The FDA granted Breakthrough Therapy Designation to Sacituzumab govetican (IMMU-132) for treatment of triple-negative breast cancer (TNBC). A diagnosis of triple negative breast cancer means that the three most common types of receptors known to fuel most breast cancer growth–estrogen, progesterone, and the HER-2/neu gene– are not present in the cancer tumor. This means that the breast cancer cells have tested negative for hormone epidermal growth factor receptor 2 (HER-2), estrogen receptors (ER), and progesterone receptors (PR). Since the tumor cells lack the necessary receptors, common treatments likehormone therapy and drugs that target estrogen, progesterone, and HER-2 are ineffective.
Trop-2, a cell surface protein is widely expressed in a variety of epithelial cancers (Figure 1). This cell surface protein is presents in 90% of triple- negative breast cancer patients. Trop-1 and Trop-2 are homologous to serum IGF-11-binding proteins. IGF-binding proteins increase the half-life of insulin-like growth factor, potentiate their effect on cell proliferation, localize IGF to specific receptors on the cell surface, and block the activity of IGF by inhibiting cell surface binding. For example, p53 induces the expression of IGF-BP, which blocks Akt/PKB mediated inactivation of pro-apoptotic Bad and IkB kinase, thereby liberating NF-kB to induce anti-apoptotic Bcl-2 and Inhibitors of Apoptosis. Interestingly, Trop-2, while homologous with IGF-11 BP’s transduces signals that result in the activation of the MAPK pathway (see Figure 2).
Trop-2 is a signal-transducing receptor that results in transient elevated intracellular Ca++ levels. In epithelial ovarian cancer (EOC), Trop-2 protein overexpression correlates with an aggressive malignant phenotype.
Trop-2 expression is invariably upregulated in tumours, regardless of baseline expression in normal tissues, which suggests a corresponding selective advantage. Overexpression of wild-type Trop-2 was shown to be necessary and sufficient to drive cancer growth in a widely invariant manner across cell type and species. Upregulation of Trop-2 was shown to quantitatively stimulate tumour growth, as proportional to expression levels in vivo, and tumour cell growth was abrogated by somatic knockdown of Trop-2 expression. Above-baseline expression of wild-type Trop-2 is a key driver of human cancer growth.
In addition to transducing proliferative signals through the MAPK signaling pathway, it also mediates signaling for integrin binding.
Sacituzumab govetican is a humanized IgG antibody targeted against Trop-2 conjugated to SN-38, the active metabolite of irinotecan, which is a topoisomerase inhibitor (see Figure 3).
Topoisomerase 1 is critical for DNA uncoiling during replication; its blockade results in DNA single strand breaks (see Figure 4).
Phase II results (Figure 5) were presented at the 2015 San Antonio Breast Cancer Symposium. In the study, patients with metastatic TNBC received either 8 or 10 mg/kg of sacituzumab govitecan intravenously on days 1 and 8 of 21-day repeated cycles. Patients received a median number of 8 doses (range, 1-37). Response was measured by RECIST1.1 criteria.
- At the data cutoff, 60 patients who had progressed on at least 2 prior treatments, including a taxane, had received sacituzumab govitecan. Seventy percent of these patients had an ECOG performance status of 1, with the remaining 30% having an ECOG performance of 0. The median age was 54 years (range, 31-80 years).
- The median number of prior therapies was 5 (range, 2-12). Prior therapies received included cyclophosphamide (93%), doxorubicin (83%), carboplatin (57%), gemcitabine (50%), capecitabine (43%), eribulin (38%), cisplatin (25%), vinorelbine (17%), and bevacizumab (13%).
- Eighteen of 58 evaluable patients had a response, for an overall response rate (ORR) of 31%. There were 2 complete responses and 16 partial responses (PR). The clinical benefit ratio (CR + PR + SD) was 53% at ≥4 months and 45% at ≥6 months.
- The median progression-free survival (PFS) was 6.0 months (95% CI, 4.1-9.4 months) and the overall survival (OS) data were not yet mature, with 83% of patients still alive. The 10 mg/kg regimen was the dose selected for future clinical development.
- The most common all-grade adverse events (AEs) in the 10 mg/kg arm were diarrhea (27%), nausea (27%), neutropenia (23%), vomiting (22%), alopecia (18%), anemia (17%), fatigue (17%), constipation (13%), rash (13%), and abdominal pain (10%).
- The most frequently reported grade ≥3 AEs in the 10 mg/kg cohort were neutropenia (15%), leukopenia (8%), diarrhea (5%), fatigue (3%), dyspnea (3%), febrile neutropenia (2%), and anemia (2%).