Abstract
Pazopanib is the first and only tyrosine kinase inhibitor currently approved for the treatment of multiple histological subtypes of soft tissue sarcoma (STS). Initially developed as a small molecule inhibitor of vascular endothelial growth factor receptors, preclinical work indicates that pazopanib exerts an anticancer effect through the inhibition of both angiogenic and oncogenic signaling pathways. Following the establishment of optimal dosing and safety profiles in early phase studies and approval for the treatment of advanced renal cell carcinoma, pazopanib was investigated in STS. A landmark phase III randomized study demonstrated improved progression-free survival with pazopanib compared to that with placebo in pretreated patients with STS of various subtypes. The efficacy of pazopanib in specific STS subtypes has been further described in real-world-based case series in both mixed and subtype-specific STS cohorts. At present, there are no clinically validated predictive biomarkers for use in selecting patients with advanced STS for pazopanib therapy, limiting the clinical effectiveness and cost-effectiveness of the drug. In this review, we summarize the preclinical and clinical data for pazopanib, outline the evidence base for its effect in STS and explore reported studies that have investigated putative biomarkers.
Introduction
Pazopanib is an oral multitarget tyrosine kinase inhibitor (TKI) with a clinical antitumor effect that is thought to be exerted through its selective inhibition of vascular endothelial growth factor receptor (VEGFR)-mediated angiogenesis, as well as its direct blockade of growth-promoting receptor tyrosine kinases (RTKs), including platelet-derived growth factor receptors (PDGFRs), fibroblast growth factor receptors (FGFRs), and KIT1,2,3,4,5. After receiving marketing authorization for the treatment of metastatic renal cell carcinoma (mRCC), pazopanib became the first (and currently only) TKI licensed for the treatment of multiple subtypes of advanced soft tissue sarcoma (STS). This approval was based on the results of a double-blind, placebo-controlled randomized phase III trial that demonstrated significant prolongation of progression-free survival (PFS) in patients with pretreated advanced STS who received pazopanib6. However, despite this evidence of an antitumor effect, no significant difference in overall survival (OS) was observed between pazopanib and placebo-treated patients. The failure of PFS gain to translate to OS benefit has adversely influenced the cost assessment of pazopanib for this indication, leading to funding limitations in certain health economies worldwide7,8,9. There is currently a poor understanding of the clinical mechanisms of pazopanib response and resistance and an unmet need for predictive biomarkers that are able to prospectively select the subgroup of STS patients most likely to benefit from pazopanib, thus improving the clinical efficiency of the drug. In this review, we summarize the preclinical and early clinical development of pazopanib, explore the evidence for efficacy in STS and outline reported data resulting from efforts to identify biomarkers for pazopanib response.
https://www.nature.com/articles/s41392-019-0049-6
Pazopanib in advanced soft tissue sarcomas
Pazopanib in advanced soft tissue sarcomas
Last edited by D.ap on Sun Jun 20, 2021 8:49 am, edited 1 time in total.
Debbie
Re: Pazopanib in advanced soft tissue sarcomas
Conclusions and future directions
The successful clinical development of pazopanib as a treatment for advanced STS has addressed the longstanding and ongoing need for effective novel agents for these rare diseases. However, reported clinical trial data indicate that only a minority of patients within the indicated STS population will receive benefit from treatment and that the duration of benefit may in many cases be short. Reported data from subgroup analyses of prospective pazopanib studies have so far failed to identify baseline clinicopathological characteristics that enrich for pazopanib benefit. Moreover, the small number of translational studies that have investigated circulating or tumor-based biomarkers have yet to provide reproducible and validated candidate biomarkers. A growing volume of biomolecular profiling data indicate the existence of biological intrinsic subgroups within individual STS histotypes. In addition, biological traits such as increased chromosomal instability can be demonstrated in a proportion of tumors across multiple STS subtypes and are associated with shared clinical phenotypes69,70,71. Assessment for differential treatment outcomes between such biologically classified STS subgroups within pazopanib-treated cohorts represents a worthwhile avenue for biomarker research.
The further development and validation of putative imaging surrogate markers for survival would provide better discriminatory trial endpoints and assist in the early detection of clinical effects. At present, it is unclear by what precise mechanism or mechanisms pazopanib exerts its anticancer effect in STS and whether this effect varies between and within different STS subtypes.
Furthermore, even in patients showing an unequivocal initial benefit from treatment, the development of pazopanib resistance is ubiquitous. A greater understanding of the mechanisms of drug effect and primary and secondary drug resistance is required to inform patient selection and the development of novel combinatorial regimens in which pazopanib might be paired with other small molecule inhibitors, cytotoxic drugs, or potential immunotherapeutic approaches. A greater degree of preclinical and translational research is required to reveal the therapeutic and resistance mechanisms of pazopanib in disease-specific contexts.
The successful clinical development of pazopanib as a treatment for advanced STS has addressed the longstanding and ongoing need for effective novel agents for these rare diseases. However, reported clinical trial data indicate that only a minority of patients within the indicated STS population will receive benefit from treatment and that the duration of benefit may in many cases be short. Reported data from subgroup analyses of prospective pazopanib studies have so far failed to identify baseline clinicopathological characteristics that enrich for pazopanib benefit. Moreover, the small number of translational studies that have investigated circulating or tumor-based biomarkers have yet to provide reproducible and validated candidate biomarkers. A growing volume of biomolecular profiling data indicate the existence of biological intrinsic subgroups within individual STS histotypes. In addition, biological traits such as increased chromosomal instability can be demonstrated in a proportion of tumors across multiple STS subtypes and are associated with shared clinical phenotypes69,70,71. Assessment for differential treatment outcomes between such biologically classified STS subgroups within pazopanib-treated cohorts represents a worthwhile avenue for biomarker research.
The further development and validation of putative imaging surrogate markers for survival would provide better discriminatory trial endpoints and assist in the early detection of clinical effects. At present, it is unclear by what precise mechanism or mechanisms pazopanib exerts its anticancer effect in STS and whether this effect varies between and within different STS subtypes.
Furthermore, even in patients showing an unequivocal initial benefit from treatment, the development of pazopanib resistance is ubiquitous. A greater understanding of the mechanisms of drug effect and primary and secondary drug resistance is required to inform patient selection and the development of novel combinatorial regimens in which pazopanib might be paired with other small molecule inhibitors, cytotoxic drugs, or potential immunotherapeutic approaches. A greater degree of preclinical and translational research is required to reveal the therapeutic and resistance mechanisms of pazopanib in disease-specific contexts.
Debbie