Need Help?
Copied to clipboard!

Molecular determinants for sensitivity to pazopanib in leiomyosarcoma, synovial sarcoma, and angiosarcoma.

Pazopanib is a tyrosine kinase inhibitor with highest activity against VEGFR1 (FLT1) and VEGFR2 (KDR) along with other targets including VEGFR3, PDGFRa, PDGFRb, cKIT, FGFR1, FGFR3, FGFR4, FAK, ABL1, JNK1, Tie-2, Met, IGF1R, and EGFR (Lee, Jones, and Huang Signal Transduct Target Ther 2019; 4:16). Its initial activity in soft tissue sarcoma (STS) was described by Sleijfer et al. (2009) where a high proportion of leiomyosarcoma (LMS) (44%) and synovial sarcoma (49%) patients remained without progression at 12 weeks. Based on these findings, a multi-institutional randomized placebo controlled phase III trial was conducted (PALLETTE trial) to investigate the activity of pazopanib in the treatment of sarcomas excluding liposarcomas (van der Graaf WT et al. Lancet 2012; 379:1879). There, a large proportion of the patients tested were of LMS histology (42; 29%) and the overall median progression free survival (PFS) was 4.6 months for the treatment as compared to 1.6 months in the placebo arm. There was no survival advantage in the pazopanib arm. Partial response rate was as low as 6% and stable disease occurred in 67% patients compared to 38% in the placebo arm. Progressive disease was observed in 23% of patients receiving pazopanib. Based on this study, pazopanib is currently approved for the treatment of advanced non-adipogenic STS patients for which standard chemotherapy has failed. Here, we conducted whole exome and transcriptome profiling of leiomyosarcoma (N = 33), synovial sarcoma (N = 25), and angiosarcoma (N = 9) patients who were given pazopanib. To date, we have collected all available pretreatment and post-treatment samples from 67 patients (Table 1) (treated from 2012 to 2017), 4 frozen and the remainder FFPE.