Lenvatinib and Eribulin in Advanced Soft Tissue Sarcoma

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Recently, the US Food and Drug Administration (FDA) granted approval to eribulin for the treatment of adipocytic sarcoma who have received a prior anthracycline-containing regimen based on a Phase III study results of improved overall survival (OS) as compared with the standard treatment dacarbazine...

Recently, the US Food and Drug Administration (FDA) granted approval to eribulin for the treatment of adipocytic sarcoma who have received a prior anthracycline-containing regimen based on a Phase III study results of improved overall survival (OS) as compared with the standard treatment dacarbazine. In the leiomyosarcoma cohort of the study, although eribulin did not demonstrate a significant benefit over dacarbazine, still about 5.1% of leiomyosarcoma patients treated with eribulin had a partial response, suggesting that eribulin may have activity against leiomyosarcoma. However, the overall response rate (ORR) and progression-free survival (PFS) remained unsatisfactory in the two most common soft tissue sarcoma (STS) subtypes-adipocytic sarcoma and leiomyosarcoma, prompting new therapeutic options of STS patients. Anti-angiogenic therapies had shown promising results in soft tissue sarcoma (ST). Pazopanib, an anti-angiogenic multi-kinase inhibitor, has shown clinical benefit with a longer median PFS of 4.6 months versus placebo in STS patients refractory to at least one line of systemic chemotherapy. Another anti-angiogenic targeted therapy, regorafenib, showed significant improvement in PFS as compared with placebo in various STS. In a phase I study of lenvatinib for solid tumors in Japan, 4 out of 6 leiomyosarcoma patients has tumor decreased more than 10%. Moreover, other tyrosine receptor targets of lenvatinib, such as fibroblast growth factor receptor (FGFR) and platelet-derived growth factor receptor (PDGFR), may also plays a role in treating STS. In high-grade STS patients, about 30% of patients had FGFR1 amplification or overexpression. FGFR1-overexpression STS cell lines are sensitive to FGFR inhibitors such as BGJ398 and AZD45475. Furthermore, a monoclonal antibody of PDGFR alpha, olaratumab, was recently approved by the FDA in combination with doxorubicin for advanced STS based on a median 10-month OS benefit compared to doxorubicin only in a randomized phase II trial. It has been demonstrated in various cancer types that an increased quantity of tumor infiltrating lymphocyte (TILs) is associated with increased response to chemotherapy or improved prognosis. One of the factors that had been shown to impede the migration and trafficking of TILs into tumor is vascular endothelial growth factor (VEGF). In renal cell carcinoma, treatment with bevacizumab, an anti-VEGF antibody, or in combination with atezolizumab, increased the recognition of tumor antigen, increased expression of major histocompatibility complex (MHC) class I receptor on tumor cells, and the amount of TIL migration into the tumor stroma9. Many of the STS were detected with scarce TILs in the tumor microenvironment, thus it would be interesting to see if anti-angiogenic tyrosine kinase inhibitors could adjust the tumor microenvironment toward a more chemotherapy-friendly milieu. Thus, we would like to propose a clinical trial to understand the anti-tumor activity of the combination of lenvatinib and eribulin in advanced STS patients.

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