FDA Approves TRODELVY® for Advanced Triple Negative Breast Cancer

SUMMARY: The FDA on April 22, 2020, granted accelerated approval to TRODELVY® (Sacituzumab govitecan-hziy), for adult patients with metastatic Triple-Negative Breast Cancer (TNBC), who received at least two prior therapies for metastatic disease. Breast cancer is the most common cancer among women in the US and about 1 in 8 women (13%) will develop invasive breast cancer during their lifetime. Approximately 276,480 new cases of invasive female breast cancer will be diagnosed in 2020 and about 42,170 women will die of the disease.

Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients and African American females. It is usually aggressive, and tumors tend to be high grade, and patients with TNBC are at a higher risk of both local and distant recurrence and often develop visceral metastases. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers. The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Overall survival among patients with pretreated metastatic TNBC has not changed over the past 2 decades and standard chemotherapy is associated with low response rates of 10-15% and a Progression Free Survival of only 2-3 months.

TRODELVY® is an Antibody-Drug Conjugate (ADC) in which SN-38, an active metabolite of Irinotecan, a Topoisomerase I inhibitor, is coupled to the humanized Anti-Trophoblast cell-surface antigen 2 (Trop-2) monoclonal antibody (hRS7 IgG1κ), through the cleavable CL2A linker. SN-38 cannot be given directly to patients because of its toxicity and poor solubility. Trop-2, a transmembrane calcium signal transducer, stimulates cancer-cell growth, and this cell surface receptor is overexpressed in several epithelial cancers including cancers of the breast, colon and lung, and has limited expression in normal human tissues. Trop-2 is expressed in more than 85% of breast tumors including Triple Negative Breast Cancer. Upon binding to Trop-2, the anti-TROP-2 monoclonal antibody is internalized and delivers SN-38 directly into the tumor cell, making it a suitable transporter for the delivery of cytotoxic drugs. Further, the cleavable linker enables SN-38 to be released both intracellularly into the tumor cells as well as the tumor microenvironment, thereby allowing for the delivery of therapeutic concentrations of the active drug in bystander cells to which the conjugate has not bound. Thus, TRODELVY®-bound tumor cells are killed by intracellular uptake of SN-38, whereas the adjacent tumor cells are killed by the extracellular release of SN-38.

IMMU-132-01 is a Phase I/II, basket design, open-label, single-group, multicenter trial involving patients with various types of advanced epithelial cancers, who have received at least one previous therapy for metastatic disease. (One example of a basket design is a single drug evaluated in multiple baskets, with each basket representing a different malignancy or tumor site with the same target). A total of 108 patients with metastatic Triple-Negative Breast Cancer (TNBC) were enrolled between June 2013 and February 2017. Patients received TRODELVY® 10 mg/kg IV on days 1 and 8 every 21 days. Tumor imaging was obtained every 8 weeks, and patients were treated until disease progression or intolerance to therapy. The median patient age was 55 years. Enrolled patients had a median of 3 prior anticancer regimens and 98% had received taxanes and 86% had received anthracyclines. The Primary efficacy end point was the Objective Response Rate (ORR). Other efficacy end points included Time to Response and Duration of Response in patients who had a response, the Clinical Benefit Rate (defined as a Complete or Partial Response or stable disease for at least 6 months), Progression Free and Overall Survival. The median duration of follow up for this basket of 108 patients with metastatic TNBC was 9.7 months.

The Objective Response Rate was 33.3% including a Complete Response Rate of 2.8%. The median Time to Response was 2.0 months and the median Duration of Response was 7.7 months. The Clinical Benefit Rate was 45.4%. There was no meaningful difference in response rates in the various patient subgroups including patient age, onset of metastatic disease, number of previous therapies and the presence or absence of visceral metastases. The median PFS was 5.5 months and median OS was 13.0 months. The most common adverse reactions were, possibly severe neutropenia and diarrhea, fatigue, nausea, vomiting, alopecia and abdominal discomfort.

It was concluded that TRODELVY® was associated with durable Objective Responses in patients with heavily pretreated metastatic Triple Negative Breast Cancer. This unique Antibody Drug Conjugate may be of potential benefit for other Trop-2 expressing advanced epithelial solid tumors.
Sacituzumab Govitecan-hziy in Refractory Metastatic Triple-Negative Breast Cancer. Bardia A, Mayer IA, Vahdat LT, et al. N Engl J Med. 2019;380:741-751.