Introduction
Soft tissue sarcomas: a clinical challenge
Biological molecular agents | Molecular target(s) | Clinical studies (phase) and clinical efficiency | Reference |
---|---|---|---|
Tyrosine kinase inhibitors (TKIs) | |||
Imatinib mesylate (IM) | c-Kit, PDGFR | Phase II study: 53.7% of patients with GISTs showed a partial response, 27.9% of patients showed stable disease, 13.6% of patients showed early resistance to imatinib, 5% of patients showed serious adverse events | [60] |
Phase III study: confirmation of the effectiveness of imatinib as primary systemic therapy for patients with incurable GIST. No advantages to higher dose treatment were reported. | [61] | ||
Sunitinib malate (SM) | VEGF-R1, VEGF-R2, VEGF-R3, c-Kit, PDGFR, Flt-3, CSF1, neurotrophic factor receptors | Phase III study: 7% of patients with GIST showed partial response, 58% had stable disease, 19% had progressive disease; 27.3 weeks was the time-to-tumor progression for sunitinib vs 6.4 weeks for placebo. Progression-free survival was similar. | [62] |
Phase II study: 3-month progression-free rate of >40% for liposarcomas leiomyosarcomas | [63] | ||
Phase II study: 52% of patients showed metabolic stable disease, 20% of patients achieved stable disease for at least 16 weeks, 47% of patients achieved partial response | [64] | ||
Phase II study (current): SM activity in patients with certain subtypes of STS. The majority of these patients showed stable disease for 16 weeks. | [65] | ||
Sorafenib | VEGF-R2, VEGF-R3, c-Kit, PDGFR, Raf/Mek/Erk | Phase II study: 14% of patients with angiosarcoma and 6% of patients with leiomyosarcoma had a response, 64% of patients developed intolerance at the drug dose used | [66] |
Phase II study: 78% patients with vascular tumors showed disease stabilization | [67] | ||
Phase II study (current): antitumor activity and acceptable toxicity profile in patients with antracycline-refractory STS | [68] | ||
Pazopanib | VEGF-Rs | Phase II study: 12-week progression-free survival was reached by 44% patients with leiomyosarcoma, 49% of patients with synovial sarcomas, and 39% of patients with the other STS types | [69] |
Nilotinib | BCR/ABL, c-Kit, PDGFR, CSF1R | Phase I study: nilotinib alone or in combination with imatinib was well tolerated and showed clinical activity in imatinib-resistant GIST patients | [70] |
Mammalian target of rapamycin (mTOR) inhibitors | |||
Tensirolimus | mTOR | Phase II study: moderate toxicity and limited clinical activity | [71] |
Everolimus | mTOR | Phase II study: acceptable toxicity. Limited clinical activity in heavily pretreated patients with bone and soft tissue sarcomas. The efficacy in imatinib-refractory and sunitinib-refractory GIST is promising. | [72] |
Ridaforolimus (AP23573) | mTOR | Phase I study: safety of the drug; 27% of patients showed stable disease. | [73] |
Phase II study: 29% of clinical benefit rate. Prolongation of survival. | [74] | ||
Phase III study (current) | [75] | ||
Insulin-like growth factor (IGF) receptor antibodies | |||
Figitumumab | IGF-1R | Phase I study: good tolerance of the drug | [76] |
R1507 | IGF-1R | Phase II study (current): R1507 is well tolerated. Significant activity has been observed in Ewing's sarcoma, RMS and OS with several dramatic responses seen in Ewing's sarcoma and RMS. | [77] |
AMG479 | IGF-1R | Phase I study: absence of severe toxicities | [78] |
Mk-0646 | IGF-1R | Phase I study (current) | [79] |