Abstract
Simple SummaryIn a double-blind, placebo-controlled, randomized phase 2 trial, Regorafenib provided a clinical benefit to patients with advanced and anthracycline-pretreated soft tissue sarcoma. However, extensive mutational analysis of tumor genes could not identify predictive markers of regorafenib efficacy, including among genes involving in angiogenesis (FLT1, FLT2, FLT3, FLT4, KDR, TEK (TIE2), and VHL). The identification of the precise mechanism of action of multikinase inhibitor in sarcoma and the identification of responding patients requires further clinical studies.Regorafenib significantly prolonged progression-free survival (PFS) in pretreated patients with advanced non-adipocytic sarcoma (HR = 0.46; p < 0.001) in a placebo-controlled, randomized, phase-II trial (NCT01900743). Thus, here, we assessed the prevalence of 57 biomarkers and their prognostic and predictive values for PFS and overall survival (OS). We analyzed 134/182 patients included in this trial, treated with regorafenib (n = 71, 53%) or placebo (n = 63, 47%). Mutational analyses were performed via full coding sequence analysis for 10 genes, and mutation hotspot panel for 50 genes (four genes in common). H19 was studied with RNA in-situ hybridization. The prognostic and predictive biomarkers’ values were studied only for biomarkers found positive/mutated in at least 10 patients. Overall, 25 out of 57 studied biomarkers, including five out of seven genes involved in angiogenesis, were found mutated/positive in at least one patient, of which 23 biomarkers had low prevalence (fewer than eight out of 134 patients), contrasting with H19 (n = 24, 18%), and TP53 (n = 35, 26%). However, in multivariable models of PFS and OS, including treatment effects and interactions, no significant prognostic or predictive values of the tested biomarkers were observed. Though several promising biomarkers were found to be positive/mutated, none of them were identified as viable predictive and prognostic biomarkers.
Highlights
Soft tissue sarcomas (STS) are rare heterogeneous malignant tumors of mesenchymal origin, with an estimated incidence averaging 4–5/100,000/year in Europe
Progression-free survival times were calculated from the date of randomization until the date of progression or death, from any cause; patients who were alive free of progression at last follow-up were censored at the time of last visit
Overall survival times were calculated from the date of randomization until the date of death, from any cause; patients who were alive at last follow-up were censored at the time of last visit
Summary
Soft tissue sarcomas (STS) are rare heterogeneous malignant tumors of mesenchymal origin, with an estimated incidence averaging 4–5/100,000/year in Europe. 2% of all adult tumors and 4–8% of pediatric malignancies. STS develop recurrent or metastatic incurable disease. Palliative chemotherapy with anthracycline (usually doxorubicin) either as monotherapy, or in combination with ifosfamide has been the conventional first-line systemic therapy for metastatic disease, which provides an overall survival (OS) of approximately 18 months. Several newly-approved secondand further-line drugs such as ifosfamide [2], dacarbazine, trabectedin, pazopanib [3], and eribulin, have shown some signs of activity, there is no consensual treatment after failure, or intolerance of doxorubicin. The prognosis of patients with doxorubicin-refractory metastatic STS remains poor, and there remains a large unmet treatment need for such patients
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