecan-hziy) for adult patients with metastatic triple-negative breast cancer (mTNBC) who have previously received at least two therapies. Currently, it has been marketed in more than 30 countries including the United States, the European Union, Australia, Canada, China, and Singapore. It is the world's first antibody-drug conjugate (ADC) approved for the treatment of triple-negative breast cancer and the world's first TROP-2 ADC drug to be marketed.

Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a type of breast cancer in which the results of three tests, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2), are negative in immunohistochemical examinations of cancer tissues, accounting for approximately 15%-20% of all breast cancer cases. The characteristics of the disease are reflected in the young age of onset (generally premenopausal women < 40 years old), strong invasiveness, and prone to local recurrence and metastasis. The 5-year survival rate of early triple-negative breast cancer is only 77%, while the 5-year survival rate of advanced patients is only 14%. At present, chemotherapy is also the common treatment method for triple-negative breast cancer in the late stage. Triple-negative breast cancer is a difficult and hot spot in clinical treatment. Due to the lack of precise therapeutic targets, there are few treatment methods other than chemotherapy. In recent years, PARP inhibitors targeting BRCA mutations have made breakthroughs in late-stage and adjuvant therapy, and PD1/PDL1 inhibitors have also made progress, bringing hope for the precise treatment of TNBC. The clinic has put forward more desires for targets that are widely applicable to TNBC, so the emergence of the third-generation ADC drug Trodelvy has changed this situation.

What is Trodelvy?

Trodelvy is mainly composed of Trop-2 humanized antibody IgG1k, cytotoxin SN-38 and linker CL2A. TROP-2 (trophoblast cell surface antigen 2) is a transmembrane glycoprotein widely expressed in a variety of solid tumors (including NSCLC). Although TROP2 is expressed in all lung cancer subtypes, it is most highly expressed in adenocarcinoma (64%) and squamous cell carcinoma (75%) (the most common forms of NSCLC). The core of Trodelvy is the use of a new type of linker that does not require an enzyme to release the payload and can deliver active drugs within tumor cells and in the tumor microenvironment, thereby producing a near-by effect. The core structure of Trodelvy includes:

Fig. 1. Structure of Trodelvy (MAbs. 2021, 13(1): 1951427).

• Sacituzumab: A high-affinity humanized monoclonal antibody IgG1k targeting TROP-2.
• SN-38 (govitecan): An active metabolite of irinotecan, a mild to moderately toxic topoisomerase I inhibitor.
• CL2A: A cleavable linker containing polyethylene glycol (PEG) that improves water solubility and avoids ADC aggregation; the linker is sensitive to pH and also ensures circulation stability.

* Trodelvy related products:

Trodelvy Mechanism of Action

The monoclonal antibody sacituzumab binds to tumor cells expressing TROP-2, and the linker CL2A hydrolyzes to release the toxin, which inhibits DNA topoisomerase I, causing DNA single-strand breaks, leading to DNA damage and tumor cell death. The linker uses a cleavable linker-CL2A, which is the most distinctive and breakthrough design of the third-generation ADC. CL2A promotes a tighter binding of Trop-2 antibody to SN-38, and aggregates at the target site inside the tumor to enhance the tumor killing effect. CL2A also introduces a PEG hydrophilic group in the structure, which can increase the hydrophilicity of the linker and improve the solubility of the ADC. However, due to the pH sensitivity of the linker, it is not easy to hydrolyze in the circulation system, but it can be hydrolyzed in the lysosome of tumor cells or in the acidic environment of the tumor microenvironment, releasing SN-38. In addition, sacituzumab is coupled with cysteine, with a maximum of 8 coupling sites, so the heterogeneity of the resulting product is small and the uniformity is higher. And thanks to the optimization of the linker technology, when the average number of coupled drug carriers is as high as 7.6 (DAR=7.6, close to the theoretical maximum value), the stability of the ADC drug can also be guaranteed, and it will not be cleared from the body due to aggregation. Not only can SN-38 be released in the target tumor cells, but the therapeutic concentration can also be delivered to the adjacent tumor cells that are difficult to mark, achieving large-scale killing.

*Common antibody conjugation technologies for ADC include:

Trodelvy Indications

• Trodelvy Breast Cancer

In April 2020, after the FDA accelerated the approval of Trodelvy, Gilead further expanded the sample size and confirmed the efficacy of Trodelvy in the second-line or higher treatment of patients with metastatic triple-negative breast cancer (mTNBC) in a Phase 3 clinical study called ASCENT. Based on this, Trodelvy was changed from accelerated approval to full approval in April 2021. In June 2022, Trodelvy was approved by NMPA for adult patients with unresectable locally advanced or metastatic TNBC who had previously received at least 2 systemic treatments, at least one of which was for metastatic disease. In February 2023, the FDA approved Trodelvy's third indication for patients with HR+/HER2- locally advanced or metastatic breast cancer who had received endocrine therapy and ≥2 lines of systemic treatment for metastatic disease.

• Trodelvy Urothelial Cancer

In April of the same year, its second indication also received accelerated approval from the FDA for the treatment of locally advanced or metastatic urothelial carcinoma after platinum-containing chemotherapy and PD-1/PD-L1 inhibitors. To date, Trodelvy has been approved for three indications worldwide, namely:

(1) For the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who have previously received at least 2 therapies, at least 1 of which was for metastatic disease;

(2) For the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who have previously received platinum-containing chemotherapy and PD-1 inhibitors or PD-L1 inhibitors;

(3) For patients with HR+/HER2- locally advanced or metastatic breast cancer who have received endocrine therapy and ≥2 lines of systemic therapy (for metastatic disease).

ADC Drug

At present, 15 ADC drugs have been approved for marketing worldwide, including Mylotarg and Besponsa from Pfizer, Kadcyla and Polivy from Roche, Lumoxiti and Enhertu from AstraZeneca, Adcetris from Seagen/Takeda Pharmaceutical, Padcev from Seagen/Ansai Tailai, Tivdak from Seagen/Genmab, Blenrep from GSK, Trodelvy from Gilead, Akalux from Rakuten Medical, Zynlonta from ADC Therapeutics, Aidixi from Remegen, and Elahere from ImmunoGen. The therapeutic areas include lymphoma, leukemia, breast cancer, multiple myeloma, breast cancer, head and neck cancer, urothelial carcinoma, etc.