Because of the heterogeneity of STS and the lack of driver mutations, the development of targeted therapy is lagging. However, the investigations of sarcoma genomics and mutations of signaling pathway have revealed several candidates for targeted therapy, and the angiogenetic pathway was found to be one of the promising targets.
Tyrosine Kinase Inhibitors (TKIs) Targeting Angiogenesis
Pazopanib is a potent and selective multi-targeted receptor tyrosine kinase (RTK) inhibitor that blocks tumour growth and inhibits angiogenesis. In the phase II EORTC 62043 study, patients were enrolled in four cohorts: LMS, liposarcoma, synovial sarcoma, and other histologies. The primary end-point was the PFR at 12 weeks, and the outcomes were evaluated in each cohort; 18 of 41 (44%) patients in LMS cohort, 18 of 37 (49%) patients in synovial sarcoma cohort, 16 of 41 (39%) patients in other histologies cohort reached the progression-free at 12 weeks. However, liposarcoma cohort was stopped because of only 5 of 19 (26%) patients reached the progression-free at 12 weeks. As a result, liposarcoma was excluded from the phase III study (PALETTE), in which median PFS was 4.6 months for the pazopanib-treated patients compared to 1.6 months for the placebo-treated patients (P<0.0001). The results of the PALETTE study led pazopanib approved by the FDA in 2012.
Anlotinib is another RTK inhibitor, targeting VEGFR, FGFR, PDGFR, C-kit, etc..[61,62] Anlotinib has shown single agent activity in a single arm, phase II study presented orally at 2016 ASCO. A randomized, double-blind, placebo-controlled phase IIb trial was aimed at confirming the efficacy of anlotinib in treating STS. Recurrent advanced STS progressed after anthracycline-contained therapies were randomized 2:1 to receive anlotinib or placebo. A total of 233 patients were enrolled in this trial. The primary endpoint was PFS and secondary endpoints were ORR, disease control rate (DCR) and OS. Median PFS was 6.27 months in the anlotinib arm versus 1.47 months in the control arm, the difference was very significant and the risk of disease progression was reduced by 67%. Moreover, ORR was 10.13% versus 1.33%, DCR was 55.7% versus 22.67%, respectively.
Other small molecular TKI targeting angiogenesis including sunitinib, sorafenib, regorafenib, cediranib and apatinib have shown moderate activity in LMS, synovial sarcoma, alveolar soft part sarcomas, solitary fibrous tumours and angiosarcomas in small sample, phase II trials. The selection should be based on histologic subtype, patient characteristics, toxicity profile and accessibility of the drug.
CDK4 has been regarded as another promising target in the treatment of STS. Overexpression of the protein in more than 90% of well-differentiated/dedifferentiated liposarcoma (WDLS/DDLS) has been found. Palbociclib is a CDK4/CDK6-inhibitor, in a phase 2 study, it was shown that a 12-week PFS rate of 66% in CDK4-positive WDLS/DDLS. The previous phase 2 study has already proved the favorable of PFS at the 200-mg dose (for 14 days, every 3 weeks). Another study of palbociclib in 60 advanced WDLS/DDLS (125 mg daily for 21 days in 28-day cycles), the results show that the 12-week PFS was 57.2 and median PFS was 17.9 weeks.
With regard to other TKIs, imatinib is effective in dermatofibrosarcoma, mammalian target of rapamycin (mTOR) inhibitors are active in a proportion of PEComas (perivascular epithelioid cell tumours) and crizotinib in ALK-rearranged inflammatory myofibroblastic tumours.
Monoclonal Antibodies: Olaratumab
A possible breakthrough in the treatment of STS is represented by the recently published results of an open-label phase Ib/II trial comparing olaratumab and doxorubicin versus doxorubicin alone for first-line treatment of STS patients. Olaratumab is a recombinant monoclonal antibody that targets PDGFRα, blocking PDGF-AA, PDGF-BB and PDGF-CC. Previous studies had revealed that olaratumab might exert anti-tumour activity in human sarcoma xenograft models. The results of the phase Ib/II study, randomising 133 patients to receive olaratumab plus doxorubicin or doxorubicin alone, showed a median PFS of 6.6 months (95% CI: 4.1–8.3 months) and 4.1 months (95% CI: 2.8–5.4 months), and an objective RR of 18.2% (95% CI: 9.8–29.6%) and 11.9% (95% CI: 5.3–22.2%), respectively. The addition of olaratumab to doxorubicin indicated a much more improvement in OS, with a 11.8-month difference between these two arms. The median OS was 26.5 months (95% CI: 20.9–31.7 months) and 14.7 months (95% CI: 9.2–17.1 months) respectively. Based upon the improvement of OS, both FDA and EMA approved its use in the first-line setting in combination with doxorubicin. Until now, a confirmatory phase 3 study, the ANNOUNCE (NCT02451943), has finished enrollment.
Chin Clin Oncol. 2018;7(4) © 2018 AME Publishing Company