Sarcomas are a heterogeneous group of rare malignancies originating from mesenchymal tissues with limited therapeutic options. Recently, alterations in components of the fibroblast growth factor receptor (FGFR) signaling pathway have been identified in a range of different sarcoma subtypes, most notably gastrointestinal stromal tumors, rhabdomyosarcomas, and liposarcomas. These alterations include genetic events such as translocations, mutations, and amplifications as well as transcriptional overexpression. Targeting FGFR has therefore been proposed as a novel potential therapeutic approach, also in light of the clinical activity shown by multi-target tyrosine kinase inhibitors in specific subtypes of sarcomas. Despite promising preclinical evidence, thus far, clinical trials have enrolled very few sarcoma patients and the efficacy of selective FGFR inhibitors appears relatively low. Here, we review the known alterations of the FGFR pathway in sarcoma patients as well as the preclinical and clinical evidence for the use of FGFR inhibitors in these diseases. Finally, we discuss the possible reasons behind the current clinical data and highlight the need for biomarker stratification to select patients more likely to benefit from FGFR targeted therapies.

S-adenosyl-l-methionine, non-competitive PRC2 inhibitor that impairs EED binding to tri-methylated lysine 27 on histone H3 (H3K27me3), preventing allosteric activation of this complex. This is a phase I/II study of MAK683, in adult pts with advanced malignancies who have exhausted or have no effective standard treatment. The primary objective was to characterize safety and tolerability and determine the maximum tolerated dose and/or recommended phase II dose.Methods: Pts received escalating doses of MAK683 in fasted conditions where appropriate. Eligible pts had specified advanced/metastatic hematological or solid malignancies. Here, we present data from a subset of pts with advanced epithelioid sarcoma. Pts were administered MAK683 120e300 mg twice daily (BID) or 500e800 mg once daily (QD) orally until unacceptable or dose-limiting toxicities (DLT) had developed, disease progression or death.Results: As of Jan 15, 2021, 14 pts with a median of 1.5 prior lines of therapy (range: 0e5) had been treated. Four (29%) were ongoing and 10 (71%) discontinued, primarily due to progressive disease (PD) (43%). Nine (64%) pts reported 1 treatmentrelated adverse event (TRAE) of any grade, with the most common (20%) being alopecia (36%), nausea, neutropenia, thrombocytopenia (29% each), and diarrhea (21%). Grade 3/4 TRAEs were reported in 50% pts, with 20% reporting neutropenia and thrombocytopenia (21% each). DLT were reported in 2 pts receiving 120 and 300 mg BID, respectively. There were no treatment-related deaths. Partial response was observed in 2 pts (14%) receiving 120 mg BID and 500 mg QD respectively. Six (43%) pts had stable disease and 3 (21%) had PD. The overall response rate was 14% (95% CI: 1.8e42.8) and the disease control rate was 57% (95% CI: 28.9e82.3). Duration of response of the two responders were 16.5+ and 5.2+ months.Conclusions: MAK683 was generally well-tolerated and there were preliminary signs of activity in pts with advanced epithelioid sarcoma.

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