The European Commission (EC) has granted marketing authorization for sacituzumab govitecan (Trodelvy®; Gilead Sciences) a first-in-class topoisomerase inhibitor antibody-drug conjugate (ADC) directed to the Trop-2 receptor, a protein overexpressed in multiple types of epithelial tumors, including metastatic triple-negative breast cancer (mTNBC).

The U.S. Food and Drug Administration (FDA) has approved the drug as a monotherapy for the treatment of adult patients with unresectable or metastatic TNBC who have received two or more prior systemic therapies, at least one of them for advanced disease.

“The metastatic stage of TNBC is particularly challenging to treat and until now we have urgently needed new treatment options for people in Europe living with this condition,” said Véronique Diéras, MD. Senior Medical Oncologist Head, Breast Cancer Group, Department of Medical Oncology, Centre Eugène Marquis, Rennes, France.

“Today’s approval including second-line metastatic TNBC is significant for the community as it’s another important step forward in helping women with this disease live longer.”

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Metastatic triple-negative breast cancer
Metastatic triple-negative breast cancer (mTNBC) is the most aggressive type of breast cancer and accounts for approximately 15% of all breast cancers. TNBC are generally high grade invasive ductal carcinomas. In addition, there are some rarer histological subtypes such as adenoid cystic carcinoma of the breast that is associated with an excellent prognosis.

It is more frequently diagnosed in younger and premenopausal women and is more prevalent in Black and Hispanic women.[1]

TNBC cells do not have estrogen and progesterone receptors and have limited human epidermal growth factor receptor 2 (HER2). As a result, effective treatment options for patients diagnosed with TNBC are extremely limited compared with other breast cancer types.[1]

In addition, TNBC has a higher chance of recurrence and metastases than other breast cancer types. The average time to metastatic recurrence for TNBC is approximately 2.6 years compared with 5 years for other breast cancers, and the relative five-year survival rate is much lower. Among women with metastatic TNBC, the five-year survival rate is 12%, compared with 28% for those with other types of metastatic breast cancer. The poor outcomes are often coupled with a significant decrease in quality of life, especially in relapsed/refractory disease.[1] This is in stark contrast to other forms of breast cancer, including ER-positive/PR-positive/HER2-negative (ER +/PR +/HER2-) disease, where the median OS is closer to 36 mo and an estimated 40% of patients are alive at four years.

Unmet medical needs
“At Gilead, we push boundaries to deliver transformative science and novel treatment options that address urgent medical needs,” said Merdad Parsey, MD, Ph.D., Chief Medical Officer, Gilead Sciences.

“We understand how difficult metastatic TNBC is to treat and we’re proud that sacituzumab govitecan can now offer a second-line treatment option with the potential to bring longer life to people living with this aggressive disease.”

NCT02574455 (Clinical Trial/ SACITUZUMAB GOVITECAN/ IMMU-132 / HRS7-SN38)Approval
The European Commission’s decision is supported by results from the Phase 3 ASCENT study (NCT02574455), a global, open-label, randomized which enrolled more than 500 patients across 230 study locations.

The study evaluated the efficacy and safety of sacituzumab govitecan compared with a single-agent chemotherapy of the physician’s choice in patients with unresectable, locally advanced, or metastatic TNBC who had received at least two prior systemic treatments. Participating patients were randomly allocated to receive either sacituzumab govitecan or a chemotherapy chosen by the patient’s treating physician.

The primary endpoint was progression-free survival (PFS, as determined by blinded independent central review) in patients without brain metastases. Secondary endpoints included: PFS for full study population or intention-to-treat (ITT) population, overall survival in both the ITT population and in the subgroup without brain metastasis, independently determined objective response rate, duration of response, time to onset of response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1), quality of life and safety.

The results of this study demonstrated that in patients diagnosed with mTNBC, sacituzumab govitecan reduced the risk of death by 49% and improved median overall survival to 11.8 months versus 6.9 months with physician’s choice of chemotherapy (HR: 0.51; 95% CI: 0.41-0.62; p<0.0001).

These data also showed a statistically significant and clinically meaningful 57% reduction in the risk of death or disease worsening and improved median progression-free survival (PFS) to 4.8 months from 1.7 months seen with physician’s choice of chemotherapy alone among all randomized patients, which included those with and without brain metastases (HR: 0.43; 95% CI: 0.35-0.54; p<0.0001).

Adverse events
The most common Grade 3 or higher adverse reactions were neutropenia (49.5%), leukopenia (12.0%), diarrhea (10.7%), anemia (10.1%), febrile neutropenia (6.6%), fatigue (5.2%), hypophosphatemia (5.2%), nausea (4.1%) and vomiting (3.0%).

Clinical trials
Trial of Sacituzumab Govitecan in Participants With Refractory/Relapsed Metastatic Triple-Negative Breast Cancer Triple-Negative Breast Cancer (ASCENT) – NCT02574455

Highlights of prescribing information
Sacituzumab govitecan (Trodelvy®; Gilead Sciences)(Prescribing Information)

[1] Syed YY. Sacituzumab Govitecan: First Approval. Drugs. 2020 Jul;80(10):1019-1025. doi: 10.1007/s40265-020-01337-5. PMID: 32529410; PMCID: PMC7288263.

Featured image: Breast cancer. Photo Courtesy: National Cancer Institute on Unsplash

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